Ventricular Enlargement In Schizophrenia Research Articles

Regional Differences in Human Ependymal and Subventricular Zone Cytoarchitecture Are Unchanged in Neuropsychiatric Disease

Much work has focused on the possible contribution of adult hippocampal neurogenesis to neuropsychiatric diseases. The hippocampal subgranular zone and the other stem cell-containing neurogenic niche, the subventricular zone (SVZ), share several cytological features and are regulated by some of the same molecular mechanisms. However, very little is known about the SVZ in neuropsychiatric disorders. This is important since it surrounds the lateral ventricles and in schizophrenia ventricular enlargement frequently follows forebrain nuclei shrinkage. Also, adult neurogenesis has been implicated in pharmacotherapy for affective disorders and many of the molecules associated with neuropsychiatric disorders affect SVZ biology. To assess the neurogenic niche, we examined material from 60 humans (Stanley Collection) and characterized the cytoarchitecture of the SVZ and ependymal layer in age-, sex- and post mortem interval-matched controls, and patients diagnosed with schizophrenia, bipolar illness, and depression (n = 15 each). There is a paucity of post mortem brains available for study in these diseases, so to maximize the number of possible parameters examined here, we quantified individual sections rather than a large series. Previous work showed that multiple sclerosis is associated with increased width of the hypocellular gap, a cell-sparse region that typifies the human SVZ. Statistically there were no differences between disease groups and controls in the width of the hypocellular gap or in the density of cells in the hypocellular gap. Because ventricular enlargement in schizophrenia may disrupt ependymal cells, we quantified them, but observed no difference between diagnostic groups and controls. There are significant differences in the prevalence of neuropsychiatric illness between the sexes. Therefore, we looked for male versus female differences, but did not observe any in the parameters quantified. We next turned to a finer spatial resolution and asked if there were differences amongst the disease groups in dorsal ventral subdivisions of the SVZ. Similar to when we treated the SVZ as a whole, we did not find such differences. However, compared to the dorsal SVZ, the ventral SVZ had a wider hypocellular gap and more ependymal cells in all four groups. In contrast, cell density was similar in dorsal ventral subregions of the SVZ hypocellular gap. These results show that though there are regional differences in the SVZ in humans, neuropsychiatric disorders do not seem to alter several fundamental histological features of this adult neurogenic zone.

Can PET/CT imaging advance our understanding of the neurobiology of schizophrenia?

Schizophrenia is a severe psychiatric disorder affecting approximately 1% of the population worldwide. The disorder is ranked among the top 10 causes of disability worldwide. New drugs and therapeutic interventions are therefore warranted to reduce symptomatology, delay onset, or potentially cure this devastating disorder. This would greatly help individuals in the early stages of schizophrenia. Although schizophrenia has a strong genetic basis (80%), owing to the nature of the neurobiological and genetic heterogeneity of the disorder, its a etiology has remained elusive. Schizophrenia is characterized by psychotic symptoms, emotional disturbances, and cognitive dysfunction. These symptoms may be the result of dopamine dysregulation in individuals with schizophrenia [1]. Advances in anatomical and functional imaging have provided useful insights into the neurobiological mechanisms of schizophrenia, enabling brain function to be studied at a molecular level. Recent imaging investigations using computed tomography (CT) and magnetic resonance imaging (MRI) have reported grey matter reduction and ventricular enlargement in schizophrenia [2], and functional MRI studies have reported abnormalities in the frontotemporal and frontoparietal function regions. Diffusion tensor imaging is used to provide an insight into white matter tract integrity and regional cerebral connectivity. Recent studies show abnormalities in frontoparietal and left cerebellar white matter tract integrity in schizophrenia [3]. Positron emission tomography (PET) is an effective functional imaging technique that uses radioactive tracers to help identify regions associated with brain function. It has been used to detect levels of dopaminergic activity in individuals with major psychiatric disorders. The most consistent findings from adult-onset schizophrenia studies are differences in dopaminergic content in the prefrontal cortex (PFC), anterior cingulate gyrus, and hippocampus between normal controls and patients with schizophrenia. Several PET tracers have been used to identify brain

