Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds.

Several genes have recently been identified as risk factors for schizophrenia (SZ) by genome-wide association studies (GWAS), including ZNF804A which is thought to function in transcriptional regulation. However, the downstream pathophysiological changes that these genes confer remain to be elucidated. In 143 subjects (68 clinical high risk, first episode or chronic cases; 75 controls), we examined the association between 21 genetic markers previously identified by SZ GWAS or associated with putative intermediate phenotypes of SZ against three event-related potential (ERP) measures: mismatch negativity (MMN), amplitude of P300 during an auditory oddball task, and P300 amplitude during an auditory novelty oddball task. Controlling for age and sex, significant genetic association surpassing Bonferroni correction was detected between ZNF804A marker rs1344706 and P300 amplitude elicited by novel sounds (beta=4.38, P=1.03 × 10(-4)), which is thought to index orienting of attention to unexpected, salient stimuli. Subsequent analyses revealed that the association was driven by the control subjects (beta=6.35, P=9.08 × 10(-5)), and that the risk allele was correlated with higher novel P300b amplitude, in contrast to the significantly lower amplitude observed in cases compared to controls. Novel P300b amplitude was significantly correlated with a neurocognitive measure of auditory attention under interference conditions, suggesting a relationship between novel P300b amplitude and higher-order attentional processes. Our results suggest pleiotropic effects of ZNF804A on risk for SZ and neural mechanisms that are indexed by the novel P300b ERP component.

Sensory-based and higher-order operations contribute to abnormal emotional prosody processing in schizophrenia: an electrophysiological investigation.

BACKGROUND: Schizophrenia is characterized by deficits in emotional prosody (EP) perception. However, it is not clear which stages of processing prosody are abnormal and whether the presence of semantic content contributes to the abnormality. This study aimed to examine event-related potential (ERP) correlates of EP processing in 15 chronic schizophrenia individuals and 15 healthy controls. METHOD: A total of 114 sentences with neutral semantic content [sentences with semantic content (SSC) condition] were generated by a female speaker (38 with happy, 38 with angry, and 38 with neutral intonation). The same sentences were synthesized and presented in the 'pure prosody' sentences (PPS) condition where semantic content was unintelligible. RESULTS: Group differences were observed for N100 and P200 amplitude: patients were characterized by more negative N100 for SSC, and more positive P200 for angry and happy SSC and happy PPS. Correlations were found between delusions and P200 amplitude for happy SSC and PPS. Higher error rates in the recognition of EP were also observed in schizophrenia: higher error rates in neutral SSC were associated with reduced N100, and higher error rates in angry SSC were associated with reduced P200. CONCLUSIONS: These results indicate that abnormalities in prosody processing occur at the three stages of EP processing, and are enhanced in SSC. Correlations between P200 amplitude for happy prosody and delusions suggest a role that abnormalities in the processing of emotionally salient acoustic cues may play in schizophrenia symptomatology. Correlations between ERP and behavioral data point to a relationship between early sensory abnormalities and prosody recognition in schizophrenia.

Gray matter volume reduction in rostral middle frontal gyrus in patients with chronic schizophrenia.

The dorsolateral prefrontal cortex (DLPFC) is a brain region that has figured prominently in studies of schizophrenia and working memory, yet the exact neuroanatomical localization of this brain region remains to be defined. DLPFC primarily involves the superior frontal gyrus and middle frontal gyrus (MFG). The latter, however is not a single neuroanatomical entity but instead is comprised of rostral (anterior, middle, and posterior) and caudal regions. In this study we used structural MRI to develop a method for parcellating MFG into its component parts. We focused on this region of DLPFC because it includes BA46, a region involved in working memory. We evaluated volume differences in MFG in 20 patients with chronic schizophrenia and 20 healthy controls. Mid-rostral MFG (MR-MFG) was delineated within the rostral MFG using anterior and posterior neuroanatomical landmarks derived from cytoarchitectonic definitions of BA46. Gray matter volumes of MR-MFG were then compared between groups, and a significant reduction in gray matter volume was observed (p<0.008), but not in other areas of MFG (i.e., anterior or posterior rostral MFG, or caudal regions of MFG). Our results demonstrate that volumetric alterations in MFG gray matter are localized exclusively to MR-MFG. 3D reconstructions of the cortical surface made it possible to follow MFG into its anterior part, where other approaches have failed. This method of parcellation offers a more precise way of measuring MR-MFG that will likely be important in further documentation of DLPFC anomalies in schizophrenia.

Abnormal inhibitory processes in semantic networks in schizophrenia.

