Yoshio Hirayasu

MRI anatomy of schizophrenia.

Structural magnetic resonance imaging (MRI) data have provided much evidence in support of our current view that schizophrenia is a brain disorder with altered brain structure, and consequently involving more than a simple disturbance in neurotransmission. This review surveys 118 peer-reviewed studies with control group from 1987 to May 1998. Most studies (81%) do not find abnormalities of whole brain/intracranial contents, while lateral ventricle enlargement is reported in 77%, and third ventricle enlargement in 67%. The temporal lobe was the brain parenchymal region with the most consistently documented abnormalities. Volume decreases were found in 62% of 37 studies of whole temporal lobe, and in 81% of 16 studies of the superior temporal gyrus (and in 100% with gray matter separately evaluated). Fully 77% of the 30 studies of the medial temporal lobe reported volume reduction in one or more of its constituent structures (hippocampus, amygdala, parahippocampal gyrus). Despite evidence for frontal lobe functional abnormalities, structural MRI investigations less consistently found abnormalities, with 55% describing volume reduction. It may be that frontal lobe volume changes are small, and near the threshold for MRI detection. The parietal and occipital lobes were much less studied; about half of the studies showed positive findings. Most studies of cortical gray matter (86%) found volume reductions were not diffuse, but more pronounced in certain areas. About two thirds of the studies of subcortical structures of thalamus, corpus callosum and basal ganglia (which tend to increase volume with typical neuroleptics), show positive findings, as do almost all (91%) studies of cavum septi pellucidi (CSP). Most data were consistent with a developmental model, but growing evidence was compatible also with progressive, neurodegenerative features, suggesting a two-hit model of schizophrenia, for which a cellular hypothesis is discussed. The relationship of clinical symptoms to MRI findings is reviewed, as is the growing evidence suggesting structural abnormalities differ in affective (bipolar) psychosis and 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.

Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study

Functional and structural abnormalities of the anterior cingulate gyrus (ACG) in patients with schizophrenia have been repeatedly reported. However, one remaining issue is whether gray matter volume reduction in ACG exists to an extent comparable with, or even in excess of, that in other prefrontal and temporolimbic regions. High-spatial-resolution magnetic resonance imaging was performed on patients with schizophrenia (n=27) and on age-, gender-, and parental socioeconomic-status-matched healthy control subjects (n=27). After the gray and white matter were semiautomatically segmented, whole prefrontal and temporal lobes were manually parceled into 15 subregions-by-two hemispheres (30 regions of interest) constituting seven prefrontal gray matter regions, six temporal gray matter regions, the prefrontal white matter, and the temporal white matter. Compared with healthy subjects, schizophrenic patients showed significant gray matter volume reduction in the bilateral ACG, this being the largest effect size (left, 0.84; right, 0.56) among all the regions examined. There were also significant gray matter volume reductions in the bilateral posterior STG, bilateral inferior frontal gyrus, left posterior amygdala-hippocampal complex (mostly hippocampus), and the left insula. These results suggest that gray matter volume reductions in the ACG are prominent among prefrontal and temporolimbic regions in patients with schizophrenia. These findings indicate the importance of ACG abnormalities in the pathophysiology of schizophrenia.

Schizotypal personality disorder and MRI abnormalities of temporal lobe gray matter

BACKGROUNDnStructural 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.nnnMETHODSnTo 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.nnnRESULTSnAs 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.nnnCONCLUSIONSnThese 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

Abstract 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. At the level of anatomical system substrates, considerable MRI data indicate abnormalities in the temporal lobe structures that subserve language and verbal associations. Gray matter volume is reduced in the posterior portion of the dominant superior temporal gyrus in both chronic and first episode schizophrenics (but not in manic-depressive psychosis), with the magnitude of reduction correlating with the degree of thought disorder. At the level of in vitro cellular and molecular analysis, NMDA receptors on inhibitory neurons are much more sensitive to blockade than are excitatory projections. A resulting failure of recurrent inhibition may account for the psychotomimetic effects of such NMDA receptor blockers as ketamine and phencyclidine, and may also be present in schizophrenia, where an endogenous NMDA receptor blocker, NAAG, is increased, and where other abnormalities of recurrent inhibition may be present. A biophysical simulation of this circuit abnormality in a model of learned pattern recognition produced, because of the reduction in recurrent inhibition, aberrant spread of excitation, resulting in confusion of normally distinguishable patterns. We suggest the neural circuit failure of inhibition and consequent aberrant spread of activation may be the substrate for an inability to use context, with the behavioral and functional consequences just described. Furthermore, there is the possibility that the unbalanced excitation might lead to progressive, neurodegenerative changes in gray matter, marked by progressive volume reduction.

