Computational Synaptic Modeling of Pitch and Duration Mismatch Negativity in First-Episode Psychosis Reveals Selective Dysfunction of the N-Methyl-D-Aspartate Receptor.

Mismatch negativity (MMN) to pitch (pMMN) and to duration (dMMN) deviant stimuli is significantly more attenuated in long-term psychotic illness compared to first-episode psychosis (FEP). It was recently shown that source-modeling of magnetically recorded MMN increases the detection of left auditory cortex MMN deficits in FEP, and that computational circuit modeling of electrically recorded MMN also reveals left-hemisphere auditory cortex abnormalities. Computational modeling using dynamic causal modeling (DCM) can also be used to infer synaptic activity from EEG-based scalp recordings. We measured pMMN and dMMN with EEG from 26 FEP and 26 matched healthy controls (HCs) and used a DCM conductance-based neural mass model including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, N-methyl-D-Aspartate (NMDA), and Gamma-aminobutyric acid receptors to identify any changes in effective connectivity and receptor rate constants in FEP. We modeled MMN sources in bilateral A1, superior temporal gyrus, and inferior frontal gyrus (IFG). No model parameters distinguished groups for pMMN. For dMMN, reduced NMDA receptor activity in right IFG in FEP was detected. This finding is in line with literature of prefrontal NMDA receptor hypofunction in chronic schizophrenia and suggests impaired NMDA-induced synaptic plasticity may be present at psychosis onset where scalp dMMN is only moderately reduced. To the best of our knowledge, this is the first report of impaired NMDA receptor activity in FEP found through computational modeling of dMMN and shows the potential of DCM to non-invasively reveal synaptic-level abnormalities that underly subtle functional auditory processing deficits in early psychosis.

Attenuated modulation of the N170 ERP by facial expressions in schizophrenia.

In psychiatrically-well subjects the modulation of event related potentials (ERPs) by emotional facial expressions is found in several ERPs from -100 ms and later. A face-related EPR, the N170, is abnormally reduced in schizophrenia to faces relative to other complex objects and research suggests emotional modulation of N170 may be reduced as well. To further examine facial emotion modulation of N170, subjects detected neutral facial expressions from among five emotional expressions (happy, sad, fearful, angry, and disgusted). Over occipitotemporal sites, psychiatrically-well subjects showed bilateral differences in N170 amplitude among expressions (P = 0.014). Schizophrenia subjects failed to show this modulation (P = 0.551). Accuracy on the task did not differ between groups, nor did the pattern of errors. However, in patients, greater positive and negative symptom ratings were associated with increased failure to button press to neutral faces, suggesting misattribution of emotion to neutral expressions in the more ill patients. Because the N170 is largely specific to faces, these results suggest that an impairment specific to the visual processing of facial expressions contributes to the well-known behavioral abnormalities in facial emotion tasks in schizophrenia.

Voxel-based morphometric analysis of gray matter in first episode schizophrenia.

Voxel-based morphometry (VBM) may afford a more rapid and extensive survey of gray matter abnormalities in schizophrenia than manually drawn region of interest (ROI) analysis, the current gold standard in structural MRI. Unfortunately, VBM has not been validated by comparison with ROI analyses, nor used in first-episode patients with schizophrenia or affective psychosis, who lack structural changes associated with chronicity. An SPM99-based implementation of VBM was used to compare a group of 16 patients with first-episode schizophrenia and a group of 18 normal controls and, as a further comparison, 16 first-episode patients with affective psychosis. All groups were matched for age and handedness. High spatial resolution structural images were normalized to the SPM99 template and then segmented, smoothed, and subjected to an ANCOVA. Schizophrenia vs control group comparisons: Voxel-by-voxel comparison of gray matter densities showed that only the left STG region was significantly different when corrected for multiple comparisons (P <.05), consistent with our previously reported manual ROI results. Analysis of the extent of voxel clusters, replicated with permutation analyses, revealed group differences in bilateral anterior cingulate gyri and insula (not previously examined by us with manually drawn ROI) and unilateral parietal lobe, but not in medial temporal lobe (where our ROI analysis had shown differences). However, use of a smaller smoothing kernel and a small volume correction revealed left-sided hippocampal group differences. Affective psychosis comparisons: When the same statistical thresholding criteria were used, no significant differences between affective psychosis patients and controls were noted. Since a major interest was whether patients with affective psychosis shared some anatomical abnormalities with schizophrenia, we applied a small volume correction and searched within the regions that were significantly less dense in schizophrenia compared to control subjects. With this statistical correction, the insula showed, bilaterally, the same pattern of differences in affective disorder subjects as that in schizophrenic subjects, whereas both left STG and left hippocampus showed statistical differences between affectives and schizophrenics, indicating the abnormalities specific to first-episode schizophrenia. These findings suggest both the promise and utility of VBM in evaluating gray matter abnormalities. They further suggest the importance of comparing VBM findings with more traditional ROI analyses until the reasons for the differences between methods are determined.