Abnormal language in schizophrenia has been regarded as a hallmark of this disorder. Language abnormalities include loose and unusual associations, tangentiality, and inability to maintain a topic. Recent theories of language dysfunction have invoked working memory abnormalities, as well as abnormal processes within semantic memory in schizophrenia. Two views, often construed as opposing, have been offered to account for language peculiarities in schizophrenia: one holds that initial processes of activation are abnormal while the other holds that late processes of context utilization might be disturbed. We suggest that these views may be complementary rather than mutually exclusive. Given the relative paucity of data on the early processes within semantic networks, we present new evidence using ERP short SOA paradigm that these processes are abnormal in schizophrenia. Furthermore, reduced N400 in the unrelated condition found in this study suggests that the abnormality was related to inefficient early inhibitory processes.

Diffusion tractography of the fornix in schizophrenia.

BACKGROUND: White matter fiber tracts, especially those interconnecting the frontal and temporal lobes, are likely implicated in pathophysiology of schizophrenia. Very few studies, however, have focused on the fornix, a compact bundle of white matter fibers, projecting from the hippocampus to the septum, anterior nucleus of the thalamus and the mamillary bodies. Diffusion Tensor Imaging (DTI), and a new post-processing method, fiber tractography, provides a unique opportunity to visualize and to quantify entire trajectories of fiber bundles, such as the fornix, in vivo. We applied these techniques to quantify fornix diffusion anisotropy in schizophrenia. METHODS: DTI images were used to evaluate the left and the right fornix in 36 male patients diagnosed with chronic schizophrenia and 35 male healthy individuals, group matched on age, parental socioeconomic status, and handedness. Regions of interest were drawn manually, blind to group membership, to guide tractography, and fractional anisotropy (FA), a measure of fiber integrity, was calculated and averaged over the entire tract for each subject. The Doors and People test (DPT) was used to evaluate visual and verbal memory, combined recall and combined recognition. RESULTS: Analysis of variance was performed and findings demonstrated a difference between patients with schizophrenia and controls for fornix FA (p=0.006). Protected post-hoc independent sample t-tests demonstrated a bilateral FA decrease in schizophrenia, compared with control subjects (left side: p=0.048; right side p=0.006). Higher fornix FA was statistically significantly correlated with DPT and measures of combined visual memory (r=0.554, p=0.026), combined verbal memory (r=0.647, p=0.007), combined recall (r=0.516, p=0.041), and combined recognition (r=0.710, p=0.002) for the control group. No such statistically significant correlations were found in the patient group. CONCLUSIONS: Our findings show the utility of applying DTI and tractography to study white matter fiber tracts in vivo in schizophrenia. Specifically, we observed a bilateral disruption in fornix integrity in schizophrenia, thus broadening our understanding of the pathophysiology of this disease.

Future directions for examining semantic memory in schizophrenia spectrum disorders.

Language abnormalities in schizophrenia are regarded as a hallmark of the disease. Clinical investigations provided accurate descriptions of the different manifestations of abnormal language use, and behavioral studies suggested several mechanisms that might contribute to these abnormalities. This review focuses on semantic memory dysfunction and, primarily, on functional methodologies such as ERP and fMRI that provide more direct measures of abnormal neural mechanisms related to language use in schizophrenia. In addition, the review points to future directions of study of the areas that received little attention thus far and whose investigation might contribute to a more detailed understanding of semantic memory dysfunction in schizophrenia.

DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity.

Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.

Semantic disturbance in schizophrenia and its relationship to the cognitive neuroscience of attention.

We view schizophrenia as producing a failure of attentional modulation that leads to a breakdown in the selective enhancement or inhibition of semantic/lexical representations whose biological substrata are widely distributed across left (dominant) temporal and frontal lobes. Supporting behavioral evidence includes word recall studies that have pointed to a disturbance in connectivity (associative strength) but not network size (number of associates) in patients with schizophrenia. Paralleling these findings are recent neural network simulation studies of the abnormal connectivity effect in schizophrenia through 'lesioning' network connection weights while holding constant network size. Supporting evidence at the level of biology are in vitro studies examining N-methyl-D-aspartate (NMDA) receptor antagonists on recurrent inhibition; simulations in neural populations with realistically modeled biophysical properties show NMDA antagonists produce a schizophrenia-like disturbance in pattern association. We propose a similar failure of NMDA-mediated recurrent inhibition as a candidate biological substrate for attention and semantic anomalies of schizophrenia.

Lateralized P3 deficit in schizotypal personality disorder.