PL.03 The schizophrenia paradigm: a hundred-year challenge

After more than 100 years of research, the neuropathology of schizophrenia remains unknown and this is despite the fact that both Kraepelin (1919/1971: Kraepelin, E., 1919/1971. Dementia praecox. Churchill Livingston Inc., New York) and Bleuler (1911/1950: Bleuler, E., 1911/1950. Dementia praecox or the group of schizophrenias. International Universities Press, New York), who first described ‘dementia praecox’ and the ‘schizophrenias’, were convinced that schizophrenia would ultimately be linked to an organic brain disorder. Alzheimer (1897: Alzheimer, A., 1897. Beitrage zur pathologischen anatomie der hirnrinde und zur anatomischen grundlage einiger psychosen. Monatsschrift fur Psychiarie und Neurologie. 2, 82–120) was the first to investigate the neuropathology of schizophrenia, though he went on to study more tractable brain diseases. The results of subsequent neuropathological studies were disappointing because of conflicting findings. Research interest thus waned and did not flourish again until 1976, following the pivotal computer assisted tomography (CT) finding of lateral ventricular enlargement in schizophrenia by Johnstone and colleagues. Since that time significant progress has been made in brain imaging, particularly with the advent of magnetic resonance imaging (MRI), beginning with the first MRI study of schizophrenia by Smith and coworkers in 1984 (Smith, R.C., Calderon, M., Ravichandran, G.K., et al. (1984). Nuclear magnetic resonance in schizophrenia: A preliminary study. Psychiatry Res. 12, 137–147). MR in vivo imaging of the brain now confirms brain abnormalities in schizophrenia.The 193 peer reviewed MRI studies reported in the current review span the period from 1988 to August, 2000. This 12 year period has witnessed a burgeoning of MRI studies and has led to more definitive findings of brain abnormalities in schizophrenia than any other time period in the history of schizophrenia research. Such progress in defining the neuropathology of schizophrenia is largely due to advances in in vivo MRI techniques. These advances have now led to the identification of a number of brain abnormalities in schizophrenia. Some of these abnormalities confirm earlier post-mortem findings, and most are small and subtle, rather than large, thus necessitating more advanced and accurate measurement tools. These findings include ventricular enlargement (80% of studies reviewed) and third ventricle enlargement (73% of studies reviewed). There is also preferential involvement of medial temporal lobe structures (74% of studies reviewed), which include the amygdala, hippocampus, and parahippocampal gyrus, and neocortical temporal lobe regions (superior temporal gyrus) (100% of studies reviewed). When gray and white matter of superior temporal gyrus was combined, 67% of studies reported abnormalities. There was also moderate evidence for frontal lobe abnormalities (59% of studies reviewed), particularly prefrontal gray matter and orbitofrontal regions. Similarly, there was moderate evidence for parietal lobe abnormalities (60% of studies reviewed), particularly of the inferior parietal lobule which includes both supramarginal and angular gyri. Additionally, there was strong to moderate evidence for subcortical abnormalities (i.e. cavum septi pellucidi—92% of studies reviewed, basal ganglia—68% of studies reviewed, corpus callosum—63% of studies reviewed, and thalamus—42% of studies reviewed), but more equivocal evidence for cerebellar abnormalities (31% of studies reviewed).The timing of such abnormalities has not yet been determined, although many are evident when a patient first becomes symptomatic. There is, however, also evidence that a subset of brain abnormalities may change over the course of the illness. The most parsimonious explanation is that some brain abnormalities are neurodevelopmental in origin but unfold later in development, thus setting the stage for the development of the symptoms of schizophrenia. Or there may be additional factors, such as stress or neurotoxicity, that occur during adolescence or early adulthood and are necessary for the development of schizophrenia, and may be associated with neurodegenerative changes. Importantly, as several different brain regions are involved in the neuropathology of schizophrenia, new models need to be developed and tested that explain neural circuitry abnormalities effecting brain regions not necessarily structurally proximal to each other but nonetheless functionally interrelated.Future studies will likely benefit from: (1) studying more homogeneous patient groups so that the relationship between MRI findings and clinical symptoms become more meaningful; (2) studying at risk populations such as family members of patients diagnosed with schizophrenia and subjects diagnosed with schizotypal personality disorder in order to define which abnormalities are specific to schizophrenia spectrum disorders, which are the result of epiphenomena such as medication effects and chronic institutionalization, and which are needed for the development of frank psychosis; (3) examining shape differences not detectable from measuring volume alone; (4) applying newer methods such as diffusion tensor imaging to investigate abnormalities in brain connectivity and white matter fiber tracts; and, (5) using methods that analyze brain function (fMRI) and structure simultaneously.