Button-pressing affects P300 amplitude and scalp topography.

BACKGROUND: Scant and equivocal research exists examining the effects of button-pressing on P300. Button-pressing may decrease P300 latency and amplitude. The melding of motor potentials and P300 may also confound studies of P300 topography, such as studies of temporal scalp-area asymmetries in schizophrenia. METHOD: P300 was measured on button-press and silent-count tasks in control subjects. An estimate of motor activity was constructed from a simple reaction time task, with reaction times matched to the button-press task. The motor estimate was subtracted from the button-press P300 to assess Kok's (1988) additive model. Lastly, lateral P300 from schizophrenia patients was compared with each condition's P300. RESULTS: P300 was smaller and its topography different in the button-pressing task relative to silent-counting. The motor-correction procedure generated a P300 with normal topography. Comparison of the button-press P300 in controls to the silent-count P300 in schizophrenia patients reduced a significant lateral asymmetry to trend level. This asymmetry was significant after the correction procedure. CONCLUSIONS: Button-pressing generates smaller P300 than silent-counting. Also, P300 topography in button-pressing tasks is confounded by motor potentials. The distortion can be corrected with a motor potential estimate. Motor potentials can occlude differences in P300 topography between groups.

A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.

OBJECTIVE: Previous research has noted functional and structural temporal lobe abnormalities in schizophrenia that relate to symptoms such as auditory hallucinations and thought disorder. The goal of the study was to determine whether the functional abnormalities are present in schizophrenia at early stages of auditory processing. METHOD: Functional magnetic resonance imaging activity was examined during the presentation of the mismatch stimuli, which are deviant tones embedded in a series of standard tones. The mismatch stimuli are used to elicit the mismatch negativity, an early auditory event-related potential. Ten patients with schizophrenia and 10 comparison subjects were presented the mismatch stimuli condition and a control condition in which only one tone was presented repeatedly. RESULTS: The superior temporal gyrus showed the most prevalent and consistent activation. The superior temporal gyrus showed less activation in the schizophrenic subjects than in the comparison subjects only during the mismatch stimuli condition. CONCLUSIONS: This result is consistent with those of mismatch negativity event-related potential studies and suggests that early auditory processing is abnormal in chronic schizophrenia.

Prefrontal gray matter volume reduction in first episode schizophrenia.

Functional measures have consistently shown prefrontal abnormalities in schizophrenia. However, structural magnetic resonance imaging (MRI) findings of prefrontal volume reduction have been less consistent. In this study, we evaluated prefrontal gray matter volume in first episode (first hospitalized) patients diagnosed with schizophrenia, compared with first episode patients diagnosed with affective psychosis and normal comparison subjects, to determine the presence in and specificity of prefrontal abnormalities to schizophrenia. Prefrontal gray and white matter volumes were measured from first episode patients with schizophrenia (n = 17), and from gender and parental socio-economic status-matched subjects with affective (mainly manic) psychosis (n = 17) and normal comparison subjects (n = 17), age-matched within a narrow age range (18--29 years). Total (left and right) prefrontal gray matter volume was significantly reduced in first episode schizophrenia compared with first episode affective psychosis and comparison subjects. Follow-up analyses indicated significant left prefrontal gray matter volume reduction and trend level reduction on the right. Schizophrenia patients showed 9.2% reduction on the left and 7.7% reduction on the right compared with comparison subjects. White matter volumes did not differ among groups. These data suggest that prefrontal cortical gray matter volume reduction is selectively present at first hospitalization in schizophrenia but not affective psychosis.

Event-related potentials elicited during a context-free homograph task in normal versus schizophrenic subjects.

Thought disorder in schizophrenia may involve abnormal semantic activation or faulty working memory maintenance. Event-related potentials (ERPs) were recorded while sentences reading "THE NOUN WAS ADJECTIVE/VERB" were presented to 34 schizophrenic and 34 control subjects. Some nouns were homographs with dominant and subordinate meanings. Their sentence ending presented information crucial for interpretation (e.g., The bank was [closed, steep]). Greatest N400 activity to subordinate homograph-meaning sentence endings in schizophrenia would reflect a semantic bias to strong associates. N400 to all endings would reflect faulty verbal working memory maintenance. Schizophrenic subjects showed N400 activity to all endings, suggesting problems in contextual maintenance independent of content, but slightly greater N400 activity to subordinate endings that correlated with the severity of psychosis. Future research should help determine whether a semantic activation bias in schizophrenia toward strong associates is reflected in ERP activity or whether this effect is overshadowed by faulty verbal working memory maintenance of context.

Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients.

BACKGROUND: Magnetic resonance imaging studies in schizophrenia have revealed abnormalities in temporal lobe structures, including the superior temporal gyrus. More specifically, abnormalities have been reported in the posterior superior temporal gyrus, which includes the Heschl gyrus and planum temporale, the latter being an important substrate for language. However, the specificity of the Heschl gyrus and planum temporale structural abnormalities to schizophrenia vs affective psychosis, and the possible confounding roles of chronic morbidity and neuroleptic treatment, remain unclear. METHODS: Magnetic resonance images were acquired using a 1.5-T magnet from 20 first-episode (at first hospitalization) patients with schizophrenia (mean age, 27.3 years), 24 first-episode patients with manic psychosis (mean age, 23.6 years), and 22 controls (mean age, 24.5 years). There was no significant difference in age for the 3 groups. All brain images were uniformly aligned and then reformatted and resampled to yield isotropic voxels. RESULTS: Gray matter volume of the left planum temporale differed among the 3 groups. The patients with schizophrenia had significantly smaller left planum temporale volume than controls (20.0%) and patients with mania (20.0%). Heschl gyrus gray matter volume (left and right) was also reduced in patients with schizophrenia compared with controls (13.1%) and patients with bipolar mania (16.8%). CONCLUSIONS: Compared with controls and patients with bipolar manic psychosis, patients with first-episode schizophrenia showed left planum temporale gray matter volume reduction and bilateral Heschl gyrus gray matter volume reduction. These findings are similar to those reported in patients with chronic schizophrenia and suggest that such abnormalities are present at first episode and are specific to schizophrenia.

Subgenual cingulate cortex volume in first-episode psychosis.

OBJECTIVE: Gray matter volume and glucose utilization have been reported to be reduced in the left subgenual cingulate of subjects with familial bipolar or unipolar depression. It is unclear whether these findings are secondary to recurrent illness or are part of a familial/genetic syndrome. The authors' goal was to clarify these findings. METHOD: Volumetric analyses were performed by using magnetic resonance imaging in 41 patients experiencing their first episode of affective disorder or schizophrenia and in 20 normal comparison subjects. RESULTS: The left subgenual cingulate volume of the patients with affective disorder who had a family history of affective disorder was smaller than that of patients with affective disorder with no family history of the illness and the normal comparison subjects. Patients with schizophrenia did not differ from comparison subjects in left subgenual cingulate volume. CONCLUSIONS: Left subgenual cingulate abnormalities are present at first hospitalization for psychotic affective disorder in patients who have a family history of affective disorder.

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.

P300 topography differs in schizophrenia and manic psychosis.

BACKGROUND: Overall and left temporal scalp area reductions of P300 have been demonstrated in schizophrenia. P300 amplitude and topography in psychotic affective disorder, a crucial comparison in assessing the specificity of P300 abnormalities to schizophrenia, are not well studied. METHODS: P300 was recorded from 35 schizophrenic, 20 psychotic manic, and 30 control subjects. All were right-handed men. RESULTS: P300 was reduced in both psychotic groups relative to control subjects. Anteroposterior P300 topography differed between patient groups, with schizophrenic subjects showing posterior reduction and bipolar subjects showing anterior reduction. Schizophrenic subjects showed an abnormal asymmetry, with smaller P300 over the left temporal scalp site than the right. Both bipolar and control subjects showed a left greater than right asymmetry. CONCLUSIONS: Widespread auditory P300 reductions were present in schizophrenia and bipolar disorder with psychosis, but subtle topographic differences were present in the two diseases. Although unequivocal knowledge of neural generators cannot be derived from topography alone, differences in topography imply different generator configurations. Based on previous studies, the posterior P300 reductions in schizophrenia may reflect abnormalities of a generator located in the left superior temporal gyrus. The frontal reductions in bipolar psychosis may reflect abnormalities in a hypothetical frontal generator, consonant with reports of altered frontal lobe function in mania.

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.

Multimodal imaging in psychiatry: the electroencephalogram as a complement to other modalities.

