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22q11.2 deletion syndrome (22q11.2DS) is a multisystemic disorder characterized by a wide range of clinical features, ranging from life-threatening to less severe conditions. One-third of individuals with the deletion live with mild to moderate intellectual disability; approximately 60% meet criteria for at least one psychiatric condition.22q11.2DS has become an important model for several medical, developmental, and psychiatric disorders. We have been particularly interested in understanding the risk for psychosis in this population: Approximately 30% of the individuals with the deletion go on to develop schizophrenia. The characterization of cognitive and neural differences between those individuals who develop schizophrenia and those who do not, despite being at genetic risk, holds important promise in what pertains to the clarification of paths to disease and to the development of tools for early identification and intervention.Here, we review our previous event-related potential (ERP) findings as potential markers for 22q11.2DS and the associated risk for psychosis, while discussing others' work. We focus on auditory processing (auditory-evoked potentials, auditory adaptation, and auditory sensory memory), visual processing (visual-evoked potentials and visual adaptation), and inhibition and error monitoring.The findings discussed suggest basic mechanistic and disease process effects on neural processing in 22q11.2DS that are present in both early sensory and later cognitive processing, with possible implications for phenotype. In early sensory processes, both during auditory and visual processing, two mechanisms that impact neural responses in opposite ways seem to coexist-one related to the deletion, which increases brain responses; another linked to psychosis, decreasing neural activity. Later, higher-order cognitive processes may be equally relevant as markers for psychosis. More specifically, we argue that components related to error monitoring may hold particular promise in the study of risk for schizophrenia in the general population., (© 2023. The Author(s).)

22q11.2 Deletion Syndrome (22q11.2DS) is the strongest known molecular risk factor for schizophrenia. Brain responses to auditory stimuli have been studied extensively in schizophrenia and described as potential biomarkers of vulnerability to psychosis. We sought to understand whether these responses might aid in differentiating individuals with 22q11.2DS as a function of psychotic symptoms, and ultimately serve as signals of risk for schizophrenia. A duration oddball paradigm and high-density electrophysiology were used to test auditory processing in 26 individuals with 22q11.2DS (13-35 years old, 17 females) with varying degrees of psychotic symptomatology and in 26 age- and sex-matched neurotypical controls (NT). Presentation rate varied across three levels, to examine the effect of increasing demands on memory and the integrity of sensory adaptation. We tested whether N1 and mismatch negativity (MMN), typically reduced in schizophrenia, related to clinical/cognitive measures, and how they were affected by presentation rate. N1 adaptation effects interacted with psychotic symptomatology: Compared to an NT group, individuals with 22q11.2DS but no psychotic symptomatology presented larger adaptation effects, whereas those with psychotic symptomatology presented smaller effects. In contrast, individuals with 22q11.2DS showed increased effects of presentation rate on MMN amplitude, regardless of the presence of symptoms. While IQ and working memory were lower in the 22q11.2DS group, these measures did not correlate with the electrophysiological data. These findings suggest the presence of two distinct mechanisms: One intrinsic to 22q11.2DS resulting in increased N1 and MMN responses; another related to psychosis leading to a decreased N1 response.

22q11.2 deletion syndrome (also known as DiGeorge syndrome or velo-cardio-facial syndrome) is characterized by increased vulnerability to neuropsychiatric symptoms, with approximately 30% of individuals with the deletion going on to develop schizophrenia. Clinically, deficits in executive function have been noted in this population, but the underlying neural processes are not well understood. Using a Go/No-Go response inhibition task in conjunction with high-density electrophysiological recordings (EEG), we sought to investigate the behavioral and neural dynamics of inhibition of a prepotent response (a critical component of executive function) in individuals with 22q11.2DS with and without psychotic symptoms, when compared to individuals with idiopathic schizophrenia and age-matched neurotypical controls. Twenty-eight participants diagnosed with 22q11.2DS (14-35 years old; 14 with at least one psychotic symptom), 15 individuals diagnosed with schizophrenia (18-63 years old) and two neurotypical control groups (one age-matched to the 22q11.2DS sample, the other age-matched to the schizophrenia sample) participated in this study. Analyses focused on the N2 and P3 no-go responses and error-related negativity (Ne) and positivity (Pe). Atypical inhibitory processing was shown behaviorally and by significantly reduced P3, Ne, and Pe responses in 22q11.2DS and schizophrenia. Interestingly, whereas P3 was only reduced in the presence of psychotic symptoms, Ne and Pe were equally reduced in schizophrenia and 22q11.2DS, regardless of the presence of symptoms. We argue that while P3 may be a marker of disease severity, Ne and Pe might be candidate markers of risk., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several structural brain abnormalities have been associated with aggression in patients with schizophrenia. However, little is known about shared and distinct abnormalities underlying aggression in these subjects and non-psychotic violent individuals. We applied a region-of-interest volumetric analysis of the amygdala, hippocampus, and thalamus bilaterally, as well as whole brain and ventricular volumes to investigate violent (n = 37) and non-violent chronic patients (n = 26) with schizophrenia, non-psychotic violent (n = 24) as well as healthy control subjects (n = 24). Shared and distinct volumetric abnormalities were probed by analysis of variance with the factors violence (non-violent versus violent) and diagnosis (non-psychotic versus psychotic), adjusted for substance abuse, age, academic achievement and negative psychotic symptoms. Patients showed elevated vCSF volume, smaller left hippocampus and smaller left thalamus volumes. This was particularly the case for non-violent individuals diagnosed with schizophrenia. Furthermore, patients had reduction in right thalamus size. With regard to left amygdala, we found an interaction between violence and diagnosis. More specifically, we report a double dissociation with smaller amygdala size linked to violence in non-psychotic individuals, while for psychotic patients smaller size was linked to non-violence. Importantly, the double dissociation appeared to be mostly driven by substance abuse. Overall, we found widespread morphometric abnormalities in subcortical regions in schizophrenia. No evidence for shared volumetric abnormalities in individuals with a history of violence was found. Finally, left amygdala abnormalities in non-psychotic violent individuals were largely accounted for by substance abuse. This might be an indication that the association between amygdala reduction and violence is mediated by substance abuse. Our results indicate the importance of structural abnormalities in aggressive individuals., Competing Interests: The authors have declared that no competing interests exist.