Ventricular enlargement in schizophrenia is associated with a genetic polymorphism at the interleukin-1 receptor antagonist gene

Magnetic resonance imaging (MRI) studies have shown some morphological and volumetric peculiarities in brains of schizophrenic patients. The authors explored the influence of genetic polymorphisms at interleukin-1β (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) genes on these abnormalities. Hippocampus, lateral ventricles, and dorsolateral prefrontal cortex gray matter volumes were measured in a sample of 23 DSM-IV diagnosed schizophrenic patients of Spanish origin using MRI scans; MRI data were adjusted for age and brain volume using regression parameters from a healthy control group ( n = 45). IL-1B and IL-1RN genes, involved in neurodevelopment and neurodegenerative processes, were analyzed in the patient sample. Patients carrying VNTR-allele*2 of IL-1RN gene showed a significant enlargement of both left ( P = 0.002) and right ( P = 0.01) ventricles. Sex and illness duration were controlled for in the analyses. Our results, though preliminary, suggest that IL-1RN gene might contribute to the ventricular volumetric changes observed in schizophrenic patients.

Ventricular enlargement in schizophrenia related to volume reduction of the thalamus, striatum, and superior temporal cortex.

Enlargement of the lateral ventricles is among the most frequently reported macroscopic brain structural changes in schizophrenia, although variable in extent and localization. The authors investigated whether ventricular enlargement is related to regionally specific volume loss. High-resolution magnetic resonance imaging scans from 39 patients with schizophrenia were analyzed with deformation-based morphometry, a voxel-wise whole brain morphometric technique. Significant negative correlations with the ventricle-brain ratio were found for voxels in the left and right thalamus and posterior putamen and in the left superior temporal gyrus and insula. Thalamic shrinkage, especially of medial nuclei and the adjacent striatum and insular cortex, appear to be important contributors to ventricular enlargement in schizophrenia.

Cerebral ventricular enlargement as a generalized feature of schizophrenia: a distribution analysis on 502 subjects

Enlargement of cerebral ventricles is one of the most replicated biological features, and the one quantitatively most deviant in schizophrenia. It occurs in the early phases of the disease and may have pathogenetic relevance. Whether this abnormality is limited to a specific subgroup of patients or is a common feature to most or all patients affected by schizophrenia, however, is still a matter of debate. The answer to this question would improve our comprehension of the nature of this abnormality and contribute to the debate between the competing hypotheses of biological homogeneity vs heterogeneity of schizophrenia. We performed a distribution analysis of lateral ventricular dimensions of 340 schizophrenic patients and 162 non-psychiatric controls. All subjects underwent cerebral computerized tomographic scan, and ventricular dimensions were expressed as ventricular brain ratio (VBR). After removing the effect of confounding variables (age, sex and type of scanner) on individual VBR, data were power-transformed and different distribution hypotheses were tested by means of the maximum log-likelihood ratio method. Our findings indicate that, in the mixed sample of patients and controls, a mixture of two gaussian curves represents the distribution better than a single gaussian curve, but no evidence emerged leading to rejection of the normality hypothesis in the schizophrenic patients sample. Lateral ventricular enlargement in schizophrenia is not a marker of a discrete subgroup of schizophrenia, but occurs in most, if not all, schizophrenic patients. This supports the hypothesis of biological homogeneity of the disease, at least relative to its major brain morphological abnormality.

