Childhood neglect predicts disorganization in schizophrenia through grey matter decrease in dorsolateral prefrontal cortex.

OBJECTIVE: Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms. METHOD: Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry (VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis. RESULTS: Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex (DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score. CONCLUSION: Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC.

Cortical surface complexity in frontal and temporal areas varies across subgroups of schizophrenia.

Schizophrenia is assumed to be a neurodevelopmental disorder, which might involve disturbed development of the cerebral cortex, especially in frontal and medial temporal areas. Based on a novel spherical harmonics approach to measuring complexity of cortical folding, we applied a measure based on fractal dimension (FD) to investigate the heterogeneity of regional cortical surface abnormalities across subgroups of schizophrenia defined by symptom profiles. A sample of 87 patients with DSM-IV schizophrenia was divided into three subgroups (based on symptom profiles) with predominantly negative (n = 31), disorganized (n = 23), and paranoid (n = 33) symptoms and each compared to 108 matched healthy controls. While global FD measures were reduced in the right hemisphere of the negative and paranoid subgroups, regional analysis revealed marked heterogeneity of regional FD alterations. The negative subgroup showed most prominent reductions in left anterior cingulate, superior frontal, frontopolar, as well as right superior frontal and superior parietal cortices. The disorganized subgroup showed reductions in bilateral ventrolateral/orbitofrontal cortices, and several increases in the left hemisphere, including inferior parietal, middle temporal, and midcingulate areas. The paranoid subgroup showed only few changes, including decreases in the right superior parietal and left fusiform region, and increase in the left posterior cingulate cortex. Our findings suggest regional heterogeneity of cortical folding complexity, which might be related to biological subgroups of schizophrenia with differing degrees of altered cortical developmental pathology.

Symptom dimensions are associated with progressive brain volume changes in schizophrenia.

BACKGROUND: There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression). METHODS: Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders. RESULTS: In patients, the disorganization dimension was associated with change in total brain (ß=-0.295, p=0.003) and cerebellar (ß=-0.349, p<0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes. CONCLUSION: Heterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies.

Aging effects on regional brain structural changes in schizophrenia.

BACKGROUND: Although mostly conceptualized as a neurodevelopmental disorder, there is an increasing interest in progressive changes of cognitive deficits and brain structure and function in schizophrenia across the life span. METHODS: In this study, we investigated age-related changes in regional gray matter using voxel-based morphometry in a sample of 99 patients (age range 18-65 years) with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia and 113 healthy controls (age range 19-59 years) using a cross-sectional design. RESULTS: We found steeper age-related decline in gray matter in patients in a cluster comprising the left superior temporal cortex and adjacent inferior parietal lobule. We then divided the schizophrenia sample in 3 subgroups based on a 3-factor model of psychopathology ratings. Age-related changes were markedly different in each of the 3 subgroups (compared with healthy controls). While patients with predominantly paranoid symptoms showed stronger age-related progression in the left superior temporal cortex and right inferior frontal gyrus, those of the disorganized subgroup had stronger gray matter loss in the left lateral cerebellum, while the predominantly negative subgroup showed minor effects in the left superior temporal gyrus. CONCLUSIONS: Our findings show that differences in brain structural changes associated with aging diverge between schizophrenia patients and healthy subjects and that different subgroups within a patient sample might be at higher risk of age-related regional gray matter loss.

Distinct pattern of brain structural deficits in subsyndromes of schizophrenia delineated by psychopathology.