Objective: Increased susceptibility to emotional triggers and poor response inhibition are important in the etiology of violence in schizophrenia. Our goal was to evaluate abnormalities in neurophysiological mechanisms underlying response inhibition and emotional processing in violent patients with schizophrenia (VS) and 3 different comparison groups: nonviolent patients (NV), healthy controls (HC) and nonpsychotic violent subjects (NPV)., Methods: We recorded high-density Event-Related Potentials (ERPs) and behavioral responses during an Emotional Go/NoGo Task in 35 VS, 24 NV, 28 HC and 31 NPV subjects. We also evaluated psychiatric symptoms and impulsivity., Results: The neural and behavioral deficits in violent patients were most pronounced when they were presented with negative emotional stimuli: They responded more quickly than NV when they made commission errors (ie, failure of inhibition), and evidenced N2 increases and P3 decreases. In contrast, NVs showed little change in reaction time or ERP amplitude with emotional stimuli. These N2 and P3 amplitude changes in VSs showed a strong association with greater impulsivity. Besides these group specific changes, VSs shared deficits with NV, mostly N2 reduction, and with violent nonpsychotic subjects, particularly P3 reduction., Conclusion: Negative affective triggers have a strong impact on violent patients with schizophrenia which may have both behavioral and neural manifestations. The resulting activation could interfere with response inhibition. The affective disruption of response inhibition, identified in this study, may index an important pathway to violence in schizophrenia and suggest new modes of treatment., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Individuals with schizophrenia are more prone to violent behaviors than the general population. It is increasingly recognized that processing of emotionally valenced stimuli is impaired in schizophrenia, a deficit that may play a role in aggressive behavior. Our goal was to establish whether patients with a history of violence would show more severe deficits in processing emotionally valenced inputs than non-violent patients. Using event-related potentials, we measured how early during processing of emotional valence, evidence of aberrant function was observed. A total of 42 schizophrenia patients (21 with history of violence; 21 without) and 28 healthy controls were tested. Participants performed an inhibitory control task, making speeded responses to pictorial stimuli. Pictures occasionally repeated twice and participants withheld responses to these repeats. Valenced pictures from the International Affective Picture System were presented. Results in controls showed modulations during the earliest phases of sensory processing (<100 ms) for negatively valenced pictures. A cascade of modulations ensued, involving sensory and perceptual processing stages. In contrast, neither schizophrenia group showed early differentiation. Non-violent patients showed earliest modulations beginning ∼150 ms. For violent patients, however, earliest modulations were further delayed and highly attenuated. The current study reveals sensory-perceptual processing dysfunction for negatively valenced inputs, which is particularly pronounced in aggressive patients.

