Daniel S. O’Leary

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.

Regional frontal abnormalities in schizophrenia: a quantitative gray matter volume and cortical surface size study.

BACKGROUND Previous structural studies of the frontal lobe in schizophrenia have had somewhat inconsistent results, but most of them have measured the frontal lobe as a single brain structure. To investigate more specific abnormalities in frontal subregions, we measured gray matter volume and cortical surface size in 10 subregions in drug-naive patients during the early stages of the illness. METHODS Magnetic resonance imaging was used to measure frontal subregions in 34 healthy male volunteers, and 26 male, drug-naive schizophrenia patients at early stages of the illness. Frontal subregions were manually traced using our locally developed parcellation method. RESULTS Patients with schizophrenia had a significant deficit in cortical surface size in the right straight gyrus and left orbitofrontal cortex. No differences were found in gray matter volumes. CONCLUSIONS Frontal structural abnormalities found in drug-naive schizophrenic patients appear to be subtle and circumscribed to ventral portions. Anomalies in the cortical surface size suggest neurodevelopmental abnormalities might occur during the early stages of the gyrogenesis. Further investigations are needed to explore the implications of paralimbic ventral frontal regions (i.e., straight gyrus and orbitofrontal cortex) in the pathophysiology of schizophrenia.

Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia

BACKGROUND Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function. METHODS Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow. RESULTS Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol. CONCLUSIONS The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.

Neuropsychological Performance in First-Episode Adolescents with Schizophrenia: A Comparison with First-Episode Adults and Adolescent Control Subjects

BACKGROUND The goal of this study was to compare the extent of cognitive deficits between adolescents and adults early in the course of schizophrenia. METHODS A comprehensive neuropsychological battery was performed on 49 adolescents with childhood- or adolescent-onset schizophrenia, 139 adults with adult-onset schizophrenia, 32 healthy adolescent volunteers, and 240 healthy adult volunteers. Both patient groups were assessed early in the course of their illness and were matched to their respective control groups on age and parental education. RESULTS The adolescent patients performed significantly worse than the adult patients on tasks of working memory, language, and motor function. The healthy adolescents also performed significantly worse than the healthy adults in working memory and language tasks but were significantly better than the adults in motor function. When accounting for developmental differences in the control group, only motor performance was worse in the adolescent patients compared with the adult patients. CONCLUSIONS These findings, when coupled with published retrospective studies reporting greater cognitive deficits in earlier onset schizophrenia, implicate a cessation in development in specific cognitive domains following the onset of schizophrenia in adolescent patients.

Cognitive deficits in recent-onset and chronic schizophrenia

Although cognitive dysfunction is a primary characteristic of schizophrenia, only recently have investigations begun to pinpoint when the dysfunction develops in the individual afflicted by the disorder. Research to date provides evidence for significant cognitive impairments prior to disorder onset. Less is known about the course of cognitive dysfunction from onset to the chronic phase of schizophrenia. Although longitudinal studies are optimal for assessing stability of cognitive deficits, practice effects often confound assessments, and large and representative subject samples have not been followed over long periods of time. We report results of a cross-sectional study of cognitive deficits early and late in the course of schizophrenia carried out at four different geographic locations to increase sample size and generalizability of findings. We examined a broad set of cognitive functions in 41 recent-onset schizophrenia patients and 106 chronic schizophrenia patients. The study included separate groups of 43 matched controls for the recent-onset sample and 105 matched controls for the chronic schizophrenia sample in order to evaluate the effects of cohort (i.e., age) and diagnosis (i.e., schizophrenia) on cognitive functions. All measures of cognitive function showed effects of diagnosis; however, select time-based measures of problem solving and fine motor dexterity exhibited interactions of diagnosis and cohort indicating that these deficits may progress beyond what is expected with normal aging. Also, worse recall of material in episodic memory was associated with greater length of illness. Nevertheless, findings indicate that nearly all cognitive deficits are comparably impaired across recent-onset and chronic schizophrenia.

The MCIC collection: a shared repository of multi-modal, multi-site brain image data from a clinical investigation of schizophrenia.