Brain morphological changes are among the best-studied potential endophenotypes in schizophrenia and linked to genetic liability and expression of disease phenotype. Yet, there is considerable heterogeneity across individual subjects making its use as a disease-specific marker difficult. In this study we consider psychopathological variability of disease phenotype to delineate subsyndromes of schizophrenia, link them to distinct brain morphological patterns, and use a classification approach to test specificity of achieved discrimination. We first applied voxel-based morphometry (VBM) to compare 99 patients with DSM-IV schizophrenia (stable psychopathology and antipsychotic medication) with 113 matched healthy controls, then delineated three subgroups within the patient cohort based on psychopathology pattern and compared differential patterns of grey matter abnormalities. Finally, we tested accuracy of assigning any individual MRI scan to either the control group or any of the three patient subgroups. While VBM analysis showed overlap of brain structural deficits mostly in prefrontal areas, the disorganised subsyndrome showed stronger deficits in medial temporal and cerebellar regions, the paranoid/hallucinatory subsyndrome showed additional effects in the superior temporal cortex, and the negative subsyndrome showed stronger deficits in the thalamus. Using an automated algorithm, we achieved 95.8% accuracy classifying any given scan to one of the subgroups. Patterns of psychopathology are meaningful parameters in reducing heterogeneity of brain morphological endophenotypes in schizophrenia.

Hippocampal pathology in two mentally ill paraphiliacs.

Paraphilias or disorders of sexual behavior have markedly increased in prevalence during the last decade. Until now no published neuropathological studies on paraphilia have appeared in the medical literature. A computerized search was done on all available medical and autopsy records of a large urban hospital (St. Elizabeths Hospital, Washington, DC) for any mention of deviant sexual behavior. Cases were then reviewed for presence of a history consistent with DSM-IV diagnoses of paraphilia. Two such cases were identified. Neuropathological examination in both cases revealed simple cell atrophy of pyramidal cells confined to different hippocampal subfields. Reactive astrocytosis was present in the outer strata of the affected regions. The pathological changes in the hippocampus resemble those reported after persistent stress or long-term chronic glucocorticoid administration. The accompanying astrocytosis indicates a reactive, ongoing process. The findings suggest new therapeutic interventions in the treatment of paraphilia.

Cell-type specific alterations of cortical interneurons in schizophrenic patients.

In the human brain, cortical GABAergic interneurons represent an important population of local circuit neurons responsible for the intrinsic modulation of neuronal information and have been supposed to be involved in the pathophysiology of schizophrenia. We conducted a quantitative study on the differentiated three-dimensional morphological structure of two types of parvalbumin-immunoreactive interneurons in the anterior cingulate cortex (ACC) of schizophrenic patients versus controls. While type A interneurons ('small bipolar cells') showed a significant reduction of their soma size in schizophrenics, type B interneurons ('small multipolar cells') of schizophrenic patients exhibited a marked decrease in the extent of their dendritic system. These results further support the assumption of a considerable significance of the ACC, an important limbic relay centre, for the etiopathogenesis of schizophrenic psychoses.

Prevalencia de algunos trastornos mentales espefíficos en cuatro comunidades rurales en Trujillo, Venezuela / Prevalence of some specific mental dysfunctions in four rural communities in Trujillo, Venezuela

El presente trabajo consta de dos partes: 1) se realizó un estudio de validez sobre el diagnóstico clínico, de una versión en español del "Diagnóstic Interview Schedule" (DIS), adaptado a los criterios diagnósticos del DSM-III para calificar los siguientes trastornos mentales: dependencia de tabaco, abuso a dependencia de alcohol, abuso o dependencia de drogas, depresión mayor, manía y esquizofrenia; 2) usando este instrumento diagnóstico se entrevistaron 599 sujetos adultos residentes en 4 comunidades rurales del Estado Trujillo, y se determinó la prevalencia de esos trastornos mentales. Los valores índice kappa (como indicador de la validez del DIS) fueron excelentes para "dependencia de tabaco" (0.84), "abuso de alcohol" (0.95), "dependencia de alcohol" (0.84), "abuso de drogas" (0.89) y "dependencia de drogas" (0.92). Los índices kappa fueron aceptables para "depresión mayor" (0.66) y esquizofrenia (0.57; y fueron bajos para "manía" (0.31). La prevalencia de por vida de los trastornos evaluados fue de 14.3 por ciento para "dependencia de tabaco", de 15.3 por ciento para abuso de alcohol", de 7.1 por ciento para "dependencia de alcohol", de 2 por ciento para "depresión mayor", de 1.8 por ciento para "manía y de 1.1 por ciento para esquizofrenia". No se detectaron sujetos con abuso o dependencia de drogas. Los resultados demuestran que en nuestro medio la validez del DIS no es uniforme para diagnósticar los diversos trastornos evaluados. Los valores de prevalencia de abuso y dependencia de alcohol en hombres y de abuso en mujeres fueron mayores que los encontrados en la población urbana de Puerto Rico en los que también se emplearon los criterios del DIS. La prevalencia de depresión mayor fue menor que la encontrada en la población general de los Estados Unidos y de Puerto Rico. Se recomienda ampliar a otros diagnósticos el estudio de validez del DIS (u otro instrumento relacionado como el CIDI) y realizar un estudio nacional de prevalencia de enfermedades...