BACKGROUND: Reduced, left-lateralized P3 amplitude has been reported in several studies focusing on electrophysiologic function in schizophrenia. Also, several lines of evidence suggest a similarity between schizophrenia and schizotypal personality disorder (SPD). This study was undertaken to determine the replicability of our previous finding of a left-lateralized P3 amplitude deficit in SPD. METHODS: We recorded event-related potentials in 21 SPD and 18 normal control subjects in an auditory "oddball" P3 paradigm. RESULTS: In the SPD subjects, but not in the control subjects, there was lower P3 amplitude at T3 compared with T4. CONCLUSIONS: These results are similar to the ones in our previous work and further support the presence of a left-lateralized P3 deficit in SPD.

Visual perception and working memory in schizotypal personality disorder.

OBJECTIVE: Patients affected by schizophrenia show deficits in both visual perception and working memory. The authors tested early-stage vision and working memory in subjects with schizotypal personality disorder, which has been biologically associated with schizophrenia. METHOD: Eleven subjects who met DSM-III-R criteria for schizotypal personality disorder and 12 normal comparison subjects were evaluated. Performance thresholds were obtained for tests of visual discrimination and working memory. Both form and trajectory processing were evaluated for each task. RESULTS: Subjects with schizotypal personality disorder showed intact discrimination of form and trajectory but were impaired on working memory tasks. CONCLUSIONS: These data suggest that subjects with schizotypal personality disorder, unlike patients affected by schizophrenia, have relatively intact visual perception. Subjects with schizotypal personality disorder do show specific deficits on tasks of comparable difficulty when working memory demands are imposed. Schizotypal personality disorder may be associated with a more specific visual processing deficit than schizophrenia, possibly reflecting disruption of frontal lobe systems subserving visual working memory operations.

Verbal and nonverbal neuropsychological test performance in subjects with schizotypal personality disorder.

OBJECTIVE: The authors contrasted verbal and nonverbal measures of attention and memory in patients with DSM-IV-defined schizotypal personality disorder in order to expand on their previous findings of verbal learning deficits in these patients and to understand better the neuropsychological profile of schizotypal personality disorder. METHOD: Cognitive test performance was examined in 16 right-handed men who met diagnostic criteria for schizotypal personality disorder and 16 matched male comparison subjects. Neuropsychological measures included verbal and nonverbal tests of persistence, supraspan learning, and short- and long-term memory retention. Neuropsychological profiles were constructed by standardizing test scores based on the means and standard deviations of the comparison subject group. RESULTS: Subjects with schizotypal personality disorder showed a mild to moderate general reduction in performance on all measures. Verbal measures of persistence, short-term retention, and learning were more severely impaired than their nonverbal analogs. Performance on measures of memory retention was independent of modality. CONCLUSIONS: The results are consistent with previous reports that have suggested a mild, general decrement in cognitive performance and proportionately greater involvement of the left hemisphere in patients with schizotypal personality disorder. The findings provide further support for a specific deficit in the early processing stages of verbal learning.

The effect of family status and schizotypy on electrophysiologic measures of attention and semantic processing.

BACKGROUND: Disturbances in both attention and language are central to the phenomenology of the schizophrenia spectrum disorders. The purpose of this study was to investigate the relative contributions of two factors, family status and schizotypy, on electrophysiologic measures of attention and semantic processing in family members of individuals with schizophrenia. METHODS: Fifteen first-degree relatives of individuals with schizophrenia and 15 comparison subject controls participated in diagnostic evaluations, an assessment of schizotypy, and two event-related potential (ERP) paradigms. The first paradigm was an auditory P300 "oddball" task designed to assess attentional functioning. The second was an N400 sentence paradigm particularly sensitive to language processing. RESULTS: Both relatives and individuals higher in schizotypy, but not their respective comparison groups, showed reductions in P300 amplitude. In the N400 paradigm, individuals higher in schizotypy, but not relatives, showed a reduced N400 effect. There were no differences in latency for either group on either component. CONCLUSIONS: The results suggest that both family status and schizotypal presentation independently contribute to disturbances in electrophysiologic measures sensitive to attention and language. Whereas higher levels of schizotypy appear to be associated with disturbances in both attention and language processing, family membership appears to place individuals at risk for attentional deficits alone.

Abnormal angular gyrus asymmetry in schizophrenia.