Expertly collected, well-curated data sets consisting of comprehensive clinical characterization and raw structural, functional and diffusion-weighted DICOM images in schizophrenia patients and sex and age-matched controls are now accessible to the scientific community through an on-line data repository (coins.mrn.org). The Mental Illness and Neuroscience Discovery Institute, now the Mind Research Network (MRN, http://www.mrn.org/), comprised of investigators at the University of New Mexico, the University of Minnesota, Massachusetts General Hospital, and the University of Iowa, conducted a cross-sectional study to identify quantitative neuroimaging biomarkers of schizophrenia. Data acquisition across multiple sites permitted the integration and cross-validation of clinical, cognitive, morphometric, and functional neuroimaging results gathered from unique samples of schizophrenia patients and controls using a common protocol across sites. Particular effort was made to recruit patients early in the course of their illness, at the onset of their symptoms. There is a relatively even sampling of illness duration in chronic patients. This data repository will be useful to 1) scientists who can study schizophrenia by further analysis of this cohort and/or by pooling with other data; 2) computer scientists and software algorithm developers for testing and validating novel registration, segmentation, and other analysis software; and 3) educators in the fields of neuroimaging, medical image analysis and medical imaging informatics who need exemplar data sets for courses and workshops. Sharing provides the opportunity for independent replication of already published results from this data set and novel exploration. This manuscript describes the inclusion/exclusion criteria, imaging parameters and other information that will assist those wishing to use this data repository.

A Controlled Quantitative MRI Volumetric Investigation of Hippocampal Contributions to Immediate and Delayed Memory Performance

MRI volumetric TLE studies show inconsistent evidence of hippocampal involvement in memory. Prior studies have not dissociated hippocampal and temporal lobe contributions to memory. We measured hippocampal and temporal lobe volumes and immediate/delayed memory performances in 64 TLE patients. Regression was used to dissociate hippocampal from temporal lobe contributions to memory. Results revealed reliable evidence for dominant hippocampal involvement in delayed verbal recall across three separate measures and less consistent evidence for nondominant hippocampal involvement. The findings point to a consistent relationship of dominant hippocampal volumes to delayed verbal recall but no involvement of the temporal lobe or nondominant hippocampus in memory.

Prism adaptation in schizophrenia

The prism adaptation test examines procedural learning (PL) in which performance facilitation occurs with practice on tasks without the need for conscious awareness. Dynamic interactions between frontostriatal cortices, basal ganglia, and the cerebellum have been shown to play key roles in PL. Disruptions within these neural networks have also been implicated in schizophrenia, and such disruptions may manifest as impairment in prism adaptation test performance in schizophrenia patients. This study examined prism adaptation in a sample of patients diagnosed with schizophrenia (N=91) and healthy normal controls (N=58). Quantitative indices of performance during prism adaptation conditions with and without visual feedback were studied. Schizophrenia patients were significantly more impaired in adapting to prism distortion and demonstrated poorer quality of PL. Patients did not differ from healthy controls on aftereffects when the prisms were removed, but they had significantly greater difficulties in reorientation. Deficits in prism adaptation among schizophrenia patients may be due to abnormalities in motor programming arising from the disruptions within the neural networks that subserve PL.

Quality Assurance in Functional MRI

Since its inception two decades ago, functional magnetic resonance imaging (fMRI) has become a leading tool for noninvasive studies of the human brain. fMRI studies require both the rapid acquisition of many brain images over a sustained period of time and a high level of MRI system stability in order to detect small activity-related fluctuations in the MR signal. These rigorous requirements have driven many improvements in the performance of MRI systems. Quality assurance (QA) procedures are critical for identifying issues with system performance and ensuring that the desired level of system stability and image quality is achieved. In addition, ongoing QA of experimental data is important for detecting issues with not only the MRI system but also other key experimental elements such as task performance, movement artifacts, and stimulus presentation equipment. Given the large size of the datasets generated by fMRI studies, QA processes rely heavily on computer-based analyses coupled with the assessment of the QA metrics by a human expert. A well-designed QA process is especially critical for ensuring data quality and uniformity for fMRI studies involving multiple sites. These multicenter studies have a number of advantages, such as increased sample size, and are becoming more widely adopted.