Sex differences in schizophrenia.
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Cerebral Cortex↗
Biomedical subjects
G D Pearlson
Publications and source records attributed to G D Pearlson.
Superior temporal gyrus and planum temporale in schizophrenia: a selective review.
1. The normal structure of the superior temporal gyrus (STG) has been elucidated from human and non-human primate research. This brain region is structurally complex, contains several distinct cellular regions and the area known as the planum temporale. 2. The STG connects with heteromodal neocortical regions and temporolimbic areas. 3. Functional studies of the normal STG in animals and in humans, using electrophysiology and PET/fMRI, emphasize the STG's role as part of a cortical network important in the interpretation, production and self-monitoring of language. 4. There is evidence for structural abnormalities of the STG in schizophrenia including both volume reductions and disturbances of normal asymmetries. 5. Functional studies of this region in schizophrenic patients, including measurements of evoked potentials and of bloodflow, are abnormal, especially when patients perform language tasks or experience hallucinations. 6. This structural and functional pathology in the STG probably represents one example of a more general disruption in schizophrenia of the neocortical network of which this region is an essential part. This disturbance may be closely associated with the symptoms of formal thought disorder and of auditory hallucinations commonly seen in the disorder.
Animals↗
Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness.
In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.
Adult↗
Planum temporale asymmetry reversal in schizophrenia: replication and relationship to gray matter abnormalities.
OBJECTIVE: The planum temporale, the posterior superior surface of the superior temporal gyrus, is a highly lateralized brain structure involved with language. In schizophrenic patients the authors previously found consistent reversal of the normal left-larger-than-right asymmetry of planum temporale surface area. The original subjects plus new patients and comparison subjects participated in this effort to replicate and extend the prior study. METHOD: High-resolution magnetic resonance imaging of 28 schizophrenic patients and 32 group-matched normal subjects was performed. The authors measured planum temporale surface area, gray matter volume underlying the planum temporale, and gray matter thickness. Asymmetry indices for areas and volumes were calculated. RESULTS: Overall gray matter and total brain volume were not significantly smaller in the patients than in the comparison subjects. As previously reported, there was striking reversal of the normal asymmetry for planum temporale surface area in the male and female schizophrenic subjects. Bilaterally, gray matter volume beneath the planum temporale was smaller in the schizophrenic patients, and the gray matter thickness of the right planum temporale was only 50% of the comparison value. Volume of planum temporale gray matter did not show significant asymmetry in either group. CONCLUSIONS: This study extends the finding of reversed planum temporale surface area asymmetry in schizophrenic patients and clarifies its relationship to underlying gray matter volume. Although right planum temporale surface area is larger than normal in schizophrenia, gray matter volume is less than the comparison value; thus, gray matter thickness is substantially less than normal.
Adult↗
PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects.
OBJECTIVE: Animal data suggest that the strong euphoriant effects of cocaine are related to the drug's enhancement of available dopamine at the synaptic cleft. The authors' goal was to determine whether this mechanism is the same in humans because the development of putative pharmacological agents for treatment of cocaine dependence depends on this knowledge. METHOD: Positron emission tomography with [11C]raclopride was used to examine the effects of the intravenous administration of 48 mg of cocaine (a typical "street" dose) on the occupancy of dopamine 2 receptors in the putamen of 11 self-identified intravenous drug abusers. RESULTS: All 11 subjects reported subjective stimulation and euphoria in response to cocaine administration. Radioligand occupancy at dopamine receptors was decreased significantly after cocaine administration, suggesting that higher dopamine concentrations were competing at the receptor site. CONCLUSIONS: These results support the concept of dopamine system involvement in human cocaine abuse.
Adult↗
Longitudinal change in basal ganglia volume in patients with Huntington's disease.
