Daniel S. O'Leary

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.

Structural MR image processing using the brains2 toolbox

Medical imaging has opened a new door into biomedical research. In order to study various diseases of the brain and detect their impact on brain structure, robust and user friendly image processing packages are required. These packages must be multi-faceted to distinguish variations in size, shape, volume, and the ability to detect longitudinal changes over the course of an illness. This paper describes the BRAINS2 image processing package, which contains both manual and automated tools for structural identification, methods for tissue classification and cortical surface generation. These features are described in detail, as well as the reliability of these procedures.

Working memory and DLPFC inefficiency in schizophrenia: The FBIRN study

BACKGROUND The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

The Neurodevelopmental Impact of Childhood‐onset Temporal Lobe Epilepsy on Brain Structure and Function

Summary:  Purpose: To characterize the neurodevelopmental correlates of childhood‐onset temporal lobe epilepsy on brain structure and cognition compared with late‐onset chronic temporal lobe epilepsy and healthy controls.

Dysregulation of Working Memory and Default- Mode Networks in Schizophrenia Using Independent Component Analysis, an fBIRN and MCIC Study

Deficits in working memory (WM) are a consistent neurocognitive marker for schizophrenia. Previous studies have suggested that WM is the product of coordinated activity in distributed functionally connected brain regions. Independent component analysis (ICA) is a data‐driven approach that can identify temporally coherent networks that underlie fMRI activity. We applied ICA to an fMRI dataset for 115 patients with chronic schizophrenia and 130 healthy controls by performing the Sternberg Item Recognition Paradigm. Here, we describe the first results using ICA to identify differences in the function of WM networks in schizophrenia compared to controls. ICA revealed six networks that showed significant differences between patients with schizophrenia and healthy controls. Four of these networks were negatively task‐correlated and showed deactivation across the posterior cingulate, precuneus, medial prefrontal cortex, anterior cingulate, inferior parietal lobules, and parahippocampus. These networks comprise brain regions known as the default‐mode network (DMN), a well‐characterized set of regions shown to be active during internal modes of cognition and implicated in schizophrenia. Two networks were positively task‐correlated, with one network engaging WM regions such as bilateral DLPFC and inferior parietal lobules while the other network engaged primarily the cerebellum. Our results suggest that DLPFC dysfunction in schizophrenia might be lateralized to the left and intrinsically tied to other regions such as the inferior parietal lobule and cingulate gyrus. Furthermore, we found that DMN dysfunction in schizophrenia exists across multiple subnetworks of the DMN and that these subnetworks are individually relevant to the pathophysiology of schizophrenia. In summary, this large multsite study identified multiple temporally coherent networks, which are aberrant in schizophrenia versus healthy controls and suggests that both task‐correlated and task‐anticorrelated networks may serve as potential biomarkers. Hum Brain Mapp, 2009.

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow

The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V158M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [15O]H2O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.

Changes in cerebral functioning associated with normal aging

It has been suggested that the normal aging process is characterized by a pattern of neuropsychological performance decline that implies relatively greater vulnerability of right-hemisphere functions. This hypothesis was tested in a sample of 68 volunteers aged 20-75 who were free of systemic and neurologic illness. Neuropsychologic measures of lateralized and focal function were specifically selected to eliminate systematic procedural differences among tests (e.g., timed vs. untimed, overlearned vs. unfamiliar). Inferences about the localizing significance of each measure were based on previously demonstrated double dissociation of function in lesion studies. Results suggested that declines in cerebral efficiency are not differentially lateralized. Age correlated performance changes implied bilateral reduction that was significantly more pronounced on operations associated with frontal-lobe function. Anatomic and theoretical explanations for this pattern were discussed.

Insular cortex abnormalities in schizophrenia: a structural magnetic resonance imaging study of first-episode patients

The insular cortex is a limbic integration region that is engaged in emotional and cognitive functions. To investigate possible insular cortex abnormalities in schizophrenia, we measured insular gray matter volume and cortical surface size in drug-naive first-episode patients. Magnetic resonance images were used to explore the morphology of the insular cortex of 25 healthy male volunteers, and 25 male schizophrenic patients. Groups were matched for age, sex, height, and parental socio-economic status. Clinical dimension scores were correlated with insular gray matter volume and cortical surface area. Patients had a significant reduction in cortical surface area [patients=2020 (206); controls=2142 (204); F=5.83, df=1, 47; P=0.01] and gray matter volume [patients=8.12 (0.77); controls=8.57 (0.94); F=3.93, df=1,47; P=0.05] in the left insular cortex. Insular gray matter volume and cortical surface size correlated negatively and significantly with the psychotic symptom dimension. Schizophrenic patients show morphological abnormalities in the insular cortex at early stages of the illness. These abnormalities are related to the severity of psychotic symptoms. Further investigations are needed to evaluate the role of the insula in the pathophysiology of schizophrenia.

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 frequent marijuana use on brain tissue volume and composition

To investigate CNS effects of frequent marijuana use, brain tissue volume and composition were measured using magnetic resonance imaging (MRI) in 18 current, frequent, young adult marijuana users and 13 comparable, non-using controls. Automated image analysis techniques were used to measure global and regional brain volumes, including, for most regions, separate measures of gray and white matter. The marijuana users showed no evidence of cerebral atrophy or global or regional changes in tissue volumes. Volumes of ventricular CSF were not higher in marijuana users than controls, but were, in fact, lower. There were no clinically significant abnormalities in any subjects MRI. Sex differences were detected in several global volume measures.