Emotion processing and theory of mind in schizophrenia patients and their unaffected first-degree relatives

Previous studies have suggested that social cognition is affected in individuals with schizophrenia. The purpose of this study was to explore to what extent social cognition deficits are shared by unaffected first-degree relatives, and the nature of the relationship between performance in different paradigms of social cognition. 20 Schizophrenia patients (7 females, 31 ± 10 years), 20 healthy age- and gender-matched individuals, 20 unaffected first-degree relatives of the schizophrenia patients (11 females, 50 ± 20 years), and 20 healthy individuals matched for age and gender were recruited. Patients showed deficits in the detection of social Faux Pas (0.80 ± 0.17 vs. controls: 0.94 ± 0.09, p = 0.025) and the correct identification of Theory of Mind stories (0.71 ± 0.13 vs. controls: 0.82 ± 0.12, p = 0.038). Relatives performed poorly in the Faces Test (0.83 ± 0.14 vs. controls: 0.9 ± 0.08, p = 0.048), the Reading the Mind in the Eyes Test (0.59 ± 0.17 vs. controls: 0.71 ± 0.14, p = 0.046) and the detection of social Faux Pas (0.8 ± 0.2 vs. controls: 0.93 ± 0.09, p = 0.024). Abnormalities were independent of age, years of education, and general cognitive performance in patients and their relatives. Performance in an Emotion Processing task (Faces Test) was correlated with performance in theory of mind tests in healthy individuals and relatives of patients with schizophrenia only. These results suggest that schizophrenia patients and their unaffected first-degree relatives display similar but nonidentical patterns of social cognition processing.     

Antisaccade performance is related to genetic loading for schizophrenia

Disturbances of the oculomotor system are promising endophenotypes for schizophrenia. Increased error rates in the antisaccade task and prolonged antisaccade latencies have been found in patients with schizophrenia and their first degree relatives. We investigated oculomotor performance in 41 parents of schizophrenia patients and 22 controls with a prosaccade task and an antisaccade task. Parents were grouped into parents with a positive family history for schizophrenia (N = 9) and parents with a negative family history for schizophrenia (N = 32). An overlap-paradigm was applied; eye movements were recorded using infrared oculography. The combined group of parents made more antisaccade direction errors than controls (p = 0.005) and there was a linear increase in direction errors from controls via negative family history parents to positive family history parents (p = 0.008). Antisaccade latencies were prolonged in the combined parent group (p = 0.057) compared to controls and there was a linear increase in latency with genetic loading (p = 0.018). No group differences were found for prosaccade parameters. These results support the hypothesis that antisaccade impairment is associated with genetic loading for schizophrenia.     

Personality in relation to genetic liability for schizophrenia and bipolar disorder: Differential associations with the COMT ValMet polymorphism

Schizophrenia and bipolar disorder may share aspects of genetic etiology. Evidence supports the Val^108/158Met polymorphism of the Catechol-o-Methyltransferase (COMT) gene as potentially contributing to the etiology of both disorders. To determine whether the COMT gene is associated with personality traits related to genetic risk for either schizophrenia or bipolar disorder, we examined dimensions of personality psychopathology in biological relatives of individuals with the disorders. Specifically, we contrasted personality characteristics of first-degree relatives of people with schizophrenia, first-degree relatives of people with bipolar-I disorder, and nonpsychiatric control participants using scores from the Dimensional Assessment of Personality Pathology-Brief Questionnaire (DAPP-BQ). We also characterized the COMT Val^108/158Met polymorphism of subjects. Compared to controls, relatives of schizophrenia patients scored lower on stimulus seeking and higher on restrictive expression and social avoidance. Compared to relatives of bipolar patients, relatives of schizophrenia patients had lower scores on narcissism, rejectionality (i.e., rejection of ideas of others), stimulus seeking, passive-aggressive oppositionality, and self-harm. The subset of relatives of schizophrenia patients who were COMT val homozygotes exhibited lower scores on narcissism, rejectionality, and stimulus seeking than met homozygote relatives of schizophrenia patients and control participants. Although relatives of bipolar patients showed scale elevations consistent with emotional dysregulation, the scores failed to be associated with the Val^108/158Met polymorphism. Abnormally low narcissism and rejectionality in val homozygote relatives of schizophrenia patients suggests that the val allele of the COMT polymorphism may be associated with an underdeveloped self-concept phenomenologically similar to made volition and passivity experiences comprising first-rank symptoms of schizophrenia.     

