Emotional scene processing in biotypes of psychosis.

Social-emotional deficits in psychosis may be indexed by deviations in emotional scene processing, but event-related potential (ERP) studies indicate such deviations may not map cleanly to diagnostic categories. Neurobiologically defined psychosis subgroups offer an alternative that may better capture neurophysiological correlates of social-emotional deficits. The current study investigates emotional scene-elicited ERPs in Biotypes of psychosis in a large (N = 622), well-characterized sample. Electroencephalography was recorded in healthy persons (N = 129), Biotype-1 (N = 195), Biotype-2 (N = 131), and Biotype-3 (N = 167) psychosis cases. ERPs were measured from posterior and centroparietal scalp locations. Neural responses to emotional scenes were compared between healthy and psychosis groups. Multivariate group discrimination analyses resulted in two composite variates that differentiated groups. The first variate displayed large differences between low-cognition (Biotype-1, Biotype-2) and intact-cognition groups (Biotype-3, healthy persons). The second indicated a small-to-moderate distinction of Biotypes-2 and -3 from Biotype-1 and healthy persons. Two multivariate correlations were identified indicating associations between 1) self-reported emotional experience and generalized cognition and 2) socio-occupational functioning and late-stage emotional processing. Psychosis Biotypes displayed emotional processing deficits not apparent in DSM psychosis subgroups. Future translational research may benefit from exploring emotional scene processing in such neurobiologically-defined psychosis groups.

Deviation from expected cognitive ability across psychotic disorders.

Patients with schizophrenia show a deficit in cognitive ability compared to estimated premorbid and familial intellectual abilities. However, the degree to which this pattern holds across psychotic disorders and is familial is unclear. The present study examined deviation from expected cognitive level in schizophrenia, schizoaffective disorder, and psychotic bipolar disorder probands and their first-degree relatives. Using a norm-based regression approach, parental education and WRAT-IV Reading scores (both significant predictors of cognitive level in the healthy control group) were used to predict global neuropsychological function as measured by the composite score from the Brief Assessment of Cognition in Schizophrenia (BACS) test in probands and relatives. When compared to healthy control group, psychotic probands showed a significant gap between observed and predicted BACS composite scores and a greater likelihood of robust cognitive decline. This effect was not seen in unaffected relatives. While BACS and WRAT-IV Reading scores were themselves highly familial, the decline in cognitive function from expectation had lower estimates of familiality. Thus, illness-related factors such as epigenetic, treatment, or pathophysiological factors may be important causes of illness related decline in cognitive abilities across psychotic disorders. This is consistent with the markedly greater level of cognitive impairment seen in affected individuals compared to their unaffected family members.

Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10-11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10-8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10-10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10-8) and LMO7 (13q22.2, P=7.3x10-8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10-9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10-2-9.8 × 10-4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.

Unitary construct of generalized cognitive ability underlying BACS performance across psychotic disorders and in their first-degree relatives.

Despite robust evidence of neurocognitive dysfunction in psychotic patients, the degree of similarity in cognitive architecture across psychotic disorders and among their respective first-degree relatives is not well delineated. The present study examined the latent factor structure of the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. Analyses were conducted on 783 psychosis spectrum probands (schizophrenia, schizoaffective, psychotic bipolar), 887 of their first-degree relatives, and 396 non-psychiatric controls from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Exploratory factor analysis of BACS subtest scores indicated a single-factor solution that was similar across all groups and provided the best overall data fit in confirmatory analyses. Correlations between the standard BACS composite score and the sum of subscale scores weighted by their loadings on this unitary factor were very high in all groups (r≥.99). Thus, the BACS assesses a similar unitary cognitive construct in probands with different psychotic disorders, in their first-degree relatives, and in healthy controls, and this factor is well measured by the test's standard composite score.

Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study.

Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10,422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development.

Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder.

Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.

Multichannel electroencephalographic assessment of auditory evoked response suppression in schizophrenia.

