Peg Nopoulos

Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients

BACKGROUND There have been reports that patients with schizophrenia have decreased metabolic activity in prefrontal cortex. However, findings have been confounded by medication effects, chronic illness, and difficulties of measurement. We aimed to address these problems by examination of cerebral blood flow with positron emission tomography (PET). METHODS We studied 17 neuroleptic-naïve patients at the early stages of illness by means of image analysis and statistical methods that can detect abnormalities at the gyral level. FINDINGS An initial omnibus test with a randomisation analysis indicated that patients differed from normal controls at the 0.06 level. In the follow-up analysis, three separate prefrontal regions had decreased perfusion (lateral, orbital, medial), as well as regions in inferior temporal and parietal cortex that are known to be anatomically connected. Regions with increased perfusion were also identified (eg, thalamus, cerebellum, retrosplenial cingulate), which suggests an imbalance in distributed cortical and subcortical circuits. INTERPRETATION These distributed dysfunctional circuits may form the neural basis of schizophrenia through cognitive impairment of the brain, which prevents it from processing input efficiently and producing output effectively, thereby leading to symptoms such as hallucinations, delusions, and loss of volition.

Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms

All research on schizophrenia depends on selecting the correct phenotype to define the sample to be studied. Definition of the phenotype is complicated by the fact that there are no objective markers for the disorder. Further, the symptoms are diverse, leading some to propose that the disorder is heterogeneous and not a single disorder or syndrome. This article explores an alternative possibility. It proposes that schizophrenia may be a single disorder linked by a common pathophysiology (a neurodevelopmental mechanism), which leads to a misconnection syndrome of neural circuitry. Evidence for disruption in a specific circuit is explored: the cortical-thalamic-cerebellar-cortical circuit (CCTCC). It is suggested that a disruption in this circuit leads to an impairment in synchrony, or the smooth coordination of mental processes. When synchrony is impaired, the patient suffers from a cognitive dysmetria, and the impairment in this basic cognitive process defines the phenotype of schizophrenia and produces its diversity of symptoms.

Sexual dimorphism in the human brain : evaluation of tissue volume, tissue composition and surface anatomy using magnetic resonance imaging

Magnetic resonance imaging (MRI) was used to evaluate sex differences in brain morphology by comparing measures of brain tissue volume, brain tissue composition (proportions of gray and white matter), and measures of cortical surface anatomy. A large and well-matched sample of healthy women (n=42) and healthy men (n=42) were evaluated. There was a significant gender effect on intracranial volume, males being larger. However, this increase in size was limited to the cerebrum as there was no sex difference in the volume of the cerebellum. The gender difference in size of the cerebral volume was evenly distributed, with all four lobes equally larger in males compared to females. Gray and white matter tissue proportions were similar between the sexes globally. Regional tissue composition analysis showed sex differences within the parietal lobes with females having proportionately more gray matter on the right side. There were no differences between the sexes in cortical surface anatomy measures. Overall, against the background of similarity in morphology, there are differences between the sexes with regard to general and regional brain measures. The functional significance of these sex differences is unclear, but may represent the differential effects of gonadal hormones during brain growth and development.

Progressive Brain Change in Schizophrenia: A Prospective Longitudinal Study of First-Episode Schizophrenia

BACKGROUND Schizophrenia has a characteristic onset during adolescence or young adulthood but also tends to persist throughout life. Structural magnetic resonance studies indicate that brain abnormalities are present at onset, but longitudinal studies to assess neuroprogression have been limited by small samples and short or infrequent follow-up intervals. METHODS The Iowa Longitudinal Study is a prospective study of 542 first-episode patients who have been followed up to 18 years. In this report, we focus on those patients (n = 202) and control subjects (n = 125) for whom we have adequate structural magnetic resonance data (n = 952 scans) to provide a relatively definitive determination of whether progressive brain change occurs over a time interval of up to 15 years after intake. RESULTS A repeated-measures analysis showed significant age-by-group interaction main effects that represent a significant decrease in multiple gray matter regions (total cerebral, frontal, thalamus), multiple white matter regions (total cerebral, frontal, temporal, parietal), and a corresponding increase in cerebrospinal fluid (lateral ventricles and frontal, temporal, and parietal sulci). These changes were most severe during the early years after onset. They occur at severe levels only in a subset of patients. They are correlated with cognitive impairment but only weakly with other clinical measures. CONCLUSIONS Progressive brain change occurs in schizophrenia, affects both gray matter and white matter, is most severe during the early stages of the illness, and occurs only in a subset of patients. Measuring severity of progressive brain change offers a promising new avenue for phenotype definition in genetic studies of schizophrenia.