Cross-sectional MRI studies demonstrating an association between caudate atrophy and symptom severity and duration of symptoms in patients with Huntington's disease (HD) have been assumed to reflect longitudinal changes in basal ganglia, but such neuropathologic progression has never been directly demonstrated. Subjects in the current study were 23 HD patients at various stages of the disorder who had two MRI images at least 10 months apart (mean interimage interval = 20.8 months). We measured volumes of caudate, putamen, and globus pallidus blind to the order of the images. For each structure, we calculated a change score by subtracting the volume obtained on the follow-up imaging from that obtained on the initial imaging. Results indicated significant decreases over time in caudate, putamen, and total basal ganglia volume. Age at onset and length of trinucleotide repeat correlated significantly with amount of volume change in caudate and total basal ganglia, even after controlling for length of interimage interval, duration of disease, and measures of symptom severity. Amount of change in basal ganglia structures was not significantly correlated with neurologic symptom severity at the time of the initial imaging or duration of symptoms. This is the first longitudinal MRI study to document progressive basal ganglia atrophy in HD, and suggests that quantitative neuroimaging with serial MRI may be useful in monitoring effectiveness of potential treatments. In addition, demonstration of greater rate of basal ganglia atrophy in patients with earlier symptom onset suggests that treatment effects may be more quickly observed in this subgroup of patients than in the general HD population.
Adult↗
A Quantitative MRI Study of the Basal Ganglia in Depression in HIV Seropositive Men.
UNLABELLED: HIV (Human Immunodeficiency Virus) infection is associated with high rates of depressive symptomatology. There is evidence that such infection is associated with damage to the basal ganglia. It has also been suggested that the basal ganglia are implicated in the aetiology of affective disorders. OBJECTIVE: This study examined the association between basal ganglia atrophy and depression in HIV seropositive men. We hypothesized that depressed HIV seropositive patients would have smaller basal ganglia compared with nondepressed HIV positive comparison subjects. METHOD: Using quantitative magnetic resonance imaging (MRI) techniques we compared for the basal ganglia volumes of sixteen depressed, and sixteen group-matched nondepressed HIV seropositive homosexual men. RESULTS: We found no significant difference in basal ganglia volumes between the two groups. CONCLUSIONS: We suggest that depression, at least in the early stages of HIV infection, is not associated with basal ganglia atrophy.
Basal Ganglia↗
Reduced survival of apolipoprotein E4 homozygotes in Down's syndrome?
An increased frequency of apolipoprotein E (ApoE) allele epsilon 4 has been established in Alzheimer's disease (AD) subjects. Based on the observation that all individuals with Down's syndrome (DS) develop the neuropathology of AD by the age of 40 years we sought to determine whether ApoE genotype affected the clinical symptoms of AD. Unexpectedly, we failed to find any epsilon 4 homozygotes, as have other published studies: this is highly significant statistically. We suggest this is due to decreased survival or, less likely, embryonic lethality of epsilon 4 homozygotes in DS.
Adult↗
Single photon emission computed tomographic blood flow and magnetic resonance volume imaging of basal ganglia in Huntington's disease.
OBJECTIVE: To examine basal ganglia dysfunction and atrophy in patients with mild to moderate Huntington's disease, with correlation of imaging measures with clinical and neuropsychological measures. DESIGN: Survey study in patients with Huntington's disease and matched controls, with imaging measures being evaluated by investigators unaware of the diagnosis. SETTING: Baltimore Huntington's Disease Project, The Johns Hopkins Hospital, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 10 patients with mild to moderate Huntington's disease and nine healthy age-matched control subjects. MAIN OUTCOME MEASURES: Imaging measures included single photon emission computed tomographic regional cerebral blood flow in caudate, putamen, and thalamus, and magnetic resonance imaging measures of caudate and putamen volumes and bicaudate ratios. Patients underwent neurologic and mental status examinations and neuropsychological tests. RESULTS: The measure with the greatest difference between patients and control subjects was mean putamen volume, reduced 54.3% in patients, with no overlap between groups (P<.001). Of the cerebral blood flow measures, caudate showed the greatest difference (21.5% decrease; P<.001). Quantitative neurologic indexes of disease severity correlated with both putamen measures (P<.03), while Mini-Mental State Examination scores correlated with caudate volume (P<.02). Bicaudate ratio correlated with both clinical measures and was the best index of neurologic deterioration (r=.95; P<.001), while global atrophy (measured by cerebrospinal fluid percentage) was the best correlate of several neuropsychological tests, such as the Trail Making Test (r=93; P<.001). CONCLUSIONS: Volumetric measurement of putamen best discriminated patients with Huntington's disease from healthy subjects. Measures of caudate atrophy or single photon emission computed tomographic measures performed less well. Neurologic decline correlated best with subcortical atrophy measured by the bicaudate ratio, but neuropsychological performance best corresponded to cerebrospinal fluid percentage, a measure of global atrophy.