163. Third ventricle enlargement and developmental delay in first episode schizophrenia

Enlargement of the lateral ventricles provides the most consistent evidence of structural brain abnormality in schizophrenia. The third ventricle has been studied to a lesser extent. The causes, effects, timing and course of ventricular pathology remain unclear. Establishing the processes underlying ventricular enlargement in schizophrenia will contribute to unraveling it’s aetiology. Detailed information on childhood development was collected from the mothers of 21 patients experiencing their first episode of schizophrenia, schizoaffective disorder or schizophreniform psychosis. T1-weighted images were obtained in 1.5 mm contiguous sections for the whole brain in the axial plane. Volumes were calculated for ventricular CSF, whole brain, prefrontal, premotor, sensorimotor, occipitoparietal regions including grey matter. There was a significant correlation between third ventricle volume and developmental score (r = 0.709, p < 0.0001). 7 patients with developmental delay had significantly larger third and lateral ventricles than the 14 without. The groups were comparable for age, gender, height, handedness, education and socio-economic status. There were no other differences in whole brain volume adjusted measures between the groups. Patients with first episode schizophrenia with a history of developmental delay have larger ventricles. The presence of developmental delay may discriminate between ventricular pathology and other structural abnormality in schizophrenia. These findings are in keeping with a developmental model of schizophrenia.

Lateral ventricular enlargement in schizophrenic probands and their siblings with schizophrenia-related isorders

To investigate possible genetic determinants of ventricular enlargement in schizophrenia, we compared lateral ventricle/brain ratios (VBRs) in schizophrenic patients with their own siblings, some with and some without other schizophrenia-related disorders [e.g., schizotypal personality disorder (SPD)], as well as with a group of unrelated normal controls. VBRs, measured by computed tomography, were compared in both groupwise and within-sibship analyses, the latter method providing a measure of control over familial/genetic factors related to VBR, but unrelated to schizophrenia. The VBRs were significantly different across the groups, but the only significant pairwise group comparison was between the schizophrenia and no-SRD family member groups. In the within-sibship analyses, however, the VBRs of those with SPD and schizophrenia were similar, and both groups had significantly larger VBRs than their own siblings without SRD. In addition, siblings with a negative family history for SRD had larger VBRs than family history positive siblings. The results suggest that specific schizophrenia-related genetic factors may help determine ventricular enlargement in familial schizophrenia. The larger VBRs in family history negative siblings might be attributable to genetic factors not specifically associated with schizophrenia, but which nevertheless increase its susceptibility.

Ventricular Enlargement and Poor Prognosis of Schizophrenia Revisited

Results of longitudinal studies have differed about whether ventricular enlargement in schizophrenia is static or progressive. This prospective comparison of male schizophrenic patients, 22 with sustained symptoms and inability to function independently (Kraepelinian group), 31 with better outcomes (non-Kraepelinian group), and 13 male controls suggests …

Time course of cerebral ventricular enlargement in schizophrenia supports the hypothesis of its neurodevelopmental nature

In the absence of direct and conclusive data demonstrating the ‘neurodevelopmental hypothesis’ of schizophrenia, several neuromorphological findings provide relevant clues in support of it. In this paper, we review a number of results obtained by our group in this area of research. In particular, the demonstration of stability of cerebral ventricular dimensions both in chronic schizophrenia and around the onset of the disease, and that of an identical effect of ageing on this morphological feature in large samples of patients and controls, strongly support the neurodevelopmental nature of brain pathomorphology in schizophrenia.