Visual processing studies have repeatedly shown impairment in patients with schizophrenia compared to healthy controls. Electroencephalography (EEG) and, specifically, visual evoked potential (VEP) studies have identified an early marker of this impairment in the form of a decrement in the P1 component of the VEP in patients and their clinically unaffected first-degree relatives. Much behavioral and neuroimaging research has implicated specific dysfunction of either the subcortical magnocellular pathway or the cortical visual dorsal stream in this impairment. In this study, EEG responses were obtained to the contrast modulation of checkerboard stimuli using the VESPA (Visual Evoked Spread Spectrum Analysis) method. This was done for a high contrast condition and, in order to bias the stimuli towards the magnocellular pathway, a low contrast condition. Standard VEPs were also obtained using high contrast pattern reversing checkerboards. Responses were measured using high-density electrical scalp recordings in 29 individuals meeting DSM-IV criteria for schizophrenia and in 18 control subjects. Replicating previous research, a large (Cohen's d=1.11) reduction in the P1 component of the VEP was seen in patients when compared with controls with no corresponding difference in the VESPA response to high contrast stimuli. In addition, the low-contrast VESPA displayed no difference between patients and controls. Furthermore, no differences were seen between patients and controls for the C1 components of either the VEP or the high-contrast VESPA. Based on the differing acquisition methods between VEP and VESPA, we discuss these results in terms of contrast gain control and the possibility of dysfunction at the cortical level with initial afferent activity into V1 along the magnocellular pathway being intact when processing is biased towards that pathway using low contrast stimuli., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The N1 component of the auditory evoked potential (AEP) is a robust and easily recorded metric of auditory sensory-perceptual processing. In patients with schizophrenia, a diminution in the amplitude of this component is a near-ubiquitous finding. A pair of recent studies has also shown this N1 deficit in first-degree relatives of schizophrenia probands, suggesting that the deficit may be linked to the underlying genetic risk of the disease rather than to the disease state itself. However, in both these studies, a significant proportion of the relatives had other psychiatric conditions. As such, although the N1 deficit represents an intriguing candidate endophenotype for schizophrenia, it remains to be shown whether it is present in a group of clinically unaffected first-degree relatives. In addition to testing first-degree relatives, we also sought to replicate the N1 deficit in a group of first-episode patients and in a group of chronic schizophrenia probands. Subject groups consisted of 35 patients with schizophrenia, 30 unaffected first-degree relatives, 13 first-episode patients, and 22 healthy controls. Subjects sat in a dimly lit room and listened to a series of simple 1,000-Hz tones, indicating with a button press whenever they heard a deviant tone (1,500 Hz; 17% probability), while the AEP was recorded from 72 scalp electrodes. Both chronic and first-episode patients showed clear N1 amplitude decrements relative to healthy control subjects. Crucially, unaffected first-degree relatives also showed a clear N1 deficit. This study provides further support for the proposal that the auditory N1 deficit in schizophrenia is linked to the underlying genetic risk of developing this disorder. In light of recent studies, these results point to the N1 deficit as an endophenotypic marker for schizophrenia. The potential future utility of this metric as one element of a multivariate endophenotype is discussed.

Context: Perceptual closure is the ability to identify objects based on partial information and depends on the function of a distributed network of brain regions that include the dorsal and the ventral visual streams, prefrontal cortex (PFC), and hippocampus., Objective: To evaluate network-level interactions during perceptual closure in schizophrenia using parallel event-related potential (ERP), functional magnetic resonance imaging (fMRI), and neuropsychological assessment., Design: Case-control study., Setting: Inpatient and outpatient facilities associated with the Nathan Kline Institute for Psychiatric Research. Patients Twenty-seven patients with schizophrenia or schizoaffective disorder and 23 healthy controls. Intervention Event-related potentials were obtained from 24 patients and 20 healthy volunteers in response to fragmented (closeable) and control-scrambled (noncloseable) line drawings. Functional MRI was performed in 11 patients and 12 controls. Main Outcome Measure Patterns of between-group differences for predefined ERP components and fMRI regions of interest were determined using both analysis of variance and structural equation modeling. Global neuropsychological performance was assessed using standard neuropsychological batteries., Results: Patients showed impaired generation of event-related components reflecting early sensory and later closure-related activity. In fMRI, patients showed impaired activation of the dorsal and ventral visual regions, PFC, and hippocampus. Impaired activation of dorsal stream visual regions contributed significantly to impaired PFC activation, which contributed significantly to impaired activation of the hippocampus and ventral visual stream. Impaired ventral stream and hippocampal activation contributed significantly to deficits on neuropsychological measures of perceptual organization., Conclusions: Schizophrenia is associated with severe activation deficits across a distributed network of sensory and higher order cognitive regions. Deficit in early visual processing within the dorsal visual stream contributes significantly to impaired frontal activation, which, in turn, leads to dysregulation of the hippocampus and ventral visual stream. Dysfunction within this network underlies deficits in more traditional neurocognitive measures, supporting distributed models of brain dysfunction in schizophrenia.

Objective: Schizophrenia is characterized by widespread cognitive deficits that reflect distributed dysfunction across multiple cortical regions. Here the authors examined the relationship between lower- and higher-level dysfunction within the auditory domain using the event-related brain potentials mismatch negativity (MMN) and P300., Method: Event-related brain potentials were obtained from 50 schizophrenia patients and 21 healthy subjects in two conditions: a standard condition employing fixed differences between standard tones and pitch deviants and a novel individualized condition employing tones matched to each individual's tone-discrimination threshold. The relationship among measures was assessed by multiple regression analysis and structural equation modeling., Results: In the standard fixed-deviance condition, schizophrenia patients showed deficits of large effect size in generation of MMN (d>1.26) and P300 (d=1.08) relative to comparison subjects. Assessment of deviance-detection thresholds showed that patients required significantly elevated tone-matching thresholds relative to comparison subjects (d=0.97). When tone differences were individually adjusted to equate tone-matching performance across groups, the groups no longer differed significantly in MMN amplitude during deviant pitch tones, and the degree of deficit in P300 generation was significantly reduced. In both multiple regression analysis and structural equation modeling, MMN and diagnostic group were significant independent predictors of reduced P300 amplitude. MMN generation was well explained (>90% variance) by dipoles seeded within the bilateral auditory cortex., Conclusions: These findings confirm and extend previous reports of impaired basic sensory processing in schizophrenia and demonstrate significant contributions of early sensory processing dysfunction to higher-order cognitive impairments. Overall, the findings support distributed, hierarchical models of cognitive impairment in schizophrenia, consistent with glutamatergic and other widespread neurochemical models of the disorder.