Adult↗
Basal ganglia volume and proximity to onset in presymptomatic Huntington disease.
OBJECTIVE: To determine in presymptomatic individuals who carry the gene mutation for Huntington disease whether proximity to estimated age at onset is associated with volume of basal ganglia, as measured on magnetic resonance imaging scans. DESIGN: Survey study involving correlations between basal ganglia volume, measured blind to subject status, and estimation of subjects' age at onset. SETTING: Huntington's Disease Presymptomatic Testing Program at The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 47 individuals at risk for Huntington disease (ie, off-spring of patients with Huntington disease). Twenty subjects tested positive for the gene mutation but were not symptomatic. Twenty-seven subjects tested negative. MAIN OUTCOME MEASURES: Estimated age at onset was calculated for each of 20 gene-positive individuals using an empirically derived formula based on the subject's trinucleotide repeat length and parental age at onset. Each subject's age at the time of the magnetic resonance imaging scan was subtracted from his or her estimated age at onset, yielding estimated years to onset. Volumes of caudate, putamen, and globus pallidus were measured on magnetic resonance imaging scans. RESULTS: After controlling for the subject's age at the time of the scan, significant correlations were found between volumes of all basal ganglia structures and years to onset. Gene-positive subjects who were far from onset had smaller basal ganglia volumes than gene-negative subjects for all structures except globus pallidus. Gene-positive subjects who were close to onset had smaller volumes than gene-negative subjects for all basal ganglia structures and had smaller volumes than subjects far from onset for all structures except caudate. CONCLUSIONS: The results suggest that atrophy of the basal ganglia occurs gradually, beginning years before symptom onset.
Adult↗
Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging.
BACKGROUND: Prior neuroimaging studies have not consistently demonstrated a structural or functional abnormality of the caudate nucleus in patients with obsessive-compulsive disorder (OCD). However, there is theoretical support for some associated dysfunction of the caudate nucleus. METHODS: We examined volumes of the caudate nucleus and putamen with magnetic resonance imaging in 24 patients with adult-onset OCD and 21 control subjects, group-matched on age, race, education, and sex. Patients were relatively free from tics. To evaluate function (metabolism or blood flow) of the caudate nucleus, we performed a quantitative review, including a meta-analysis, of normalized data from functional neuroimaging studies that compared patients who had OCD with normal control subjects. RESULTS: All structural basal ganglia measures failed to exhibit differences between patients with OCD and matched normal control subjects. Patients did not demonstrate evidence of ventricular enlargement. Quantitative meta-analysis of the functional neuroimaging literature did not demonstrate a consistent abnormality of the caudate nucleus. CONCLUSIONS: We did not observe evidence of a structural abnormality of the caudate nucleus in patients with OCD. Prior reports of a structural aberration of the caudate nucleus were mixed. We also did not find strong support for relative caudate metabolic or perfusion dysfunction in the literature, although increased function in the frontal cerebral cortex was identified. The heterogeneous nature of this disorder may account for inconsistencies between studies. For example, ventricular enlargement or reduced caudate volume or blood flow might be evident in patients with soft neurological signs (eg, tics), while patients in the current study were relatively free from tics. Although theories of OCD suggest a dysfunction of the caudate nucleus, the structural and functional neuroimaging literature has not consistently verified this.
Adult↗
Exploratory factor analysis of MRI brain structure measures in schizophrenia.