OBJECTIVE: Few studies have evaluated the parietal lobe in schizophrenia despite the fact that it has an important role in attention, memory, and language-all functions that have been reported to be abnormal in schizophrenia. The inferior parietal lobule, in particular, is of interest because it is not only part of the heteromodal association cortex but also is part of the semantic-lexical network, which also includes the planum temporale. Both the inferior parietal lobule, particularly the angular gyrus of the inferior parietal lobule, and the planum temporale are brain regions that play a critical role as biological substrates of language and thought. The authors compared volume and asymmetry measures of the individual gyri of the parietal lobe by means of magnetic resonance imaging (MRI) scans. METHOD: MRI scans with a 1. 5-Tesla magnet were obtained from 15 male chronic schizophrenic and 15 comparison subjects matched for age, gender, and parental socioeconomic status. RESULTS: Inferior parietal lobule volumes showed a leftward asymmetry (left 7.0% larger than right) in comparison subjects and a reversed asymmetry (left 6.3% smaller than right) in schizophrenic subjects. The angular gyrus accounted for this difference in asymmetry, with the left angular gyrus being significantly larger (18.7%) than the right in comparison subjects, a finding that was not observed in schizophrenic patients. A further test of angular gyrus asymmetry showed a reversal of the normal left-greater-than-right asymmetry in the schizophrenic patients. CONCLUSIONS: Patients with schizophrenia showed a reversed asymmetry in the inferior parietal lobule that was localized to the angular gyrus, a structure belonging to the heteromodal association cortex as well as being part of the semantic-lexical network. This finding contributes to a more comprehensive understanding of the neural substrates of language and thought disorder in schizophrenia.

Large CSF volume not attributable to ventricular volume in schizotypal personality disorder.

OBJECTIVE: The purpose of this study was to determine whether schizotypal personality disorder, which has the same genetic diathesis as schizophrenia, manifests abnormalities in whole-brain and CSF volumes. METHOD: Sixteen right-handed and neuroleptic-naive men with schizotypal personality disorder were recruited from the community and were age-matched to 14 healthy comparison subjects. Magnetic resonance images were obtained from the subjects and automatically parcellated into CSF, gray matter, and white matter. Subsequent manual editing separated cortical from noncortical gray matter. Lateral ventricles and temporal horns were also delineated. RESULTS: The men with schizotypal personality disorder had larger CSF volumes than the comparison subjects; the difference was not attributable to larger lateral ventricles. The cortical gray matter was somewhat smaller in the men with schizotypal personality disorder, but the difference was not statistically significant. CONCLUSIONS: Consistent with many studies of schizophrenia, this examination of schizotypal personality disorder indicated abnormalities in brain CSF volumes.

Electrophysiological correlates of language processing in schizotypal personality disorder.

OBJECTIVE: This study examined whether the electrophysiological correlates of language processing found previously to be abnormal in schizophrenia are also abnormal in schizotypal individuals. The authors used the N400 component to evaluate language dysfunction in schizotypal individuals. METHOD: Event-related potentials were recorded in 16 comparison subjects and 17 schizotypal individuals (who met full DSM-III-R criteria) to sentences presented both visually and aurally; half of the sentences ended with an expected word completion (congruent condition), and the other half ended with an unexpected word completion (incongruent condition). RESULTS: In the congruent condition, the N400 amplitude was more negative in individuals with schizotypal personality disorder than in comparison subjects in both the visual and auditory modalities. In addition, in the visual modality, the N400 latency was prolonged in the individuals with schizotypal personality disorder. CONCLUSIONS: The N400 was found to be abnormal in the individuals with schizotypal personality disorder relative to comparison subjects. The abnormality was similar to the abnormality the authors' laboratory reported earlier in schizophrenic subjects, in which the N400 amplitude was found to be more negative in both congruent and incongruent sentence completions. The N400 abnormality is consistent with the inefficient use of context.

Identification of neural circuits underlying P300 abnormalities in schizophrenia.

Event-related potentials (ERPs) provide a noninvasive method to evaluate neural activation and cognitive processes in schizophrenia. The pathophysiological significance of these findings would be greatly enhanced if scalp-recorded ERP abnormalities could be related to specific neural circuits and/or regions of the brain. Using quantitative approaches in which scalp-recorded ERP components are correlated with underlying neuroanatomy in schizophrenia, we focused on biophysical and statistical procedures (partial least squares) to relate the auditory P300 component to anatomic measures obtained from quantitative magnetic resonance imaging. These findings are consistent with other evidence that temporal lobe structures contribute to the generation of the scalp-recorded P300 component and that P300 amplitude asymmetry over temporal recording sites on the scalp may reflect anatomic asymmetries in the volume of the superior temporal gyrus in schizophrenia.