Background: Recent studies have shown that schizophrenia is characterized by visual perceptual deficits, especially in the ability to integrate stimulus details into a global percept. Also, several studies have found amplitude attenuation of the visual P1 component of the event-related brain potential (ERP), probably indicating impaired visual feedforward processing in schizophrenia. However, there is little knowledge on the role of feedbackward processing in this group. This question is of importance, as recent studies indicate that feedback processing is critical in stimulus integration., Methods: In the present study we tested whether there is evidence for atypical recurrent processing in a group of 14 young adults with recent-onset schizophrenia (mean age 21.7 years, mean TIQ 92.7) and 17 age and IQ matched control subjects, all males. To achieve this aim, we used a texture segregation task and measured ERP activity concurrently., Results: We found normal amplitudes, but longer latencies of activity related to feedbackward processing in the schizophrenia group. In addition, we found enhanced occipito-temporal activity around 160 ms that is probably the reflection of increased detail processing., Discussion: We show for the first time evidence for abnormal timing in feedback activity related to visual perception in subjects with schizophrenia. It is hypothesized that this latency effect is the functional reflection of abnormal structural connectivity in this group, and might result in increased processing of stimulus detail.

Background: Mismatch negativity (MMN) is a negative-going event-related potential (ERP) component that occurs in response to intermittent changes in constant auditory backgrounds. A consistent finding across a large number of studies has been impaired MMN generation in schizophrenia, which has been interpreted as evidence for fundamental deficits in automatic auditory sensory processing. The aim of this study was to investigate the extent to which dysfunction in MMN generation might represent an endophenotypic marker for schizophrenia., Methods: We measured MMN to deviants in duration (25 msec, 1000 Hz) and deviants in pitch (50 msec, 1200 Hz) relative to standard tones (50 msec, 1000 Hz) in 45 chronic schizophrenia patients, 25 of their first-degree unaffected biological relatives, 12 first-episode patients, and 27 healthy control subjects., Results: In line with previous work, MMN amplitudes to duration deviants (but not to pitch deviants) were significantly reduced in patients with chronic schizophrenia compared with control subjects. However, both duration and pitch MMNs were completely unaffected in the first-degree biological relatives and this was also the case for the first-episode patients. Furthermore, length of illness did not predict the extent of MMN deficit., Conclusions: These findings suggest that the MMN deficit seen in schizophrenia patients is most likely a consequence of the disease and that MMN, at least to basic auditory feature deviants, is at best only weakly endophenotypic for schizophrenia.

Context: Visual Evoked Potential (VEP) abnormalities have been a fairly consistent finding in patients with schizophrenia, and it has been suggested that electrophysiological markers of early sensory processing may be useful as trait markers for the illness, and for development as potential diagnostic measures., Objective: Clear amplitude reductions in the occipital P1 component of the VEP (approximately 100 ms), have been repeatedly demonstrated in patients with schizophrenia. Here, we investigated whether the extent of this deficit was related to age, clinical symptoms, medication status and length of illness, in a large cohort of ethnically homogenous patients., Design, Setting and Participants: VEP responses to simple isolated-check stimuli were examined in 52 DSM-IV diagnosed patients with schizophrenia, and compared with responses from 26 healthy age-matched control subjects. Using high-density electrical scalp recordings, we assessed the integrity of the visual P1 component across the two groups. This study was conducted at St.Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland., Results: Substantially reduced P1 amplitude was demonstrated in the patient group compared to controls. The deficit was not linked to age, length of illness or medication status. A small positive correlation, accounting for about 11% of the variance, was found between P1 amplitude and clinical symptoms scales (BPRS and SANS). In addition, we found that a slightly later (~110 ms) fronto-central component was relatively increased in the patient group, and was inversely correlated with the occipital P1 amplitude in the patients, but not in the healthy control subjects., Conclusions: Our findings clearly demonstrate a deficit in early visual processing in patients with schizophrenia (with a large effect size; Cohen's d = 0.7) that is unrelated to chronicity. The results are consistent with recent findings showing that the P1 deficit is endophenotypic of the disorder and related to genetic risk factors rather than the disease process itself.

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.

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.

Electrophysiological research has shown clear dysfunction of early visual processing mechanisms in patients with schizophrenia. In particular, the P1 component of the visual evoked potential (VEP) is substantially reduced in amplitude in patients. A novel visual evoked response known as the VESPA (Visual Evoked Spread Spectrum Analysis) was recently described. This response has a notably different scalp topography from that of the traditional VEP, suggesting preferential activation of a distinct subpopulation of cells. As such, this method constitutes a potentially useful candidate for investigating cellular contributions to early visual processing deficits. In this paper we compare the VEP and VESPA responses between a group of healthy control subjects and a group of schizophrenia patients. We also introduce an extension of the VESPA method to incorporate nonlinear processing in the visual system. A significantly reduced P1 component was found in patients using the VEP (with a large effect size; Cohen's d=1.6), while there was no difference whatsoever in amplitude between groups for either the linear or nonlinear VESPA. This pattern of results points to a highly specific cellular substrate of early visual processing deficits in schizophrenia, suggesting that these deficits are based on dysfunction of magnocellular pathways with parvocellular processing remaining largely intact.