Reduced auditory evoked response (AER) suppression in a paired-stimulus paradigm (where suppression equals the difference between S1 and S2 amplitudes divided by S1 amplitude) may index genetic liability for schizophrenia. The present report is a multiple-channel electroencephalographic (EEG) study of AER suppression among 20 normal and 20 schizophrenia subjects. The typical paired-stimulus paradigm was used to evoke time-locked AERs. AER responses were scored at P50 and N100 in the time domain using both single (Cz) and multichannel data (after reduction using principal components analysis, PCA), and were scored for information in the gamma (20-50 Hz) and low-frequency (1-20 Hz) ranges using multichannel information (also after PCA). The time domain analyses demonstrated that schizophrenia patients differ from normal in amplitude of response to the first, but not to the second, stimulus for both P50 and N100. The frequency domain data demonstrated that schizophrenia patients differed from normal on amplitude of the low-frequency response (LFR) to the first, but not to the second, stimulus. The groups did not differ significantly on amplitudes of the gamma-band responses. Group separations were largest for the multichannel N100 and LFR data, with the LFR demonstrating a modestly better risk ratio for differentiating schizophrenia from normal subjects. The present results suggest two novel differences from previous AER suppression studies: (1) S1 amplitudes largely determine differences between normal and schizophrenia groups on AER suppression, and (2) frequency domain analyses may provide important complimentary information when studying AERs in schizophrenia.

Response to the first stimulus determines reduced auditory evoked response suppression in schizophrenia: single trials analysis using MEG.

OBJECTIVE: Reduced auditory evoked response (AER) suppression in a paired-stimulus paradigm may index genetic liability for schizophrenia. In most published studies of AER suppression, scores are based on data averaged over numerous stimulus presentations and recorded from few channels. It is unclear whether averaged data are equally representative of single trial responses in normal and schizophrenia subjects. In the present report, we used 148 channel magnetoencephalography to investigate grand-average and single trial responses on AER suppression. METHODS: The typical paired-stimulus paradigm was used to evoke time-locked AERs from 20 normal and 20 schizophrenia patients. Gamma band response (GBR) and low frequency response (LFR) characteristics were measured on grand-averaged and single trial data. Generalized eigenvalue decomposition was used to reduce the multiple channel information to a vector that accounted for the most AER variance for the GBR and LFR. RESULTS: Group performances on grand-average and single trials were similar. A remarkable difference, which replicates previous studies, was that schizophrenia subjects had smaller LFR amplitudes in response to the first stimulus than normal. CONCLUSIONS: These findings are inconsistent with the "poor suppression" theory often used to explain schizophrenia-normal group differences when using the paired-stimulus paradigm.

Behavioral and brain imaging studies of saccadic performance in schizophrenia.

Data are reviewed from a series of saccadic studies demonstrating that schizophrenia subjects have normal performance on some types, and abnormal performance on other types, of tasks. Normal refixation saccade characteristics and BOLD signal change among schizophrenia subjects suggest that basic saccade generating circuitry is functionally intact among these subjects. Schizophrenia patients and their relatives, however, demonstrate difficulty with saccadic inhibition, a function ostensibly mediated by DLPFC circuitry. We review additional evidence for saccadic inhibition being associated with prefrontal circuitry provided by EEG and fMRI data. Minimum norm analysis of EEG data suggests that dipolar activity preceding correct antisaccades occurred preferentially in prefrontal cortex. Furthermore, there is an indication from the fMRI data that prefrontal activity may be increased in normal, but not in schizophrenia, subjects during antisaccade tasks. These data suggest that a research program relying on multiple functional imaging technologies may be helpful for furthering our understanding of schizophrenia's essential neuropathology.

Timing and magnitude of frontal activity differentiates refixation and anti-saccade performance.

EEG data were recorded while 10 subjects generated refixation saccades towards a visual target and antisaccades away from a visual cue. Theoretically, the same basic neural circuitry supports refixation and correct anti-saccade performances, with additional activity in primarily dorsolateral prefrontal cortex circuitry supporting antisaccade-associated inhibitory processes. Analyses demonstrated that sensory registration of visual stimuli is similar for refixation and anti-saccade conditions. Increased frontal brain activity at 5 and 15 Hz was observed preceding correct antisaccades when compared to refixation saccades. These analyses provide specific information suggesting that 160-60 ms before saccade generation is the critical period for response inhibition.

Saccadic inhibition among schizotypal personality disorder subjects.