Ventricular Volumes In Patients With Temporal Lobe Epilepsy And Psychosis

A similar neuropathology could be one reason for the similarities of the psychosis in patients with temporal lobe epilepsy (TLE) to schizophrenia. We investigated whether these two patient groups show comparable increases of ventricular volumes indicating a common neuropathology differentiating them from non-psychotic patients with TLE and from normal controls. The volumes of the lateral ventricles of 9 patients with TLE and psychosis were measured on high resolution MRI brain scans and compared to the corresponding values of 9 patients with TLE and no psychosis, 9 schizophrenics and 9 normal controls, matched on age, sex and duration of epilepsy, respectively. The schizophrenic patients showed significantly larger volumes than the normal controls, while the values of both TLE groups lay in between, neither significantly different from each other nor from the two other groups. We found no evidence that patients with TLE and psychosis show an increase of ventricular volumes similar to the one observed in schizophrenic patients. In so far as the neuropathology underlying ventricular enlargement in schizophrenia is related to psychopathology, this study does not support the notion that schizophrenia-like symptoms in patients with TLE are based on a similar neuropathology.

Ventricular volumes in patients with temporal lobe epilepsy and psychosis

A similar neuropathology could be one reason for the similarities of the psychosis in patients with temporal lobe epilepsy (TLE) to schizophrenia. We investigated whether these two patient groups show comparable increases of ventricular volumes indicating a common neuropathology differentiating them from non-psychotic patients with TLE and from normal controls. The volumes of the lateral ventricles of 9 patients with TLE and psychosis were measured on high resolution MRI brain scans and compared to the corresponding values of 9 patients with TLE and no psychosis, 9 schizophrenics and 9 normal controls, matched on age, sex and duration of epilepsy, respectively. The schizophrenic patients showed significantly larger volumes than the normal controls, while the values of both TLE groups lay in between, neither significantly different from each other nor from the two other groups. We found no evidence that patients with TLE and psychosis show an increase of ventricular volumes similar to the one observed in schizophrenic patients. In so far as the neuropathology underlying ventricular enlargement in schizophrenia is related to psychopathology, this study does not support the notion that schizophrenia-like symptoms in patients with TLE are based on a similar neuropathology.

Third-ventricle enlargement and neuropsychological deficit in schizophrenia

Cerebral ventricular enlargement is present in a substantial subgroup of schizophrenic patients. Most, but not all studies examining neuropsychological performance and ventricular size in schizophrenics show more severe cognitive impairment in those patients with greatest ventricular enlargement. Inconsistencies in this literature have been attributed to different neuroimaging techniques, variation in patient characteristics across studies, and the variety of neuropsychological batteries used. In the present study, schizophrenic patients (n = 49 men, n = 23 women) and normal controls (n = 13 men, n = 18 women) underwent magnetic resonance (MR) imaging of the brain and extensive neuropsychological testing including measures of frontal and temporal lobe function. A complete coronal set of MR images was used to calculate volumetric estimates of lateral and third cerebral ventricles. Highly significant associations were found between cognitive deficits and third-ventricle volume, with measures of frontal functioning, attention, and concentration showing the most robust correlations. In contrast, neuropsychological performance was not highly associated with lateral ventricular size. These findings further support the pathophysiological relevance of ventricular enlargement in schizophrenia. More specifically, third, but not lateral, ventricular enlargement was associated with greater cognitive disturbance in this sample. Results are consistent with pathological involvement of periventricular diencephalic structures resulting in dysfunctional frontal and limbic processing in a subgroup of patients.

Stability of ventricular size after the onset of psychosis in schizophrenia

This study examined whether ventricular enlargement in schizophrenia is progressive by scanning 15 schizophrenic patients at the onset of their first psychotic episodes and again 1–3 years later. Sizes of the body of the lateral ventricles, the frontal horns, and the third ventricle were assessed. The results indicated no tendency for the ventricles to get larger in this sample, with lateral ventricular size actually showing a significant decrease across the rescanning interval when the ventricle-to-brain ratio was used as the dependent variable. Methodological issues related to computed tomography and the quantification of ventricular size were considered by developing an alternative method of calculating ventricle-to-brain ratios and examining the reliability of measurements made on a group of 11 medical patients who were scanned twice on the same day.