Background: Viewing a speaker's articulatory movements substantially improves a listener's ability to understand spoken words, especially under noisy environmental conditions. In this study we investigated the ability of patients with schizophrenia to integrate visual and auditory speech. Our objective was to determine to what extent they experience benefit from visual articulation and to detail under what listening conditions they might show the greatest impairments., Methods: We assessed the ability to recognize auditory and audiovisual speech in different levels of noise in 18 patients with schizophrenia and compared their performance with that of 18 healthy volunteers. We used a large set of monosyllabic words as our stimuli in order to more closely approximate performance in everyday situations., Results: Patients with schizophrenia showed deficits in their ability to derive benefit from visual articulatory motion. This impairment was most pronounced at signal-to-noise levels where multisensory gain is known to be maximal in healthy control subjects. A surprising finding was that despite known early auditory sensory processing deficits and reports of impairments in speech processing in schizophrenia, patients' performance in unisensory auditory speech perception remained fully intact., Conclusions: Thus, the results showed a specific deficit in multisensory speech processing in the absence of any measurable deficit in unisensory speech processing and suggest that sensory integration dysfunction may be an important and, to date, rather overlooked aspect of schizophrenia.

Objective: Individuals with schizophrenia show severe deficits in their ability to decode emotions based upon vocal inflection (affective prosody). This study examined neural substrates of prosodic dysfunction in schizophrenia with voxelwise analysis of diffusion tensor magnetic resonance imaging (MRI)., Method: Affective prosodic performance was assessed in 19 patients with schizophrenia and 19 comparison subjects with the Voice Emotion Identification Task (VOICEID), along with measures of basic pitch perception and executive processing (Wisconsin Card Sorting Test). Diffusion tensor MRI fractional anisotropy valves were used for voxelwise correlation analyses. In a follow-up experiment, performance on a nonaffective prosodic perception task was assessed in an additional cohort of 24 patients and 17 comparison subjects., Results: Patients showed significant deficits in VOICEID and Distorted Tunes Task performance. Impaired VOICEID performance correlated significantly with lower fractional anisotropy values within primary and secondary auditory pathways, orbitofrontal cortex, corpus callosum, and peri-amygdala white matter. Impaired Distorted Tunes Task performance also correlated with lower fractional anisotropy in auditory and amygdalar pathways but not prefrontal cortex. Wisconsin Card Sorting Test performance in schizophrenia correlated primarily with prefrontal fractional anisotropy. In the follow-up study, significant deficits were observed as well in nonaffective prosodic performance, along with significant intercorrelations among sensory, affective prosodic, and nonaffective measures., Conclusions: Schizophrenia is associated with both structural and functional disturbances at the level of primary auditory cortex. Such deficits contribute significantly to patients' inability to decode both emotional and semantic aspects of speech, highlighting the importance of sensorial abnormalities in social communicatory dysfunction in schizophrenia.

Visual processing deficits are an integral component of schizophrenia and are sensitive predictors of schizophrenic decompensation in healthy adults. The primate visual system consists of discrete subcortical magnocellular and parvocellular pathways, which project preferentially to dorsal and ventral cortical streams. Subcortical systems show differential stimulus sensitivity, while cortical systems, in turn, can be differentiated using surface potential analysis. The present study examined contributions of subcortical dysfunction to cortical processing deficits using high-density event-related potentials. Event-related potentials were recorded to stimuli biased towards the magnocellular system using low-contrast isolated checks in Experiment 1 and towards the magnocellular or parvocellular system using low versus high spatial frequency (HSF) sinusoidal gratings, respectively, in Experiment 2. The sample consisted of 23 patients with schizophrenia or schizoaffective disorder and 19 non-psychiatric volunteers of similar age. In Experiment 1, a large decrease in the P1 component of the visual event-related potential in response to magnocellular-biased isolated check stimuli was seen in patients compared with controls (F = 13.2, P = 0.001). Patients also showed decreased slope of the contrast response function over the magnocellular-selective contrast range compared with controls (t = 9.2, P = 0.04) indicating decreased signal amplification. In Experiment 2, C1 (F = 8.5, P = 0.007), P1 (F = 33.1, P < 0.001) and N1 (F = 60.8, P < 0.001) were reduced in amplitude to magnocellular-biased low spatial frequency (LSF) stimuli in patients with schizophrenia, but were intact to parvocellular-biased HSF stimuli, regardless of generator location. Source waveforms derived from inverse dipole modelling showed reduced P1 in Experiment 1 and reduced C1, P1 and N1 to LSF stimuli in Experiment 2, consistent with surface waveforms. These results indicate pervasive magnocellular dysfunction at the subcortical level that leads to secondary impairment in activation of cortical visual structures within dorsal and ventral stream visual pathways. Our finding of early visual dysfunction is consistent with and explanatory of classic literature showing subjective complaints of visual distortions and is consistent with early visual processing deficits reported in schizophrenia. Although deficits in visual processing have frequently been construed as resulting from failures of top-down processing, the present findings argue strongly for bottom-up rather than top-down dysfunction at least within the early visual pathway. Deficits in magnocellular processing in this task may reflect more general impairments in neuronal systems functioning, such as deficits in non-linear amplification and may thus represent an organizing principle for predicting neurocognitive dysfunction in schizophrenia.