Aberrant auditory processing in schizophrenia and in subjects at ultra-high-risk for psychosis

The N1 and the mismatch negativity (MMN) responses observed in electroencephalographic and magnetoencephalographic (MEG) recordings reflect sensory processing, sensory memory, and adaptation and are usually abnormal in patients with schizophrenia. However, their differential sensitivity to ultra-high-risk (UHR) status is controversial. The current study evaluated the sensitivity of MEG N1m, N1m adaptation, and magnetic counterpart of MMN (MMNm) in 16 UHR subjects, 15 schizophrenia patients, and 18 healthy controls (HCs) during a passive auditory oddball task. N1m adaptation was assessed using the difference in N1m dipole moment between the first and last standard tones in a standard stimulus sequence. N1m adaptation occurred in HCs, whereas neither the UHR nor the schizophrenia groups showed adaptation to the standard tone on repeated presentations. The UHR group had values between those for HCs and schizophrenia patients. Additionally, MMNm dipole moment was reduced in both the UHR and patient groups compared with HCs, whereas the UHR and schizophrenia groups did not differ from each other. These findings indicated that both N1m adaptation and MMNm were altered in UHR subjects and in schizophrenia patients, despite unaffected N1m dipole moment to the first standard tones. Moreover, both UHR and schizophrenia groups failed to show adaptation of the N1m to repeated standard tones. This failure in adaptation was more severe in patients than UHR subjects, suggesting that auditory adaptation may be sensitive to the progression of the illness and be an early biomarker of UHR for psychosis. Deficits in auditory sensory memory, on the other hand, may be similarly impaired in both groups.     

Decreased spatial frequency sensitivities for processing faces in male patients with chronic schizophrenia

ObjectiveSchizophrenia impairs early visual cognitive processing. Low and high spatial frequency (LSF, HSF) visual information are differentially processed in humans. We investigated whether electrophysiological abnormalities exist in visual processing for spatial frequency (SF)-filtered neutral/emotional faces in schizophrenics.MethodsSubjects consisted of 16 male chronic schizophrenics and 23 controls. Event-related potentials (ERPs) to SF-filtered (LSF or HSF) and unfiltered (broad SF; BSF) pictures of neutral, happy, and fearful faces were recorded at 20 scalp sites. The relationships between the P100 (P1)/N170 amplitudes and the Global Assessment of Functioning (GAF) scores in patients were also evaluated.ResultsFor the P1 amplitudes at O1/O2, controls exhibited a significant LSF > BSF difference, while schizophrenics showed no LSF > BSF difference. For the N170 amplitudes at T5/T6, controls revealed a significant HSF > BSF difference, while schizophrenics showed no such difference. For the P1 latencies, controls but not schizophrenics showed a significant difference (LSF > BSF = HSF). For the N170 latencies, no significant SF differentiation was found between the two groups. For both P1 and N170 amplitudes, no significant effects of facial expressions were observed in controls and patients regardless of SFs. There were significant negative correlations between the GAF scores and the N170 amplitudes to BSF faces in schizophrenics, but not for P1 amplitudes.ConclusionsSchizophrenics showed abnormal P1 and N170 responses to SF changes in faces, thus indicating decreased SF sensitivities for processing of faces.SignificanceAbnormal early visual processing may underlie some of the deficits associated with face recognition in schizophrenia.     

Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic 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.     