Schizotypal personality disorder (SPD) is theoretically part of the schizophrenia spectrum both clinically and neurobiologically. A liability for developing schizophrenia may be associated with dysfunction of dorsolateral prefrontal cortex (DLPFC) and its cortical and/or subcortical circuitry. If so, abnormalities on tasks associated with DLPFC functioning among SPD subjects would support the thesis that SPD is neurobiologically related to schizophrenia. Antisaccade and ocular motor delayed response performance, both of which are ostensibly supported by DLPFC circuitry, were assessed among 29 SPD, 17 schizophrenia, and 25 normal subjects. Generally, the SPD subjects' performance was more similar to normal than to schizophrenia groups. There was evidence, however, for inhibition abnormalities in a subgroup of SPD subjects. Antisaccade performance identified more SPD subjects as "abnormal" than delayed response measures.

Ocular motor delayed-response task performance among patients with schizophrenia and their biological relatives.

Schizophrenia patients and their relatives have saccadic abnormalities characterized by problems inhibiting a response. The dorsolateral prefrontal cortex and its associated circuitry ostensibly mediate inhibition and support correct delayed response performance. In this context, two components of delayed response task performance are of interest: memory saccade metrics and error saccades made during the delay. To evaluate these variables, an ocular motor delayed response task was presented to 23 schizophrenia patients, 25 of their first-degree biological relatives, and 19 normal subjects. The measure that best differentiated groups was an increased frequency of error saccades generated during the delay by schizophrenia subjects and relatives. Decreased memory saccade gain also characterized patients and relatives. The similar pattern of results demonstrated by the patients with schizophrenia and their relatives suggests that performance on ocular motor delayed response tasks, either alone or in combination with other saccadic variables, may provide useful information about neural substrates associated with a liability for developing schizophrenia.

Clinical and biological concomitants of resting state EEG power abnormalities in schizophrenia.

BACKGROUND: This study investigated the clinical and biological concomitants of electroencephalogram power abnormalities in schizophrenia. METHODS: We examined the power characteristics of resting electroencephalograms in 112 schizophrenic patients. Also collected were measures of psychotic symptomatology, brain morphology, ocular motor functioning, electrodermal activity, and nailfold plexus visibility. Seventy-eight nonschizophrenic psychosis patients (e.g., mood disorder patients with psychosis) and 107 nonpsychiatric control subjects were included for comparison. RESULTS: Schizophrenic patients whose electroencephalograms were characterized by augmented low-frequency power and diminished alpha-band power had more negative symptoms, larger third ventricles, larger frontal horns of the lateral ventricles, increased cortical sulci widths, and greater ocular motor dysfunction compared with schizophrenic patients without these electroencephalogram characteristics. In nonschizophrenic psychosis patients, augmented low-frequency and diminished alpha-band powers failed to be associated with any clinical or biological indices. CONCLUSIONS: Results suggest that clinical and biological concomitants of low-frequency and alpha-band power abnormalities in schizophrenia are unique, perhaps indicating the presence of thalamic and frontal lobe dysfunction.

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications.

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.

Hemispheric differences on auditory evoked response suppression in schizophrenia.

Using binaural stimuli, schizophrenia subjects have worse auditory evoked response (AER) suppression than normals in a paired-click paradigm. In this study we investigated hemispheric differences in AER suppression between groups using monaural and binaural stimulus presentation. Auditory evoked responses from 12 schizophrenia and 12 normal subjects were recorded with a 148-channel whole-head biomagnetometer. One hundred and twenty pairs of clicks were presented in three counterbalanced blocks (left, right, binaural). With monaural stimuli, patients had worse M100 suppression than normals in ipsilateral (effect size -2.13) but not in contralateral hemisphere (effect size -0.43). The groups did not differ on gamma band response suppression. Overall, the best group separations were obtained with binaural stimulus presentation on M100 suppression (effect size -4.14).

Linkage of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families.

Eight Utah multigenerational families, each with three to six cases of schizophrenia, were phenotyped with two specific measures of inhibitory neurophysiological functioning, P50 auditory sensory gating (P50), and antisaccade ocular motor performance (AS). A genomewide linkage analysis was performed to screen for loci underlying a qualitative phenotype combining the P50 and AS measures. For this composite inhibitory phenotype, the strongest evidence for linkage was to the D22s315 marker on chromosome 22q (lod score = 3.55, theta = 0) under an autosomal dominant model. Simulation analyses indicate that this 3.55 lod score is unlikely to represent a false positive result. Lod scores were 2.0 or greater for markers flanking D22s315. A nonparametric linkage (NPL) analysis of the chromosome 22 data showed evidence for allele sharing over the broad region surrounding D22s315 with a maximum NPL score of 3.83 (p = .002) for all pedigrees combined.