Objective: Patients with schizophrenia have visual-processing deficits. This study examines visual white matter integrity as a potential mechanism for these deficits., Method: Diffusion tensor imaging was used to examine white matter integrity at four levels of the visual system in 17 patients with schizophrenia and 21 comparison subjects. The levels examined were the optic radiations, the striate cortex, the inferior parietal lobule, and the fusiform gyrus., Results: Schizophrenia patients showed a significant decrease in fractional anisotropy in the optic radiations but not in any other region., Conclusions: This finding indicates that white matter integrity is more impaired at initial input, rather than at higher levels of the visual system, and supports the hypothesis that visual-processing deficits occur at the early stages of processing.

Context: The imperative to establish so-called endophenotypes-quantifiable measures of risk for neurological dysfunction-is a growing focus of research in schizophrenia. Electrophysiological markers of sensory processing, observable in human event-related potentials, hold great promise in this regard, lying closer to underlying physiology than descriptive clinical diagnostic tests., Objective: Early visual processing deficits, as measured by clear amplitude reductions in the occipital P1 component of the visual event-related potential, have been repeatedly demonstrated in patients with schizophrenia. However, before P1 amplitude may be considered as an endophenotypic marker for schizophrenia, it is necessary to establish its sensitivity to genetic liability., Design, Setting, and Participants: Event-related potential responses to simple visual isolated-check stimuli were examined in 25 clinically unaffected first-degree relatives of patients with schizophrenia and 15 DSM-IV-diagnosed schizophrenia probands and compared with responses from 26 healthy, age-matched control subjects. Using high-density electrical scalp recordings, between-groups analysis assessed the integrity of the visual P1 component across the 3 groups. The study was conducted at St Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland., Results: Substantially reduced P1 amplitude was demonstrated in both relatives and probands compared with controls with topographical mapping and inverse source analysis localizing this deficit largely to midline regions in early visual sensory cortices and regions of the dorsal visual stream. Additional later differences between these groups, where the relatives actually show larger amplitude responses, may point toward compensatory mechanisms at play in relatives., Conclusions: Our findings demonstrate a deficit in early visual processing in clinically unaffected first-degree relatives of patients with schizophrenia, providing evidence that this deficit may serve as a genetic marker for this disorder. The efficacy of using P1 amplitude as an endophenotype is underscored by the observation of a large effect size (d=0.9) over scalp sites where the deficit was maximal.

Evidence is accumulating that patients with schizophrenia exhibit relatively severe deficits in early visual sensory processing within the dorsal stream, while processing within the ventral stream appears to be relatively more intact. Here, illusory contour (IC) processing was investigated in a cohort of schizophrenia patients and age-matched healthy controls using high-density visual evoked potentials (VEPs), spatiotemporal topographic analyses and the Local Auto-Regressive Average distributed linear inverse source estimation. IC processing was assessed because it is now known to be an excellent metric of early processing within regions of the ventral visual stream. Results in the present study show that IC processing (106-194 ms) is spared in patients with schizophrenia, providing strong evidence that early ventral stream processing is essentially normal. This is so despite equally strong evidence that early dorsal stream processing is severely impaired in this population, as indexed by a robust decrement in amplitude of the P1 component in patients and a large topographic difference between groups for this component (54-104 ms). Source analysis confirmed that the flow of activity into the dorsal stream was substantially decreased in patients. As such, these results suggest that some aspects of early ventral processing are not entirely reliant on intact inputs from the dorsal stream. Lastly, we show that later phases of visual processing (240-400 ms) also rely on the activity of different brain networks in controls and patients, with the latter recruiting strong frontal activity perhaps as compensation for impaired ventral stream processing during this period. We interpret the present findings in the context of a two-stage processing model. Under this model, it is suggested that the second stage of ventral stream processing is dependent on the fidelity of inputs from the dorsal visual stream and that impairment of this critical modulatory input may underlie the failure of 'higher-level' ventral stream processes in this population.

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.