Cross-diagnostic comparison of visual processing in bipolar disorder and schizophrenia

Patients with Schizophrenia (SZ) show deficits across various stages of visual information processing. Whether patients with Bipolar Disorder (BD) exhibit these deficits is unclear. In this study, we conducted a detailed comparison of specific stages of early visual perception in BD and SZ. Forty-three BD patients, 43 SZ patients, and 51 matched healthy control subjects (HC) were administered three visual processing paradigms emphasizing: 1) an early stage of object formation (location backward masking), 2) a middle stage of object substitution (four-dot backward masking), and 3) a later stage at the perception–attention interface (rapid serial visual processing (RSVP) task eliciting the attentional blink). SZ performed significantly worse than BD and HC on location and four-dot masking. BD did not significantly differ from HC on either masking task. Both patient groups performed significantly worse than HC on the RSVP task; unlike SZ, BD did not show a significant attentional blink effect compared to HC. Our results indicate that BD patients were intact at the early and middle stages of visual processing (object formation and substitution) but intermediate between the SZ and HC groups at a later processing stage involving perceptual and attentional processes (RSVP task). These findings suggest that SZ is characterized by a diffuse pathophysiology affecting all stages of visual processing whereas in BD disruption is only at the latest stage involving higher order attentional functions.     

Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. METHODS: MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. RESULTS: We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). CONCLUSIONS: These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.     

Evoked gamma band synchronization and the liability for schizophrenia

Objective: Electroencephalographic (EEG) synchronization in the gamma band is thought to represent a neuronal mechanism by which the brain integrates information processed in different cortical areas to build a coherent internal representation. Previous studies have reported abnormal gamma range (40 Hz) synchronization in schizophrenic patients. We tested a group of first-degree relatives of schizophrenic probands who have schizophrenia spectrum personality symptoms, and a group of schizophrenic patients, to examine whether individuals with increased liability for schizophrenia have reduced gamma synchronization. Method: A steady-state auditory evoked potential paradigm was used to evaluate the brain's capacity to sustain 20, 30, and 40 Hz EEG synchronization in 11 relatives, 24 schizophrenic patients (11 on conventional, 13 on new generation antipsychotic medications), and 17 normal controls. Results: Relatives with schizophrenic spectrum personality symptoms had reduced power at 40 Hz synchronization compared to normal controls (p=0.022). Previous findings of reduced steady-state gamma band synchronization in schizophrenic patients were not directly replicated in this study. Patients as a group did not significantly differ from controls, but patients taking new generation antipsychotics had significantly enhanced 40 Hz synchronization compared to patients taking conventional antipsychotics (p<0.001). There were no group differences in 20 or 30 Hz synchronization. Conclusions: Gamma band synchronization was found to be reduced in first-degree relatives with schizophrenia spectrum personality symptoms. Patients on new generation antipsychotic medications may exhibit enhanced gamma band synchronization.     

分裂症听感觉加工障碍与较高程度功能障碍的关系

目的 用失匹配负波(MMN)和P300去评定分裂症听信息加工中听感觉加工障碍与较高程度功能障碍的相关性.方法 52例分裂症患者和44例正常对照组采用事件相关脑电位检查,测量MMN和P300潜伏期和波幅,并采用SPSS和结构方程模型进行分析.结果 患者组产生的MMN的潜伏期、波幅与正常对照组比较差异有统计学意义(t=6.18,P＜0.01;t=2.42,P＜0.05),患者组产生的P300的波幅与正常对照组比较差异有统计学意义(t=2.64,P=0.01),患者组产生的P300的潜伏期与正常对照组比较差异无统计学意义(t=1.71,P＞0.05).结构方程模型评定显示Group(疾病过程)和MMN波幅及Group和P300波幅显示出有显著路径的内相关(B=-1.01,P=0.015;B=-0.60,P -0.039),MMN波幅与P300波幅显示出有显著路径的内相关(B=0.17,P=0.015).结论 分裂症听信息加工中听感觉加工的障碍直接影响着较高程度的功能障碍.     

Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia

Smooth pursuit eye movement (SPEM) and antisaccade deficits have been proposed as endophenotypes in the search for schizophrenia genes. We assessed these measures in 24 schizophrenia patients, 24 of their healthy siblings, and 24 healthy controls closely matched to the siblings. Between-group differences were assessed using a random effects regression model taking into account the relatedness between patients and siblings. Patients showed reduced SPEM gain, increased frequency of saccades during pursuit, increased antisaccade error rate, and reduced antisaccade gain compared to controls. Siblings performed intermediate, i.e. between patients and controls, on most measures, but were particularly characterised by reduced antisaccade gain. SPEM gain at one target velocity was significantly correlated between patients and siblings, highlighting the necessity of taking into account within-family correlations in the statistical analysis of between-group differences. It is concluded that subtle SPEM and antisaccade deficits are observed in clinically unaffected siblings of schizophrenia patients; these deficits may be useful markers of genetic liability to schizophrenia.     