Much of the literature shows various regional structural brain abnormalities in schizophrenia, but the complexity and variability of brain makes it difficult to determine how these regions are related. Statistical methods which estimate factors underlying patterns of covariance have not been widely used, but could be useful for analyzing such complex data. We applied exploratory and confirmatory factor analysis procedures to specific cortical and subcortical regional brain volume measures from MRI data in 60 normal and 44 schizophrenic subjects. Basal ganglia, heteromodal cortical gray, and medial temporal lobe factors were present in both the normal and the schizophrenia groups. The factor structure observed in the normal group showed a high degree of bilateral symmetry which is present but disrupted in the schizophrenia group. In the bilateral data, the disruption is most pronounced with medial and lateral temporal lobe structures including entorhinal cortex and anterior and posterior superior temporal gyri. There was a significant correlation between the basal ganglia factor and the heteromodal cortical gray factor in the normal group that was not present in the schizophrenia group. In the unilateral data, left posterior superior temporal gyrus did not load onto any factor in the schizophrenia group. Confirmatory factor analyses showed significant differences between the two groups in factor structure. A number of specific brain regions are affected in schizophrenia, and structural relationships between groups of regions also are abnormal. The results suggest that heteromodal dorsolateral prefrontal and superior temporal cortical gray regions are structurally related, whereas inferior parietal cortical gray is less so. These results should be viewed as preliminary as the ratio of parameters to subjects was relatively low, and replication is needed. However, the results demonstrate the potential utility of latent structure methods such as factor analysis in study of complex relationships in neuropsychiatric data.
Adult↗
Schizophrenia, the heteromodal association neocortex and development: potential for a neurogenetic approach.
The heteromodal association neocortex is believed to be a major site of involvement in schizophrenia. This system includes the prefrontal cortex and portions of the superior temporal and inferior parietal cortices, which are linked in cognitive networks observing complex executive functions. The heteromodal cortex is highly elaborated in humans and is believed to continue to develop past birth. The neuropathology of schizophrenia is likely to be heterogeneous and appears to involve developmental abnormalities, with a prominent genetic component. However, the genes involved in the development of the neocortex, and particularly the heteromodal cortex, are not well understood. A candidate-gene approach to schizophrenia using techniques of differential expression might now be feasible and could illuminate the basic neurobiology of the heteromodal cortical network.
Cerebral Cortex↗
Schizophrenia: a disease of heteromodal association cortex?
There is considerable evidence of disturbances of multiple brain areas in schizophrenia. The clinical features and findings from pathologic and neuro-imaging studies suggest primary involvement of a system of parallel distributed networks within the neocortex--the phylogenetically recent heteromodal association cortex (HASC). There is evidence that HASC is a family of higher-order parallel distributed networks of circuits, mediating complex representationally guided behaviors. We argue that HASC regions are especially involved in schizophrenia. Lesions of HASC in the disease are likely to be neurodevelopmental in origin (as evidenced by such examples as reversed planum temporale asymmetry) which have been identified by magnetic resonance imaging as specific regions of disproportionately reduced local gray matter volumes, and by neuropathologic examination as cellular migration disruptions. We believe the hypothesis of preferential heteromodal cortical abnormalities has heuristic value, and briefly indicate how it opens new avenues for investigating this debilitating condition.
Cerebral Cortex↗
CT measurement of suprasellar cistern predicts rate of cognitive decline in Alzheimer's disease.
Previous studies reveal significant relationships between some quantitative computed tomography (CT) measures and level of cognitive functioning in patients with Alzheimer's disease (AD). This study was designed to determine whether measurements from CT scans of AD patients could predict future rates of decline in cognitive function. Subjects were 8 men and 19 women diagnosed with probable AD. CT measures included bifrontal ratio, bicaudate ratio, and areas of lateral ventricles, third ventricle, and suprasellar cistern (SSC). Measures of cognitive and adaptive functioning were obtained at the time of the scan and on follow-up. Of the CT measures, the SSCR (SSC corrected for intracranial area) was the most highly correlated with Mini-Mental State Exam (MMSE) score and other cognitive measures at the time of the scan. Follow-up data were obtained for those 20 individuals who were mildly to moderately demented at the time of the scan (MMSE > or = 10). Rate of change was calculated for each neuropsychological measure. The SSCR correlated significantly with rate of change for MMSE and other measures of cognitive and adaptive functioning. This study demonstrates that CT measurement of the SSC can predict the subsequent rate of neurocognitive decline in AD patients.