Background: Schizophrenia is associated with well-documented deficits in high-order cognitive processes such as attention and executive functioning. The integrity of sensory-level processing, however, has been evaluated only to a limited degree. Our study evaluated the ability of patients with schizophrenia to recognize complete objects based on fragmentary information, a process termed perceptual closure. Perceptual closure processes are indexed by closure negativity (N(cl)), a recently defined event-related potential (ERP) component that is generated within the visual association cortex. This study assessed the neural integrity of perceptual closure processes in schizophrenia by examining N(cl) generation. Generation of the preceding positive (P1) and negative (N1) ERP components was also examined., Methods: We evaluated 16 patients with chronic schizophrenia and 16 healthy comparison subjects. Successively less fragmented images were presented during high-density ERP recording, which permitted the monitoring of brain activity during perceptual closure processes prior to object recognition. Analyses were performed at parieto-occipital and occipitotemporal sites consistent with dorsal and ventral stream generators of P1, N1, and N(cl)., Results: Patients with schizophrenia showed significant impairment in the ability to recognize fragmented objects, along with impaired generation of N(cl). The amplitude of visual P1 was significantly reduced, particularly over dorsal stream sites. In contrast, the generation of visual N1 was intact., Conclusions: Patients with schizophrenia are profoundly impaired in perceptual closure as indicated by both impaired performance and impaired N(cl) generation. The selective impairment in dorsal stream P1 is consistent with prior reports of impaired magnocellular processing in schizophrenia. By contrast, intact ventral N1 generation suggests that the initial stages of ventral stream processing are relatively preserved and that impaired magnocellular dorsal stream functioning in schizophrenia may lead to secondary dysregulation of ventral stream object recognition processing.

Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci. [ABSTRACT FROM AUTHOR]

Background: The nitric oxide synthasase-1 gene ( NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia has recently been associated with variation in general intelligence and working memory in both patients and healthy participants. Whether this variant is also associated with variation in early sensory processing remains unclear. Methods: We investigated differences in the P1 visual evoked potential in a high density EEG study of 54 healthy participants. Given both NOS1's association with cognition and recent evidence that cognitive performance and P1 response are correlated, we investigated whether NOS1's effect on P1 response was independent of its effects on cognition using CANTAB's spatial working memory (SWM) task. Results: We found that carriers of the previously identified risk 'G' allele showed significantly lower P1 responses than non-carriers. We also found that while P1 response and SWM performance were correlated, NOS1 continued to explain a significant proportion of variation in P1 response even when its effects on cognition were accounted for. Conclusion: The schizophrenia implicated NOS1 variants rs6490121 influences visual sensory processing as measured by the P1 response, either as part of the gene's pleiotropic effects on multiple aspects of brain function, or because of a primary influence on sensory processing that mediates the effects already seen in higher cognitive processes. Hum Brain Mapp, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Etiological commonalities are apparent between bipolar disorder and schizophrenia. For example, it is becoming clear that both populations show similar electrophysiological deficits in the auditory domain. Recent studies have also shown robust visual sensory processing deficits in patients with schizophrenia using the event-related potential technique, but this has not been formally tested in those with bipolar disorder. Our goal here was to assess whether early visual sensory processing in patients with bipolar disorder, as indexed by decreased amplitude of the P1 component of the visual evoked potential (VEP), would show a similar deficit to that seen in those with schizophrenia. Since the P1 deficit has already been established as an endophenotype in schizophrenia, a finding of commonality between disorders would raise the possibility that it represents a measure of common genetic liability. Methods: We visually presented isolated-check stimuli to euthymic patients with a diagnosis of bipolar disorder and age-matched healthy controls within a simple go/no-go task and recorded VEPs using high-density (72-channel) electroencephalography. Results: The P1 VEP amplitude was substantially reduced in patients with bipolar disorder, with an effect size of f = 0.56 (large according to Cohen's criteria). Limitations: Our sample size was relatively small and as such, did not allow for an examination of potential relations between the physiologic measures and clinical measures. Conclusion: This reduction in P1 amplitude among patients with bipolar disorder represents a dysfunction in early visual processing that is highly similar to that found repeatedly in patients with schizophrenia and their healthy first-degree relatives. Since the P1 deficit has been related to susceptibility genes for schizophrenia, our results raise the possibility that the deficit may in fact be more broadly related to the development of psychosis and that it merits further investigation as a candidate endophenotype for bipolar disorder. [ABSTRACT FROM AUTHOR]