Ventricular Enlargement in Schizophrenia Evaluated With Computed Tomographic Scanning

We evaluated ventricular-brain ratio with computed tomographic scanning in a sample of 108 DSM-III-diagnosed schizophrenic patients and 75 healthy normal volunteers. Significant differences were noted between the patients and controls, but our large sample size also permitted us to determine that the statistically significant difference was contributed primarily through the male patients. Ventricular enlargement occurs only in some schizophrenic patients. In this particular sample, only 6% of schizophrenics had ventricular-brain ratios greater than 2 SDs from the control mean, and 28% were 1 SD greater than the control mean. However, the corresponding figures for male schizophrenics were 19% and 43%, indicating that there is much less overlap between normal individuals and ill subjects in the male population. First-admission schizophrenic patients also had significantly greater ventricular enlargement than did their age-equivalent normal controls, suggesting that ventricular enlargement in schizophrenia may antedate the onset of symptoms. Examination of ventricular size in schizophrenics and normal subjects from a broad age range suggests that ventricular enlargement does not progress over time at a greater rate in schizophrenic patients than in normal subjects.

Progressive ventricular enlargement in schizophrenia: Comparison to bipolar affective disorder and correlation with clinical course

Previos studies of long-term serial changes in ventricular size in schizophrenia (SCZ) have yielded mixed, albeit predominantly negative results. The current study examined ventricular changes in CT scans over intervals of 1- to 4 1 2 years in chronic schizophrenic and bipolar patients. The results indicated significant progression of ventricular size from initial to final scan in the schizophrenia group but not in the bipolar or control groups; the percent increase in VBR over baseline was 25% (p < 0.01) in the schizophrenia group as compared with 11% (n.s.) in the bipolar group. The increases in ventricular enlargement in the schizophrenic group did not correlate with duration of illness but did appear to show an irregular stepwise pattern in several patients. It is concluded that progressive ventricular enlargement after onset of illness does occur in a subgroup of schizophrenic patients characterized by a chronic or deteriorating clinical course. The etiological implications of this finding are discussed.

The role of limbic and paralimbic pathology in the etiology of schizophrenia

In order to determine whether ventricular enlargement in schizophrenia is due to a general brain atrophy or to a more regionally confined reduction of brain tissue, we compared the CT scans of 54 schizophrenics and 54 controls matched for age and sex. We measured the size of all cortical sulci, of the Sylvian fissure, and of lateral, third, and fourth ventricles using a specially developed planimetric method

Family history and cerebral ventricular enlargement in schizophrenia. A case control study.

Ventricular size was measured from CT scans in 48 patients meeting RDC for schizophrenia who had a first-degree relative with a history of treatment for major psychiatric disorder, in 48 age- and sex-matched schizophrenic patients with no such history in first- or second-degree relatives, and in 48 matched, healthy controls. There was no difference in ventricular size between those with and without a positive family history, although both groups showed ventricular enlargement with respect to normal controls. Ventricular enlargement was demonstrated in the subgroup of 23 patients with a family history of schizophrenia, but not in the subgroup of 18 patients with a family history of affective disorder. These observations provide further evidence that schizophrenics with a family history of affective disorder may constitute an aetiologically distinct subgroup.

Increased CSF amino acids and ventricular enlargement in schizophrenia: A preliminary study

We found significantly higher levels of cerebrospinal fluid alanine, glycine, leucine, and phenylalanine in schizophrenic patients compared to healthy controls. Ventricular enlargement was present in 4 of 11 schizophrenics, and elevated CSF alanine was highly correlated with ventricular enlargement. The implications of these findings are discussed.

The relationship of twinning to the familial-sporadic distinction in schizophrenia

Cerebral ventricular enlargement in schizophrenia may occur more often in the absence of a family history of the disorder, suggesting that it is related to some non-genetic component of aetiology. This paper shows the finding to be much more apparent in a group of twins than in a similar group of singletons. Previous studies have shown twins in general to have larger cerebral ventricles than non-twins; we suggest that it is the greater susceptibility of twins to obstetric complications that is responsible for both the larger cerebral ventricles found in normal twins, and the very marked increase in ventricular size found in family history negative schizophrenic twins. We go on to consider evidence relating to a possible increased susceptibility of twins to develop schizophrenia.