Cortical sulcal enlargement in catatonic schizophrenia: a planimetric CT study.

To determine whether patients with catatonic schizophrenia have specific alterations in brain morphology, internal (ventricles) and external (frontal, temporal, parieto-occipital) components of the cerebrospinal fluid (CSF) spaces were examined morphometrically. Planimetric measurements of computed tomographic (CT) scans from 37 patients with catatonic schizophrenia, 28 patients with hebephrenic schizophrenia, and 39 patients with paranoid schizophrenia, all diagnosed according to DSM-III-R criteria, were compared with separate age- and sex-matched non-psychiatric control groups, respectively. The areas of the frontal sulci, the parieto-occipital sulci, the inter-hemispheric fissure, and the lateral and third ventricles were measured separately for the right and left hemispheres. Catatonic patients showed significant enlargements in almost all CSF spaces, especially in the left fronto-temporal area which, in addition, correlated significantly with illness duration. Hebephrenic patients showed selective enlargements in left temporal and left/right lower frontal cortical sulci, whereas paranoid schizophrenic patients showed no enlargements but significant correlations between left temporal cortical sulcal volume and illness duration. Alterations in temporal cortical areas were present in all three sub-types of schizophrenia. In addition to temporal alterations, hebephrenic schizophrenia was characterised by lower frontal (i.e. orbitofrontal) enlargement. Catatonic schizophrenia, the most severe sub-type with regard to clinical symptomatology and brain pathology, showed fronto-parietal cortical alterations.

Multiple sclerosis presenting as chronic atypical psychosis.

Two patients with multiple sclerosis are reported in whom psychopathological symptoms were present for many years. An exact psychiatric classification of the clinical syndrome was not possible. At no time during the illness were abnormal neurological findings observed. Multiple sclerosis was proven following necropsy in one patient. In the second patient a possible diagnosis of multiple sclerosis was made. This patient was found to have multiple lesions in the white matter which were evident on MRI and in the isoelectric focusing (IEF) of cerebrospinal fluid oligoclonal bands were found.

Regional brain glucose metabolism in drug free schizophrenic patients and clinical correlates.

Regional brain glucose metabolism was investigated in healthy volunteers (n = 10) and in drug free schizophrenic patients (n = 20). The metabolism was determined by positron emission tomography (PET) with 11C-glucose as the tracer. Diagnosis of schizophrenia was made according to RDC and DSM III. Eight patients had their first psychotic episode, four patients had a subchronic course and eight patients had a chronic course with an exacerbation of their illness. Computed tomography (CT) of the brain were made in all the subjects. Regions of interest (n = 35) were drawn on displayed CT images and the marked regions were transferred to the corresponding slice of the PET examination. The PET investigation was made in a dimly lit, quiet room with the eyes of the subject covered. The time course of the 11C-glucose uptake was measured by a four ring PET scanner (PC-384-7B). Metabolic rates of glucose varied greatly among the schizophrenic patients investigated. The variance was significantly greater than that of the controls in most regions. Decreases in mean levels of metabolic rates were related to patients with subchronic or chronic courses. Changes in metabolism were not related to previous duration of neuroleptic treatment of the patients. Left-right asymmetries were found in the temporal lobe (area 22) and the basal frontal cortex (area 11), the metabolic rates of the patients being lower on the left side compared to the controls. Asymmetry of the metabolic rate of the amygdala in hebephrenic patients was the opposite of that found in paranoid patients and controls. Negative correlations between regional metabolic rates and autistic or negative symptoms were found. Thus, the lower the metabolic rate was, the more autistic the patient. Metabolic rates were not correlated to atrophic changes of the brain. No basis for a specific alteration in frontal cortical metabolism of schizophrenics was obtained. Changes in regional metabolic rates in schizophrenia are suggested to reflect disturbances in more general mechanisms which are of importance in neuronal function.