Background 22q11.2 Deletion Syndrome (22q11.2DS) is the strongest known molecular risk factor for schizophrenia, with approximately 30% of individuals going on to develop this neuropsychiatric disorder. 22q11.2DS may thus provide a unique model to investigate the trajectory of schizophrenia. In schizophrenia-spectrum disorders, decreased amplitudes of early visual evoked potentials (VEP) are consistently reported. Thus, here, our aim was to use high-density electrophysiology (EEG) to investigate basic visual processing in individuals with 22q11.2DS and to understand how their neural responses compared to those of neurotypical controls and of individuals diagnosed with schizophrenia. Methods Seventeen individuals diagnosed with 22q11.2DS (age range: 14–35 years; M = 21.89, SD = 7.63), 11 neurotypical age-matched controls (age range: 15–38 years; M = 21.63, SD = 6.55), 15 individuals diagnosed with schizophrenia (age range: 31–64 years; M = 47.44, SD = 10.47), and 15 neurotypical age-matched controls (age range: 33–62 years; M = 47, SD = 8.87) participated in this study. An EEG visual paradigm (100% contrast, black and white checkerboard annuli centered against a grey background) with three interstimulus intervals (ISIs: 495, 995, and 2495 ms) was employed to investigate differences in the visual-evoked components N1 and P2. Different ISIs were used to investigate differences in sensory load and in adaptation to repetitive stimulation. Linear mixed-effects models were implemented separately for each of the components and for the 22q11.2DS and the schizophrenia samples compared to respective controls. Analyses focused on amplitude in the major VEP response differences between the groups at an occipital channel (Oz), as a function of ISI. Results 22q11l.2DS: In the N1 time window, there was no significant main effect of group. However, there was an interaction effect of Group x ISI, indicating that the difference between the shorter ISIs (495 ms and 995 ms) was decreased in 22q11.2DS compared to controls. Furthermore, the 22q11.2DS group had a smaller response for the two longer conditions, that differed significantly (995 ms) or trended (2495 ms). In the P2 window, analyses show an overall decrease in amplitude in 22q11.2DS compared to controls, significantly for all ISIs. The Group x ISI interaction reflected that the ISI effect was smaller in 22q11.2DS versus controls. Schizophrenia: Though not significant, individuals with schizophrenia presented somewhat increased VEP amplitudes compared to controls. This result is contrary to what is described in the literature, where individuals with schizophrenia usually exhibit VEP amplitude reductions, and may be related to the older age of the sample. Discussion The 22q11.2DS sample showed reduced VEPs, consistent with what is typically described in schizophrenia-spectrum disorders and showed a different ISI function compared to controls. Further analyses will be directed at determining how the 22q11.2DS responses differ as a function of psychotic symptomatology, how they compare to control and schizophrenia groups, and with more data, if these neural responses may be predictive of psychosis. A schizophrenia sample age-matched to the 22q11.2DS sample will be crucial to better understand the similarities and differences between these populations. In such a sample (including a control group), confounding effects from variables such as age, years of medication, and neural consequences of psychotic symptomatology may be studied. [ABSTRACT FROM AUTHOR]

Background 22q11.2DS, the most common chromosomal microdeletion disorder, is characterized by greatly increased vulnerability for developmental delays and cognitive deficits, and neuropsychiatric symptoms beginning in adolescence/early adulthood, with up to 30% of these individuals developing schizophrenia. Though there have been numerous studies on the deletion's neuroanatomical signatures, its impact on brain activity is less well understood. In schizophrenia, neural circuits of the auditory system have been shown to be impaired, and this is clearly seen in differences in the auditory evoked potential (AEP) and in the mismatch negativity (MMN; an index of auditory sensory memory) from electroencephalographic recordings (EEG). We therefore asked whether basic auditory processing in individuals with 22q11.2DS, as assessed by high density EEG, would be similarly affected. We further investigated how the brain activity related to IQ and working memory (which are known to be impaired in 22q11.2DS) and psychotic symptoms. Methods Eighteen individuals diagnosed with 22q11.2DS (age range: 14–35 years old; M = 22.17; S.D. = 7.50) and 18 neurotypical age-matched controls (age range: 14–38 years old; M = 21.89; S.D. = 7.48) participated in this study. The Wechsler intelligence scales were used to obtain IQ and working memory scores and participants were interviewed using the SCID to assess psychiatric symptomatology. A duration oddball paradigm was employed during which standard tones of 100 ms (1000 Hz and ~70 dB) were interspersed with deviant tones of 180ms, while high density EEG was recorded. Analyses were focused on the basic AEP and on the MMN. Results The 22q11.2DS group was characterized by significantly lower IQ and working memory scores than neurotypical controls, and higher psychotic symptoms. The duration-MMN was observed both in controls and individuals with 22q11.2DS, signifying that both groups processed change in duration. As a group, 22q11.2DS showed significantly larger AEPs and MMNs. Nevertheless, analyses taking individual differences into consideration revealed an increased variability within the 22q11.2DS group, and a correlation between working memory and MMN amplitude (mostly driven by the 22q11.2DS group), such that the better the working memory scores, the greater the MMN amplitude. Furthermore, within the 22q11.2DS group, the number of psychotic symptoms correlated with the MMN amplitude (the more symptoms, the smaller the MMN) and with working memory (the more symptoms, the lower the working memory scores). Discussion These results are consistent with the idea of a highly variable phenotype in 22q11.2DS and stress the need for a better definition of potential subgroups within 22q11.2DS, possibly characterized by different cognitive and neural profiles. Further, differing from the typical decrease in duration-MMN in idiopathic schizophrenia, these results show that in 22q11.2DS the duration-MMN is instead larger than in age-matched controls; and that better cognitive functioning is associated with larger MMNs and less severe psychotic symptomatology. One possibility is that better working memory is a protective factor for psychosis in 22q11.2DS. These data point to potential neural and cognitive biomarkers predictive of the risk for developing schizophrenia in 22q11.2DS. The identification of individuals most at risk, prior to fully-expressed psychosis, could facilitate preventative measures and thereby shift schizophrenia's course in 22q11.2DS. [ABSTRACT FROM AUTHOR]