Michael Flaum

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.

Comorbidity of substance abuse and schizophrenia: the role of pre-morbid adjustment

Co-morbid substance use and abuse is common in schizophrenic patients, and the role of substance abuse in initiating and maintaining psychosis has important definitional and aetiological implications. We investigated the issue in a cohort of 131 schizophrenic patients. We found non-users (N = 67) were similar to pathological users (N = 64) in current symptomatology and clinical history. The pathological users did, however, have better pre-morbid adjustment levels. Only alcohol use and to some extent cannabis use contributed to this effect; use of stimulants or hallucinogens did not. These results indicate the importance of evaluating the various types of substance used when attempting to explore the significance of co-morbidity. The results also suggest that co-morbidity of substance abuse and schizophrenia may be explained by a common factor antecedent to both: better pre-morbid adjustment. A two-stage model is proposed to explain these findings: increased sociability increases exposure to opportunities of substance use in a subset of patients; subsequent onset of psychotic illness accelerates the use to a pathological level as the individual attempts to cope with the stress of the developing mental illness.

Symptom dimensions and brain morphology in schizophrenia and related psychotic disorders

The heterogeneity of symptoms in schizophrenia may reflect heterogeneity of underlying pathophysiological mechanisms. Factor analytic studies have consistently identified three symptom factors, psychotic, negative and disorganized, as independent dimensions of schizophrenic psychopathology. This study examined the relationship of these symptom dimensions with volumes of specific brain regions. One-hundred and sixty-six schizophrenia spectrum patients were clinically evaluated with the Comprehensive Assessment of Symptoms and History (CASH) and scanned with a 1.5 Tesla magnetic resonance imaging scanner. Regions of interest (ROIs) were manually traced on 5 mm and 3 mm coronal slices by a single technician, blind to all aspects of subject identity. Correlations between ROI volumes and indices of symptom severity were determined. Analyses of covariance were then used to test for specific relationships between each of the three symptom dimensions and ROI volumes. Tests were made of each dimension, controlling for all others. Overall symptom severity was significantly correlated with larger ventricle volumes (lateral, third and temporal horns) and smaller temporal lobe, hippocampal and superior temporal gyral volumes. Both psychotic and negative symptom severity predicted increased third ventricular volume. Psychotic symptom severity uniquely predicted decreased superior temporal gyral volume as well as increased temporal horn volume. Within the psychotic symptom dimension, hallucinations alone predicted left superior temporal gyral volume. No significant associations between disorganized symptoms and any ROIs were demonstrated. These results provide clues to the localization of specific brain regions underlying symptom clusters in schizophrenia, and provide further validating evidence for the construct of independent dimensions of psychopathology within schizophrenia and related psychotic disorders.

Effects of Smoking Marijuana on Brain Perfusion and Cognition

The effects of smoking marijuana on regional cerebral blood flow (rCBF) and cognitive performance were assessed in 12 recreational users in a double-blinded, placebo-controlled study. PET with [15Oxygen]-labeled water ([15O]H2O) was used to measure rCBF before and after smoking of marijuana and placebo cigarettes, as subjects repeatedly performed an auditory attention task. Smoking marijuana resulted in intoxication, as assessed by a behavioral rating scale, but did not significantly alter mean behavioral performance on the attention task. Heart rate and blood pressure increased dramatically following smoking of marijuana but not placebo cigarettes. However, mean global CBF did not change significantly. Increased rCBF was observed in orbital and mesial frontal lobes, insula, temporal poles, anterior cingulate, as well as in the cerebellum. The increases in rCBF in anterior brain regions were predominantly in “paralimbic” regions and may be related to marijuanas mood-related effects. Reduced rCBF was observed in temporal lobe auditory regions, in visual cortex, and in brain regions that may be part of an attentional network (parietal lobe, frontal lobe and thalamus). These rCBF decreases may be the neural basis of perceptual and cognitive alterations that occur with acute marijuana intoxication. There was no significant rCBF change in the nucleus accumbens or other reward-related brain regions, nor in basal ganglia or hippocampus, which have a high density of cannabinoid receptors.

Racial differences in the diagnosis of psychosis

In clinical populations, it has been reported that African-American patients are more likely to receive a diagnosis of schizophrenia than similar Caucasian patients. Factors contributing to this racial discrepancy are poorly defined. The authors examined the hypothesis that racial differences in severity of first-rank symptoms of schizophrenia contribute to this diagnostic difference. Patients were recruited as part of the DSM-IV Field Trial for Schizophrenia and Other Psychotic Disorders, and evaluated using a structured rating instrument. Symptom and diagnostic comparisons were performed between black and white patients. Black patients were significantly more likely than white patients to be diagnosed with schizophrenia and less likely with psychotic depression. Racial differences in symptom profiles were observed with black patients demonstrating more severe psychotic symptoms, in general, and first-rank symptoms, specifically. There were no racial differences in rates of affective syndromes or severity of affective symptoms. Racial disparity in diagnosis of psychotic patients may be in part secondary to more severe first-rank symptoms in black patients, causing clinicians to stray from DSM-III-R criteria.

Anatomic and functional variability: the effects of filter size in group fMRI data analysis.

In the analysis of group fMRI scans, an optimal spatial filter should be large enough to accurately blend functionally homologous anatomic regions, yet small enough not to blur the functionally distinct regions. Hanning filters varying from 0.0 to 18.0 mm were evaluated in a group analysis of six healthy controls performing a simple finger-tapping paradigm. Test-retest reliability and Talairach-based measurements of the sensorimotor region were used to explore the optimal filter size. Two distinct regions of functional activation were noted in the sensorimotor cortex in group images (n = 6) at both time 1 and time 2. These regions merge once the filter size exceeds approximately 6.0 mm. The original hypothesis that these represented a motor and sensory activation was rejected on the basis of structural and functional variability. A discussion of the inherent difficulties in choosing an appropriate filter size is presented.

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.