Hippocampal pyramidal cell orientation in schizophrenia. A controlled neurohistologic study of the Yakovlev collection.

The finding of marked disorganization of the hippocampal pyramidal cell layer in the brains of schizophrenic patients has recently been reported. The present study was undertaken to determine whether similar abnormalities could be found in the brains of a population of schizophrenic patients, most of whom were never exposed to neuroleptics. Though statistical analysis of 2808 pyramidal cells failed to reveal significantly greater disorganization in a group of seven alleged schizophrenic brains than in brains of age-matched, nonpsychotic controls, the data suggest a relationship between the degree of pyramidal cell disarray and the severity of behavioral impairment due to psychosis. The implications and pitfalls in interpreting these findings are discussed.

Clinical correlates of septum pellucidum cavities: an unusual association with psychosis.

Cavities in the septum pellucidum are widely regarded as incidental findings of little clinical importance. The prevalence of such cava on computerized tomography in a mixed sample of 22000 neurological and psychiatric patients is found to be 0.15%. A statistical association between this anomaly and a referral diagnosis of functional psychosis is reported, and 6 cases are described. These cases were male and characterized by an early history of developmental delay, with lifelong disturbances of emotion and behaviour prior to the onset in early adulthood of an atypical schizophrenia-like psychosis with disorders of speech and movement. It is suggested that septal cavities may signal an underlying abnormality of function relevant to the pathogenesis of these illnesses.

Differences in lateral brain ventricular size among various types of chronic schizophrenics. Evidence based on a CT study.

Data from a previous study of ours, based on computerised tomography of the brain in 70 chronic schizophrenics, indicated that a severe degree of lateral brain enlargement was present in a great proportion. No correlation was found between lateral ventricular enlargement and age of patients, length of illness, duration of hospitalization or ECT treatment. In order to elucidate whether other factors (e.g. type of disease) are likely to correlate with the enlargement we divided these patients into three subgroups: hebephrenics, paranoids and undifferentiated. Comparison of the mean values of ventricular brain ratio (VBR) of the above groups showed that paranoids presented a statistically greater enlargement than hebephrenics. There was no statistically significant difference between undifferentiated and hebephrenics. The difference between undifferentiated and paranoids approached statistical significance. This study provides evidence that there exists a difference between the types of schizophrenia in CT images, a finding that may suggest different degrees of underlying disease process.

Cerebral ventricular enlargement in subtypes of chronic schizophrenia.

A computed tomographic study of the brain in 55 young men with chronic schizophrenia and 27 age- and sex-matched control subjects showed a significantly higher ventricle-brain ratio (VBR) in the patients with chronic schizophrenia. Using the Tsuang-Winokur criteria, the sample was classified into paranoid and nonparanoid-hebephrenic subtypes. Nonparanoid patients who did not fulfill the criteria for hebephrenia were grouped as a nonparanoid-undifferentiated subtype. All three groups of subtypes had a significantly higher mean VBR than control subjects. Among the schizophrenia subtypes, the paranoid and nonparanoid-hebephrenic groups were not different, and both had a significantly larger mean VBR than the nonparanoid-undifferentiated group. The results suggest that although the extent of ventricular enlargement varies among schizophrenia subtypes, they all show a significant enlargement compared with the control group. Also, in contrast with previous reports linking a high VBR with negative symptoms, poor prognosis, and impaired cognition, the data in this study show the largest mean VBR in the paranoid patients who generally have a good premorbid history, positive symptoms, less impaired cognition, and relatively better prognosis.