The use of different imaging modalities provides the clinician and researcher with different views of anatomy and physiology at unprecedented levels of detail. Multimodal imaging allows for noninvasive measurement of structure and function in humans during complex behavior, and thus provides information about the inner workings of the brain previously unavailable. The present paper examines the various imaging techniques available, and describes their application to the clinic-in the case of epilepsy-and to research-in the case of schizophrenia. Because the electroencephalogram has a dynamic response in milliseconds, it provides the best temporal sensitivity of functional measures of brain activity. When coupled with high-resolution magnetic resonance imaging measures of brain structure, this multimodal approach provides a powerful tool for understanding brain activity. Clinically, the use of multimodal imaging has provided greater precision in localization of the epileptogenic focus. For researchers attempting to determine the underlying causes of schizophrenia, the use of multimodal imaging has helped lead the field away from a specific lesion view to a more distributed system abnormality view of this disorder.

Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects.

OBJECTIVE: Magnetic resonance imaging (MRI) studies of schizophrenic patients have revealed structural brain abnormalities, with low volumes of gray matter in the left posterior superior temporal gyrus and in medial temporal lobe structures. However, the specificity to schizophrenia and the roles of chronic morbidity and neuroleptic treatment in these abnormalities remain unclear. METHOD: Magnetic resonance (1.5-T) scans were obtained from 33 patients with first-episode psychosis and 18 age-matched normal comparison subjects, all right-handed. Sixteen of the patients were diagnosed with affective disorder and 17 with schizophrenia. RESULTS: Quantitative volumetric analysis showed that the patients with first-episode schizophrenia had significantly smaller gray matter volume in the left posterior superior temporal gyrus than did the patients with first-episode affective psychosis or the comparison subjects, with a significant left-less-than-right asymmetry. The schizophrenic patients also showed a smaller gray matter volume of the left posterior amygdala-hippocampal complex than the comparison subjects. Both the patients with schizophrenia and those with affective psychosis had significant left-less-than-right asymmetry of the posterior amygdala-hippocampal complex. CONCLUSIONS: These findings suggest that temporal lobe abnormalities are present at the first hospitalization for schizophrenia and that low volume of the left posterior superior temporal gyrus gray matter is specific to schizophrenia compared with affective disorder.

MRI study of cavum septi pellucidi in schizophrenia, affective disorder, and schizotypal personality disorder.

OBJECTIVE: A cavum between the septi pellucidi may reflect neurodevelopmental anomalies in midline structures of the brain. The authors examined cavum septi pellucidi in subjects with schizophrenia, affective disorder, and schizotypal personality disorder and in normal subjects. METHOD: Thirty schizophrenic patients (15 chronic, 15 first-episode), 16 patients with affective disorder (first-episode), 21 patients with schizotypal personality disorder, and 46 normal subjects were evaluated with magnetic resonance imaging. Cavum septi pellucidi was assessed by counting the number of 1.5-mm slices containing cavum septi pellucidi. RESULTS: The presence or absence of cavum septi pellucidi did not differentiate among groups. However, the prevalence of abnormal cavum septi pellucidi (i.e., cavum septi pellucidi contained on four or more slices) was 30.4% for schizophrenic patients (36.4% for chronic, 25.0% for first-episode), 20.0% for patients with affective disorder, 18.8% for patients with schizotypal personality disorder, and 10.3% for normal subjects. When the authors used the Nopoulos et al. criteria for rating cavum septi pellucidi, which omitted borderline cases with cavum septi pellucidi on three slices, the prevalence of abnormal cavum septi pellucidi increased to 35.0% for schizophrenia (40.0% for chronic, 30.0% for first-episode), 25.0% for affective disorder, 27.3% for schizotypal personality disorder, and 13.0% for normal subjects. There was a statistically significant difference in ratings between schizophrenic and normal subjects. CONCLUSIONS: The results suggest that alterations in midline structures during the course of neurodevelopment may play a role in the pathogenesis of schizophrenia.

First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over left temporal lobe.

BACKGROUND: Schizophrenia is associated with central (sagittal) midline reductions of the P300 cognitive event-related potential and topographic asymmetry of P300, with reduced left temporal voltage. This P300 asymmetry is, in turn, linked to tissue volume asymmetry in the posterior superior temporal gyrus. However, it is unknown whether P300 asymmetry is specific to schizophrenia and whether central and lateral P300 abnormalities are due to chronic morbidity, neuroleptic medication, and/or hospitalization, or whether they are present at the onset of illness. METHODS: P300 was recorded in first-episode schizophrenia, first-episode affective psychosis, and control subjects (n = 14 per group). Subjects silently counted rare (15%) target tones (1.5 kHz) among trains of standard tones (1.0 kHz). Averages were constructed from brain responses to target tones. RESULTS: Peak amplitude of P300 and integrated voltage over 300 to 400 milliseconds were significantly different between first-episode schizophrenics and controls over the posterior sagittal midline of the head. First-episode schizophrenics displayed smaller amplitudes over the left temporal lobe than first-episode affective psychotics and controls, but the groups showed no differences over the right temporal lobe. CONCLUSIONS: Left-sided P300 abnormality in first-episode schizophrenia relative to first-episode affective psychosis and controls suggests that P300 asymmetry is specific to schizophrenic psychosis and present at initial hospitalization. This P300 asymmetry suggests left temporal lobe dysfunction at the onset of schizophrenia.