Saccadic performance characteristics and the behavioural neurology of Tourette's syndrome.

OBJECTIVE: To better understand the neuropathological correlates of Tourette's syndrome (TS), measures of saccadic eye movement performance were examined among patients with TS. METHODS: A case-control design was used. Twenty one patients with DSM-IV TS (mean age 40.6 years (SD 11.0); 38% female) mainly recruited from UCSD Psychiatry Services, and a community based sample of 21 normal subjects (mean age 34.6 years (SD 13.4); 43% women) participated in this study. Participants were administered ocular motor tasks assessing visual fixation, and the generation of prosaccades, predictive saccades, and antisaccades. Saccadic reaction time, amplitude, duration, and mean and peak velocity were computed. Intrusive saccades during visual fixation and the proportion of correct antisaccade responses were also evaluated. RESULTS: The groups had similar visual fixation performance. Whereas patients with TS generated prosaccades with normal reaction times and amplitudes, their saccade durations were shorter and their mean velocities were higher than in normal subjects. During a prosaccade gap task, patients with TS exhibited an increased proportion of anticipatory saccades (RTs<90). The proportion of "express" saccades (90

Measuring liability for schizophrenia using optimized antisaccade stimulus parameters.

The ability to identify unaffected gene carriers within families may be crucial to the success of schizophrenia genetics studies. Data collected from three family samples (N = 365) demonstrated that poor antisaccade performance is an exceptionally promising indicator of liability for schizophrenia. A particular antisaccade task version provides large separations (5-6 sigma) between proband and normal groups. Poor antisaccade performance alone correctly identified 70% of patients in California, Utah, and Micronesia schizophrenia samples. Twenty-five to 50% of these patients' nonpsychotic first-degree relatives also had poor antisaccade performance, yielding risk ratios around 20:1 for simplex and 50:1 for multiplex schizophrenia families. Poor antisaccade performance is associated with dorsolateral prefrontal cortex pathology, suggesting that dysfunction of this circuitry also may predispose individuals to developing this disease.

Poor P50 suppression among schizophrenia patients and their first-degree biological relatives.

OBJECTIVE: This study's goal was to replicate the finding that family members of schizophrenia patients show poor P50 suppression during a paired-click auditory evoked response paradigm. METHOD: The paired-click paradigm was used to test 44 schizophrenia patients, 60 of their clinically unaffected first-degree relatives, and 45 normal subjects. Two clicks (83 dB[A] over a 60-dB[A] white noise background) separated by 500 msec were presented 60 times to all subjects. P50 responses to the first and second clicks were selected from the digitally filtered data by using standard methods and the Cz recording site. RESULTS: The schizophrenia patients had smaller P50 responses to click 1 than either their relatives or the normal subjects; the patients and their relatives, who did not significantly differ, had larger P50 responses to click 2 than the normal subjects. Schizophrenia patients had worse P50 suppression than either their family members or the normal subjects; the patients' family members had worse P50 suppression than the normal subjects. CONCLUSIONS: Family members of schizophrenia patients have worse P50 suppression than normal subjects. To the authors' knowledge, this is the first demonstration independent of the group associated with the University of Colorado that schizophrenia patients' family members have poor P50 suppression. This result is intrinsically important, perhaps especially because a recent report suggests genetic linkage of poor P50 suppression to the cholinergic receptor's alpha7 nicotinic subunit.

Psychophysiological measures of (dis)inhibition as liability indicators for schizophrenia.

Two psychophysiological measures, poor suppression of midlatency auditory-evoked responses in a paired stimulus paradigm and ocular motor abnormalities, may index genetic liability for schizophrenia. An important feature of these measures is that both patients and their nonpsychotic relatives exhibit basically the same performance. These measures may be successful endophenotypes for schizophrenia because they assess poor response inhibition associated with dysfunction of dorsolateral prefrontal cortex circuitry. Data bearing on this hypothesis are reviewed, and it is posited that assessment of the auditory-evoked gamma band response and saccade measures of inhibitory abilities are the most valid behavioral measures of schizophrenia's neuropathological correlates. The extant data suggest that psychophysiological studies of schizophrenia can provide consistent and theoretically meaningful information for localizing neuropathology and for assessing the genetics of this complex disorder.