Prefrontal cortical thickness in first-episode psychosis: A magnetic resonance imaging study

BACKGROUNDnFindings from postmortem studies suggest reduced prefrontal cortical thickness in schizophrenia; however, cortical thickness in first-episode schizophrenia has not been evaluated using magnetic resonance imaging (MRI).nnnMETHODSnPrefrontal cortical thickness was measured using MRI in first-episode schizophrenia patients (n = 17), first-episode affective psychosis patients (n = 17), and normal control subjects (n = 17); subjects were age-matched within 2 years and within a narrow age range (18-29 years). A previous study using the same subjects reported reduced prefrontal gray matter volume in first-episode schizophrenia. Manual editing was performed on those prefrontal segmentations before cortical thickness was measured.nnnRESULTSnPrefrontal cortical thickness was not significantly different among groups. Prefrontal gray matter volume and thickness were, however, positively correlated in both schizophrenia and control subjects. The product of boundary complexity and thickness, an alternative measure of volume, was positively correlated with volume for all three groups. Finally, age and age at first medication were negatively correlated with prefrontal cortical thickness only in first-episode schizophrenia.nnnCONCLUSIONSnThis study demonstrates the potential usefulness of MRI for the study of cortical thickness abnormalities in schizophrenia. Correlations between cortical thickness and age and between cortical thickness and age at first medication suggest that the longer the schizophrenic process has been operative, the thinner the prefrontal cortex, although this needs confirmation in a longitudinal study.

High-density recording and topographic analysis of the auditory oddball event-related potential in patients with schizophrenia

BACKGROUNDnPrior research has shown reductions of the N1, N2, and P300 auditory event-related potential (ERP) components in schizophrenic patients. Most studies have shown a greater P300 reduction in left versus right temporal leads in schizophrenic patients. These studies were done with sparse electrode arrays, covering restricted areas of the head, thus providing an incomplete representation of the topographic field distribution.nnnMETHODSnWe used a 64-channel montage to acquire auditory oddball ERPs from 24 schizophrenic patients and 24 controls subjects. The N1, P2, N2, P300, and N2 difference (N2d) amplitudes and latencies were tested for group and laterality differences. Component topographies were mapped onto a three-dimensional head model to display the group differences.nnnRESULTSnThe schizophrenic group showed reduction of the N1 component, perhaps reflecting reduced arousal or vigilance, but no N1 topographic difference. An N2d was not apparent in the schizophrenic patients, perhaps reflecting severe disruption in neural systems of stimulus categorization. In the patients, the P300 was smaller over the left temporal lobe sites than the right.nnnCONCLUSIONSnThe increased ERP spatial sampling allowed a more complete representation of the dipolar nature of the P300, which showed field contours consistent with neural sources in the posterior superior temporal plane.

Sex effects on rate of change of P300 latency with age

OBJECTIVEnRecent MRI evidence suggests that neuroanatomic structures may change more rapidly with age in males compared with females. Sex differences for P300 latency were tested to determine whether similar results might appear for P300 latency, a neurophysiological measure sensitive to age and neurodegenerative processes.nnnMETHODSnAuditory event related potentials (ERPs) were recorded using an auditory oddball to elicit the N200 and P300 components. Forty-two male and 42 female healthy normal subjects (age range 15-85 years) were entered in this study. Both linear and curvilinear correlations of N200 and P300 latency/amplitude with age were tested.nnnRESULTSnThe slope of P300 latency on age for males was steeper than for females at Pz in subjects who were 30 years of age and older. N200 and P300 latencies were inversely correlated with age in young adult males (<30 years old).nnnCONCLUSIONSnMales may experience more rapid change of P300 latency, but not amplitude, than females in middle to old age. Further research is required to determine whether those change reflects neural pathophysiology, or is mediated by such factors as neuroanatomic differences, body temperature, or mild auditory deficits.