Alterations of the early auditory evoked gamma-band response in first-degree relatives of patients with schizophrenia: hints to a new intermediate phenotype

Background

There is growing evidence of abnormalities of high-frequency oscillations in the gamma-range of the electroencephalography in schizophrenia. The generation of neural activity in the gamma-band was shown to be critically related to a glutamatergic and GABAergic microcircuit which is also known to be involved in the pathophysiology of schizophrenia. Recently, a reduction of the early auditory evoked gamma-band response (eGBR) in schizophrenic patients was reported. In order to investigate the possible applicability of this neurophysiological marker as an intermediate phenotype for schizophrenia, this is the main question of our investigation: Is the early eGBR decreased regarding evoked power and phase locking in first-degree relatives of patients with schizophrenia?

Methods

We investigated the early eGBR in 17 unaffected first-degree relatives of patients with schizophrenia and in age-, gender- and education-matched groups of schizophrenic patients and healthy controls using an auditory reaction task.

Results

First-degree relatives of patients with schizophrenia and schizophrenic patients showed a significant reduction of evoked power and phase locking of the early eGBR compared to healthy controls.

Conclusion

This study shows significantly reduced evoked power and phase locking of the early auditory eGBR in first-degree relatives of patients with schizophrenia pointing to the applicability of this marker as a heritable intermediate phenotype for schizophrenia. The findings are in line with the hypothesis of a disturbed GABAergic interneural modulation of pyramidal cells in schizophrenia and findings of different schizophrenia risk genes associated with transmission at glutamatergic and GABAergic synapses.     

Electrophysiological evidence of corollary discharge dysfunction in schizophrenia during talking and thinking

Failure of corollary discharge, a mechanism for distinguishing self-generated from externally-generated percepts, has been posited to underlie certain positive symptoms of schizophrenia, including auditory hallucinations. Although originally described in the visual system, corollary discharge may exist in the auditory system, whereby signals from motor speech commands prepare auditory cortex for self-generated speech. While associated with sensorimotor systems, it might also apply to inner speech or thought, regarded as our most complex motor act. We had four aims in the studies summarized in this paper: (1) to demonstrate the corollary discharge phenomenon during talking and inner speech in human volunteers using event-related brain potentials (ERPs), (2) to demonstrate that the corollary discharge is abnormal in patients with schizophrenia, (3) to demonstrate the role of frontal speech areas in the corollary discharge during talking, and (4) to relate the dysfunction of the corollary discharge in schizophrenia to auditory hallucinations. Using EEG and ERP measures, we addressed each aim in patients with schizophrenia (DSM IV) and healthy control subjects. The N1 component of the ERP reflected dampening of auditory cortex responsivity during talking and inner speech in control subjects but not in patients. EEG measures of coherence indicated inter-dependence of activity in the frontal speech production and temporal speech reception areas during talking in control subjects, but not in patients, especially those who hallucinated. These data suggest that a corollary discharge from frontal areas where thoughts are generated fails to alert auditory cortex that they are self-generated, leading to the misattribution of inner speech to external sources and producing the experience of auditory hallucinations.     

Sensory contributions to impaired prosodic processing in schizophrenia.

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.     

Prolonged latencies of the N2 and P3 of the auditory event-related potential in children at risk for schizophrenia

Summary In previous studies investigating long latency components of the event-related potential (ERP), schizophrenic patients generally showed reduced P3 amplitudes and in some studies prolonged N2 or P3 latencies. As there is a higher risk of offspring of schizophrenics than of mentally healthy parents developing this disease, the present study was intended to clarify whether ERP components (in particular the N2 and P3) differ between these two groups of children. Twelve high-risk and 12 age-matched control children (aged 9–16 years) performed an auditory oddball task in order to assess late ERP components. This task required the subject to covertly count rare target tone pips (P = 0.2) irregularly interspersed among frequent standard tone pips (P = 0.8) in two series of 400 pips. ERPs were recorded from midline electrodes (Fz, Cz, Pz). The results indicated distinctly prolonged N2 and P3 latencies in ERPs to target stimuli in children of schizophrenic patients. These findings suggest a slowed target classification in these children.     