Aged↗
Computerized Wisconsin Card Sorting Test: comparison with manual administration.
Computer-based testing in neuropsychology potentially offers important advantages. These include improvement in reliability and more efficient use of resources. For tests such as the Wisconsin Card Sorting Test (WCST) in which examiners must provide on-going feedback to subjects, reliability may be decreased by variability and errors in test presentation, errors in response recording and feedback, and errors in scoring. In addition, an important aspects of neuropsychological assessment is qualitative, that is, observations of the processes by which the subject responds to the test situation. The mechanics of administering the WCST hinder the examiner from allocating attention for observing these processes. Accordingly, we have automated both the administration and the scoring of the WCST. Although potential benefits of computerizing the WCST seem likely, it is possible that factors which cannot at present be duplicated by a computer may effect performance. This study compared performance between the standard manual Heaton version of the WCST and the computerized version. In a group of 33 normal and psychiatric subjects, there were significant differences in the number of Errors and the number of Correct responses, but no significant differences in performance were found for Perseverative Responses, Perseverative Errors, and Set Breaks. The mean number of Categories achieved was 2.0 for the computer administered version and 2.4 for the manual version: this difference was only marginally significant (p = 0.065). The computerized form of the WCST appears to yield similar quantitative results on scores which are most specifically affected by brain injuries in testing with the manual form. Lower variance was seen in the computer scores. This result is consistent with more reliable administration and accuracy in data acquisition and scoring in the computer version. The results overall indicate that the computer version is not a substitute for a human examiner, rather, the computer can function as a reliable partner, carrying out the mechanics of test presentation and scoring, freeing the examiner to more fully support the subject in taking the test and to observe the non-quantitative aspects of test performance.
Adolescent↗
Cingulate gyrus in schizophrenic patients and normal volunteers.
Comparable magnetic resonance imaging (MRI) sections of right and left anterior and posterior cingulate gyrus were measured blindly with a method developed by the authors in 14 patients with schizophrenia (by DSM-III-R criteria) and 14 normal volunteers individually matched to the patients for age, sex, education, and parental socioeconomic status. Interrater reliability met or exceeded 0.92 (k) on all cingulate structures measured. Brain volume in the two groups differed by 2% (normal > schizophrenia), but the difference was not significant. All cingulate gyri measures were nonsignificantly smaller in the patient group by 3-5%. There was an inverse correlation between left anterior cingulate size and severity of hallucinations that was, however, not significant after Bonferroni correction. Lateral asymmetry of the cingulate regions measured was the same in both groups, with the left being nonsignificantly smaller than the right for all regions. We demonstrate a reliable method, unreported thus far in the literature, to measure the cingulate gyrus on MRI; the results suggest that left cingulate gyrus size may be inversely related to severity of hallucinations in schizophrenia.
Adult↗
Structural differences in the cerebral cortex of healthy female and male subjects: a magnetic resonance imaging study.
There are both reproductive and nonreproductive behavioral differences between men and women. Brain regions involved in determining sexual behavior have been reported to differ between the sexes. Nonreproductive, cognitive functional differences between sexes might be reflected in higher-order cortical structural dimorphisms, which have not previously been studied. We hypothesized that cortical regions involved in verbal behavior (which is sexually dimorphic) would differ between sexes. Using magnetic resonance imaging, we assessed gray matter volumes in several cortical regions in 17 women and 43 men. Women had 23.2% (dorsolateral prefrontal cortex) and 12.8% (superior temporal gyrus) greater gray matter percentages (corrected for overall brain size and age) than men in a language-related cortical region, but not in a more visuospatially related cortical region. These data seem to establish sexually dimorphic structural differences in the cerebral cortex, consistent with prior cerebral blood flow reports.
Adult↗