Update on Electrophysiology in Schizophrenia

Event-related potentials (ERPs) provide a non-invasive, functional method to evaluate neural activation and cognitive processes in schizophrenia, with a temporal resolution in the millisecond range, literally at the speed of thought. Auditory ERP components tested in schizophrenia, in order of latency of occurrence, include the P50 sensory gating response, the mismatch negativity, P300, and the N400 component. Abnormalities in these components demonstrate pervasive disruption of auditory processing as early as 50 milliseconds after stimulus onset. All of these abnormalities appear to tasks which require sensory memory or working memory operations. The anatomic substrates for these ERP components probably include the posterior superior temporal gyrus and medial temporal lobe structures. P300 topographic asymmetries have been associated with left posterior superior temporal gyrus abnormalities. Future work will focus on relating ERP abnormalities to specific neural circuit disturbances in this disorder.

The assessment of cognitive function in a Williams syndrome patient: A case report

Williams syndrome (WMS) is a rare metabolic disease characterized by vascular disorder, mental retardation and hypersociability. Cognitive deficits have been reported in WMS including those of dissociation between language, a strong ability for face processing and weakness in spatial cognition. 1 We assessed the neuropsychological ability of a patient with WMS and found interesting cognitive aspects in regard to WMS. A 19-year-old Japanese woman presented to the Department of Neuropsychiatry, Kyorin University Hospital, Mitaka, Japan for psychiatric assessment. She had been admitted to the Department of Endocrinology for evaluation of hypertension, hyperglycemia, and amenorrhea. Her amenorrhea was due to hypothalamic disturbance as suggested by a gonadotropin releasing hormone-loading test. Her hyperglycemia was due to type I diabetes mellitus, and her hypertension was thought to be caused by stenosis of large blood vessels, which was confirmed by magnetic resonance angiography. She weighted 2030 g when delivered by cesarean section and was found to have supravalvar aortic stenosis as a neonate. A deletion of the 7q11.23 region on chromosome 7 was shown by fluorescent in situ hybridization analysis at age 11. The patient had several minor physical anomalies including a broad nasal bridge, epicanthus, and brachydactyly. Head magnetic resonance imaging was normal. Neuropsychological functions were assessed by various tests. Test scores were Wechsler Adult Intelligence Scale-Revised (WAIS-R): verbal IQ (VIQ) 63, performance IQ (PIQ) 48, total IQ 50 with low scores for similarities (2, average 4.1) and block design (1, average 3.6); Wechsler Memory Scale-Revised (WMS-R): verbal memory 53, with visual memory, total memory and attention scores all out of range (below 50); Wisconsin Card Sorting Test-Keio version (KWCST) for assessment of executive function: achievement category 3, Nelson-type perseveration 18; Gambling Task 2 (GT) for assessment of reasoning and decision-making in the future: good deck 54, bad deck 46; Frontal Assessment Battery 3 (FAB): similarity test (conceptualization) 0/3, with perfect scores on the other tasks. The results of WAIS-R indicated a low IQ and inconsistency between VIQ and PIQ. The score for each task varied widely. Although the score for the block design was low, the digit span score (6, average 4.1) was high. These inconsistencies in cognitive abilities are typical in WMS patients and also relate to the discrepancy between verbal memory and visual memory shown by the patient’s WMS-R scores. In this patient, logical memory score (7/50) was worse than the verbal paired associates score (14/24). Both the FAB and WAISR tests showed that conceptualization was impaired. Executive function was also slightly disturbed. Reasoning and decision-making were as indicated by the GT scores. These findings suggest that WMS patients have both strengths and weaknesses in frontal lobe function, not only in language but also in spatial cognition. Evaluations of frontal lobe tasks may not reflect exactly the higher cerebral function in patient’s with low IQ. Further case studies could help to understand frontal lobe function in WMS patients.