Schizotypal personality disorder and MRI abnormalities of temporal lobe gray matter.

BACKGROUND: Structural MRI data indicate schizophrenics have reduced left-sided temporal lobe gray matter volumes, especially in the superior temporal gyrus (STG) and medial temporal lobe. Our data further suggest a specificity to schizophrenia spectrum disorders of STG volume reduction. Interpretation of research studies involving schizophrenics may be complicated by the effects of exposure to neuroleptics and chronic illness. Sharing the same genetic diathesis of schizophrenics, subjects with schizotypal personality disorder (SPD) offer a unique opportunity to evaluate commonalities between schizophrenia and SPD, particularly as SPD subjects are characterized by cognitive and perceptual distortions, an inability to tolerate close friendships, and odd behavior, but they are not psychotic and so have generally not been prescribed neuroleptics nor hospitalized. Evaluation of brain structure in SPD may thus offer insight into the "endophenotype" common to both disorders. In addition, differences between groups may suggest which are the brain structures of schizophrenics that contribute to the development of psychosis. METHODS: To test the hypothesis of whether SPD subjects might show similar STG abnormalities, STG and medial temporal lobe regions of interest (ROI) were manually drawn on high resolution coronal MRI 1.5 mm thick slices. Images were derived from 16 right-handed male SPD subjects, without regard to family history, and 14 healthy, right-handed, comparison males who did not differ from the SPD group on parental socio-economic status, age, or verbal IQ. RESULTS: As predicted, SPD subjects showed a reduction in left STG gray matter volume compared with age and gender matched comparison subjects. SPD subjects also showed reduced parahippocampal left/right asymmetry and a high degree of disordered thinking. Comparisons with chronic schizophrenics previously studied by us showed the SPD group had a similarity of left STG gray matter volume reduction, but fewer medial temporal lobe abnormalities. CONCLUSIONS: These abnormalities strengthen the hypothesis of a temporal lobe abnormality in SPD, and the similarity of STG findings in schizophrenia and SPD suggest that STG abnormalities may be part of the spectrum "endophenotype." It is also possible that presence of medial temporal lobe abnormalities may help to differentiate who will develop schizophrenia and who will develop the less severe schizophrenia spectrum disorder, SPD.

Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects.

Seeking to unite psychological and biological approaches, this paper links cognitive and cellular hypotheses and data about thought and language abnormalities in schizophrenia. The common thread, it is proposed, is a dysregulated suppression of associations (at the behavioral and functional neural systems level), paralleled by abnormalities of inhibition at the cellular and molecular level, and by an abnormal anatomical substrate (reduced MRI gray matter volume) in areas subserving language. At the level of behavioral experiments and connectionist modeling, data suggest an abnormal semantic network connectivity (strength of associations) in schizophrenia, but not an abnormality of network size (number of associates). This connectivity abnormality is likely to be a preferential processing of the dominant (strongest) association, with the neglect of preceding contextual information. At the level of functional neural systems, the N400 event-related potential amplitude is used to index the extent of "search" for a semantic match to a word. In a short stimulus-onset-asynchrony condition, both schizophrenic and schizotypal personality disorder subjects showed, compared with controls, a reduced N400 amplitude to the target words that were related to cues, e.g. cat-dog, a result compatible with behavioral data. Other N400 data strongly and directly suggest that schizophrenics do not efficiently utilize context.

Word recall in schizophrenia: a connectionist model.

OBJECTIVE: The authors examined word recall of patients with schizophrenia by using an experimental paradigm generated from connectionist models of memory. METHOD: Schizophrenic patients and normal comparison subjects first studied and then recalled a list of 32 words of equal difficulty. Both the connectivity (associative strength) and the network size (number of associates) of the words varied in such a way that the list contained equal proportions of four types of words: 1) high connectivity-small network size, 2) low connectivity-small network size, 3) high connectivity-large network size, and 4) low connectivity-large network size. RESULTS: The schizophrenic patients recalled fewer words and showed a particularly pronounced effect of the connectivity of the to-be-remembered words. For the patients, regardless of network size, recall improved substantially for words of high connectivity and declined dramatically for words of low connectivity. By contrast, the comparison subjects showed the expected effects, with the best recall for words of high connectivity-small network size, followed by words of low connectivity-small network size, then by words of high connectivity-large network size, and finally by words of low connectivity-large network size. CONCLUSIONS: Schizophrenia may be characterized by faulty modulation of associative links within a putative lexicon that is thought to be widely distributed across frontal and temporal lobes.