Brain structure in preclinical Huntington's disease

BACKGROUND Huntingtons disease (HD) is traditionally conceptualized as a degenerative disease of the striatum. Recent scientific advances, however, have suggested neurodevelopmental contributions and extrastriatal brain abnormalities. This study was designed to assess the morphology of the brain in participants who had previously undergone elective DNA analyses for the HD mutation who did not currently have a clinical diagnosis of HD (preclinical HD subjects). METHODS Twenty-four preclinical participants with the gene expansion for HD underwent brain magnetic resonance imaging and were compared with a group of 24 healthy control subjects, matched by gender and age. RESULTS Huntingtons disease preclinical participants had substantial morphologic differences from controls throughout the cerebrum. Volume of the cerebral cortex was significantly increased in preclinical HD, whereas the basal ganglia and cerebral white matter volume were substantially decreased. CONCLUSIONS In individuals with the HD gene mutation who are considered healthy (preclinical for manifest disease), the morphology of the brain is substantially altered compared with matched control subjects. Although decreased volumes of the striatum and cerebral white matter could represent early degenerative changes, the novel finding of enlarged cortex suggests that developmental pathology occurs in HD.

An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept

BACKGROUND Cumulative evidence suggests the cerebellum is involved in cognition and may be important in the pathoetiology of schizophrenia. Functional imaging studies have identified a possible neural circuit that includes the cerebellum and may be abnormal in patients with schizophrenia, manifesting as a fundamental cognitive deficit conceptualized as cognitive dysmetria. To explore the role of the cerebellum in cognitive dysfunction and schizophrenia, this study was designed to evaluate the morphology of the cerebellar vermis, its relationship to other cortical areas, and to cognitive function in patients with schizophrenia. METHODS Male patients with schizophrenia (n = 65) were matched by age and gender to 65 healthy male controls. Volume measures of the 4 cerebral lobes and total cerebellum were obtained using automated methods. The area of the cerebellar vermis (divided into three lobes) was traced on a midsaggital MRI slice. RESULTS Patients had smaller frontal and temporal lobes. There were no group differences in total cerebellar volume. Patients had a smaller vermis area, accounted for by a smaller anterior lobe. The anterior vermis area was positively correlated with total cerebellar volume, temporal lobe volume, and FSIQ in patients, but not controls. CONCLUSIONS These findings support the theory that regions of the cerebellum may be involved in a neural circuit that is structurally and functionally abnormal in patients with schizophrenia, leading to cognitive dysmetria.

Correlational Studies of the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms: An Overview and Update

The interrelationships between the various symptoms of schizophrenia may be explored by examining their intercorrelations. Five different factor analytic studies, which examine these interrelationships, are summarized. Three major factors emerge consistently: psychotic, disorganized, and negative. These three factors appear to represent three dimensions of the psychopathology of schizophrenia.

Cavum septi pellucidi in normals and patients with schizophrenia as detected by magnetic resonance imaging

Cavum septi pellucidi (CSP) is a cavity between the two leaflets of the septum pellucidum. CSP is a developmental anomaly, yet the pathologic implications, if any, of an abnormally large CSP remain unclear. The reported incidence of CSP among normal populations varies greatly from 0.15% to 85%. Several studies have suggested that there is a higher incidence of CSP in patients with schizophrenia. We conducted a thin-slice magnetic resonance imaging study to evaluate the prevalence of CSP in a sample of 75 controls and 55 patients. There was a high incidence of small CSP among both groups: 58.8% in the controls and 58.2% in the patients, suggesting that a small cavum could be considered a normal variant; however, the patient group had significantly higher incidence of large CSP (20.7%) compared to the normal group (3%). The patients with large CSP were all male.

Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network

BACKGROUND Structural brain imaging studies have demonstrated an increase in caudate volume in schizophrenic patients medicated with typical neuroleptics and a volume decrease following treatment with atypical neuroleptics. The measurement of striatal volume in patients who have never been treated with neuroleptics may indicate whether these changes are superimposed on intrinsic basal ganglia pathology in schizophrenia or are solely neuroleptic-induced. METHODS We studied 36 first-episode, neuroleptic-naive schizophrenic patients and 43 control subjects using an artificial neural network (ANN) to identify and measure the caudate nucleus. The resulting volumes were analyzed using an ANCOVA controlling for intracranial volume, age, gender, and socioeconomic status. RESULTS The mean volume difference between the caudate nuclei of patients and control subjects was .297 mL, the caudate nuclei of the patients being smaller than those of controls. When we covaried for intracranial volume, this was a statistically significant difference in caudate volume (n = 79; df = 1,75; F = 4.18; p > .04). CONCLUSIONS Caudate nuclei of neuroleptic naive schizophrenic patients are significantly smaller than those of controls. This suggests that patients suffering from schizophrenia may have intrinsic pathology of the caudate nucleus, in addition to the pathology observed as a consequence of chronic neuroleptic treatment.

Structural brain abnormalities in adult males with clefts of the lip and/or palate.

Purpose: To evaluate brain morphology of adult males with nonsyndromic clefts of the lip and/or palate (NSCLP) in comparison to a matched healthy control group.Methods: Brain structure was measured using quantitative analysis of magnetic resonance images.Results: Subjects with NSCLP had significant abnormalities in brain morphology consisting of abnormally enlarged anterior regions of the cerebrum, and decreased volumes of the posterior cerebrum and cerebellum. Overall, the most severely affected region was the left temporal lobe. Furthermore, these structural abnormalities were directly related to cognitive dysfunction.Conclusions: These findings highlight the important relationship and interplay between face and brain development.