Topographic abnormalities of P3 in schizotypal personality disorder.

Schizotypy, a schizophrenia spectrum disorder, is of interest because schizotypes share traits with schizophrenics, albeit milder, without potential confounds such as chronic neuroleptic treatment and/or hospitalization. Thus, schizotypy may be particularly useful in exploring biological correlates of an underlying schizophrenic predisposition. The P3 event-related potential, which is aberrant in schizophrenia, was measured in 11 male, right-handed, DSM-III-R-defined schizotypes and 11 matched controls while subjects covertly counted 1.5 kHz target tones (15%) in trains of 1 kHz standard tones. Like schizophrenics, schizotypes displayed an asymmetrical P3, with smaller amplitudes over the left temporal lobe. Unlike schizophrenics, schizotypes were not significantly smaller in P3 amplitude over the sagittal midline of the head, although there was a trend towards reduced amplitudes at central and posterior midline sites. Asymmetry of P3 amplitude, with left-sided deficit, may be associated with the schizophrenia diathesis, but overall P3 reductions may be more associated with chronic effects.

Increased rate of P300 latency prolongation with age in schizophrenia. Electrophysiological evidence for a neurodegenerative process.

BACKGROUND: The latency of the P300 event-related potential is prolonged in disorders associated with neural damage and degeneration and also becomes prolonged in the course of neural changes that accompany aging. We tested whether the rate of P300 latency increase with age was greater in male schizophrenic patients than in normal subjects because a steeper slope in schizophrenia would suggest a progressive neurodegenerative process. We also evaluated a subset of these subjects for changes in brain volumes as determined by magnetic resonance imaging. METHOD: The P300 component was elicited during an auditory "oddball" paradigm and was recorded from 47 male patients with chronic schizophrenia whose mean age at onset was 22.4 years and from 47 age-, handedness-, and gender-matched control subjects. The relation of P300 latency and amplitude to age within each group was evaluated using correlation and regression analyses. Brain volumes determined via magnetic resonance imaging were evaluated by quantitative volumetric analyses of images acquired with three-dimensional Fourier transform and double echo-spin echo-pulse sequences. RESULTS: The slope of P300 latency on age was steeper for schizophrenic patients than for normal control subjects at midline frontal and central electrode sites. The slope of N100 latency did not differ, implying that the P300 differences were not likely to be due to peripheral hearing loss or damage affecting the initial stages of neural processing. Posterior superior temporal gyrus gray matter volume determined via magnetic resonance imaging significantly diminished with age on the left side in patients with schizophrenia but not on the right side or in controls; these slopes were not, however, statistically significantly different from each other. CONCLUSIONS: These findings provide preliminary evidence that male patients with chronic schizophrenia experience a neurodegenerative process that becomes evident in adulthood and is reflected by the rate of change of P300 latency with age. Whether this process is due to the primary effects of schizophrenia or is secondary to factors associated with schizophrenia's chronic course and treatment remains a question for future investigation.

The N2 event-related potential reflects attention deficit in schizophrenia.

Schizophrenia involves deficits in detection and filtering of irrelevant stimuli. The N2 event-related potential (ERP), most likely reflecting classification of deviant stimuli, remains largely unstudied in this group. Recently, we reported that N2 amplitude correlated highly with reduced neocortical and medial temporal lobe volumes in schizophrenics. However, little is known about the functional properties of N2 in schizophrenics. To that end, the latency and amplitude of N2 were assessed in schizophrenic and control subjects to differently pitched tones. Subjects pressed a button in response to low probability (p = .15) target tones interspersed among high probability standard tones. Tones were either NEAR (1.4 kHz standard, 1.5 kHz target) or FAR (1 kHz standard, 1.5 kHz target) in pitch. N2 was measured from difference waveforms, subtracting ERPs on a simple reaction time task (target p = 1.0) from those of the detection task. Schizophrenics performed the detection task nearly as well as controls in the FAR condition, and more poorly in the NEAR condition. Schizophrenics displayed virtually no N2 amplitudes in either condition. The results are interpreted as electrophysiological signs of disturbance in stimulus classification and attention processes in schizophrenia directly related to pathology of N2 neural generators, independent of sensory or detectability problems.