Transcranial direct current stimulation of prefrontal cortex: An auditory event-related potential study in schizophrenia

Cognitive impairment is one of the most significant factors determining the long-term rehabilitation prospects of schizophrenia patients. Cognitive training has been shown to be beneficial; however, effect sizes of cognitive remediation remain relatively low. Anodal transcranial direct current stimulation (tDCS) increases cortical excitability along with larger N1 auditory event-related potentials (ERPs), thus providing a non-invasive physiological mechanism that is potentially capable of facilitating cognitive training of schizophrenia patients. The current study investigated the effects of left-prefrontal anodal tDCS on auditory discrimination performance and N1, Mismatch Negativity (MMN), and P3b ERPs, which have been linked to cognitive and global function deficits in schizophrenia. We compared 20 min of 2 mA tDCS versus sham stimulation in 14 schizophrenia patients by employing a randomised crossover design. Patients performed equally well in a go/no-go auditory discrimination task when compared to healthy subjects but presented with significantly smaller N1, MMN and P3b amplitudes, which did not change with tDCS. Auditory discrimination performance and reaction times also remained unaffected by tDCS. Our findings suggest that a single application of tDCS has no acute effects on ERPs and associated auditory information processing in schizophrenia patients.     

Sensory-gating deficit of the N100 mid-latency auditory evoked potential in medicated schizophrenia patients

The clinical and neuro-cognitive correlates of the P50 and N100 auditory evoked responses gating deficits in schizophrenia have thus far eluded identification. Based on our prior results, we hypothesized that, in addition to the P50, gating of the N100 is significantly decreased in schizophrenia and that this deficit correlates with the negative symptoms dimension of schizophrenia. Amplitudes and gating measures of the P50 and N100 were compared between stable out-patients (N = 45) (mainly on atypical antipsychotics) with chronic schizophrenia and age- and gender-matched healthy controls (N = 49) and the clinical correlates examined. All subjects underwent the paired-stimulus paradigm in 3 or 4 different days. Data from day one and the mean of all days (MOAD) were examined. P50 and N100 amplitudes and gating measures were correlated with PANSS and Wisconsin Card Sorting Test data. Utilizing day one data, no amplitude or gating measures were significantly different between the groups. Utilizing MOAD data, both P50 and N100 gating were significantly decreased in schizophrenia patients. The N100 gating deficit correlated with the negative-symptoms cluster and measures of frontal lobe dysfunction. The data suggest a correlation between N100 gating deficit and the negative-cognitive deficits dimensions of schizophrenia. Data also suggest that improving the signal to noise ratio (MOAD data) increases the sensitivity for detecting gating abnormalities and assessing their clinical correlates.     

Better understanding of mechanisms of schizophrenia and bipolar disorder: from human gene expression profiles to mouse models

The molecular mechanisms of major mental illnesses, such as schizophrenia and bipolar disorder, are unclear. To address this fundamental question, many groups have studied molecular expression profiles in postmortem brains and other tissues from patients compared with those from normal controls. Development of unbiased high-throughput approaches, such as microarray, RNA-seq, and proteomics, have supported and facilitated this endeavor. In addition to genes directly involved in neuron/glia signaling, especially those encoding for synaptic proteins, genes for metabolic cascades are differentially expressed in the brains of patients with schizophrenia and bipolar disorder, compared with those from normal controls in DNA microarray studies. Here we propose the importance and usefulness of genetic mouse models in which such differentially expressed molecules are modulated. These animal models allow us to dissect the mechanisms of how such molecular changes in patient brains may play a role in neuronal circuitries and overall behavioral phenotypes. We also point out that models in which the metabolic genes are modified are obviously untested from mental illness viewpoints, suggesting the potential to re-address these models with behavioral assays and neurochemical assessments.