Low maternal hemoglobin during pregnancy and diminished neuromotor and neurocognitive performance in offspring with schizophrenia.

OBJECTIVE: Previous research has linked maternal anemia during pregnancy with increased risk for schizophrenia in offspring. However, no study has sought to determine whether this early insult leads to a more severe form of the disorder, characterized by worsened motor and neurocognitive functioning. METHOD: Subjects were 24 cases diagnosed with schizophrenia and 22 controls from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Hemoglobin values were measured throughout pregnancy. Among offspring, psychiatric diagnoses were determined through semi-structured interviews and medical records review and comprehensive neurocognitive assessment batteries were conducted in adulthood. RESULTS: Results indicated that among cases decreases in maternal hemoglobin led to significant decreases in scores on the Grooved Pegboard test, the Finger Tapping test and the Wechsler Adult Intelligent Scales (WAIS) information subtest. In contrast, controls only exhibited decreases in performance on the California Verbal Learning Test (CVLT) long-delay recall after fetal exposure to lower hemoglobin. There were also significant interactions between hemoglobin and case status for all of the motor tasks. CONCLUSIONS: These findings support the hypothesis that fetal exposure to decreases in maternal hemoglobin is related to preferentially poorer neuromotor function among cases compared to controls, as well as general intellectual difficulties among cases. Controls were relatively unaffected by decreased maternal hemoglobin, which suggests that liability to schizophrenia renders cases susceptible to the deleterious influences of in utero exposure to decreases in maternal hemoglobin.

Maternal-fetal blood incompatibility and neuromorphologic anomalies in schizophrenia: Preliminary findings.

Prior research has shown that maternal-fetal Rhesus (Rh) and ABO blood incompatibility increase the risk for schizophrenia. In the present study, the relationship between blood incompatibility and volumes of brain structures previously implicated in schizophrenia was assessed in schizophrenia cases and controls from a large birth cohort. Rh/ABO incompatible cases had significantly reduced cortical gray matter volume compared to compatible cases, a finding which appears to be driven by significant volume reductions in the dorsolateral prefrontal cortex and inferior frontal cortex. Larger hippocampal and putamen volumes were also observed in exposed controls compared to unexposed controls. Although the sample size is small and replications are required, these data suggest that maternal-fetal blood incompatibility may increase the risk for altered brain morphology in both schizophrenia and in controls. The findings also suggest that the larger hippocampal volume in exposed controls may indicate a mechanism of adaptive resilience which diminishes the risk that controls will develop schizophrenia.

Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8.

BACKGROUND: Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. METHODS: Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. RESULTS: Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. CONCLUSION: Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

Cognitive decline in schizophrenia from childhood to midlife: a 33-year longitudinal birth cohort study.

BACKGROUND: We examined cognitive deficits before and after onset of schizophrenia in a longitudinal study that: 1) covers a long time interval; 2) minimizes test unreliability by including the identical measure at both childhood and post-onset cognitive assessments; and 3) minimizes bias by utilizing a population-based sample in which participants were selected neither for signs of illness in childhood nor for being at risk for schizophrenia. METHODS: Participants in the present study, Developmental Insult and Brain Anomaly in Schizophrenia (DIBS), were ascertained from an earlier epidemiologic study conducted in Oakland, CA. The original version of the Peabody Picture Vocabulary Test (PPVT), a test of receptive vocabulary, was administered at age 5 or 9 and repeated as part of the DIBS study at an average age of 40. There were 10 DIBS cases with DSM-IV schizophrenia or schizoaffective disorder and 15 demographically similar DIBS controls with both child and adult PPVT scores. RESULTS: Cases scored significantly lower than controls in childhood (d=0.95) and adulthood (d=1.67). Residualized scores indicating the number of SDs above or below one's predicted adult score revealed a mean case-control difference of -1.51SDs, consistent with significant relative decline over time among the cases (p<0.0013). CONCLUSIONS: In this prospective study, individuals who developed adult schizophrenia manifested impaired receptive vocabulary during childhood and further relative deterioration (or lack of expected improvement) between childhood and midlife. Limitations should also be acknowledged, including the small sample size and the fact that we cannot be certain when the continued deterioration took place.

Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia.

OBJECTIVE: Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. The authors examined whether prenatal infection is associated with executive dysfunction in patients with schizophrenia. METHOD: The authors assessed the relationship between serologically documented prenatal exposure to influenza and toxoplasmosis and performance on the Wisconsin Card Sorting Test and the Trail Making Test, part B (Trails B), as well as other measures of executive function, in 26 patients with schizophrenia from a large and well-characterized birth cohort. RESULTS: Patients who were exposed to infection in utero committed significantly more total errors on the Wisconsin Card Sorting Test and took significantly more time to complete the Trails B than unexposed patients. Exposed patients also exhibited deficits on figural fluency, letter-number sequencing, and backward digit span. CONCLUSIONS: Prenatal infections previously associated with schizophrenia are related to impaired performance on the Wisconsin Card Sorting Test and Trails B. The pattern of results suggests that cognitive set-shifting ability may be particularly vulnerable to this gestational exposure. Further work is needed to elucidate the specificity of prenatal infection to these executive function measures and to examine correlates with neuroanatomic and neurophysiologic anomalies.

Prenatal infection and cavum septum pellucidum in adult schizophrenia.

Increased length of the cavum septum pellucidum (CSP) and in utero infection are each associated with increased risk of schizophrenia. Hence, we examined whether prenatal infections are related to CSP length in schizophrenia patients. In a well-characterized birth cohort, in utero infection was assessed using serologic biomarkers or physician diagnoses. Magnetic resonance images were acquired, and CSP length was quantified by a standard protocol. In utero infection was associated with increased CSP length in exposed schizophrenia cases compared to unexposed cases, suggesting that prenatal infection plays a role in a neurodevelopmental morphologic anomaly that has been related previously to schizophrenia.

Automatic relevance determination for identifying thalamic regions implicated in schizophrenia.

There have been many theories about and computational models of the schizophrenic disease state. Brain imaging techniques have suggested that abnormalities of the thalamus may contribute to the pathophysiology of schizophrenia. Several studies have found the thalamus to be altered in schizophrenia, and the thalamus has connections with other brain structures implicated in the disorder. This paper describes an experiment examining thalamic levels of the metabolite N-acetylaspartate (NAA), taken from schizophrenics and controls using in vivo proton magnetic resonance spectroscopic imaging. Automatic relevance determination was performed on neural networks trained on this data, identifying NAA group differences in the pulvinar and mediodorsal nucleus, underscoring the importance of examining thalamic subregions in schizophrenia.

The Wisconsin Card Sort Test and P300 responses to novel auditory stimuli in schizophrenic patients.

The authors studied the relationship between performance on the Wisconsin Card Sort Test (WCST) and P300 activity in schizophrenics and normal controls. Fourteen male predominantly medicated schizophrenics and matched non-ill controls were administered the WCST and tests of temporal lobe (delayed verbal and spatial memory) and general intellectual functioning (Shipley). Patients were rated with negative and positive symptom scales extracted from the Brief Psychiatric Rating Scale. Subjects performed a tone discrimination task requiring identification of rare targets in both a standard oddball paradigm and a three-stimulus paradigm that included rare novel sounds. Reference independent data from 16 scalp electrodes yielded Global Field Power (GFP), from which P300 latency was determined. P300 amplitude measures included amplitude at this identified latency as well as amplitude integrated over a 100 ms time window centered over it. These amplitude measures were examined at six selected electrode locations. Schizophrenics produced smaller P300 responses that tended to be slower, but there were no group differences in the relationships between neuropsychological performance and P300 responses. Across diagnostic groups percent perseverative errors predicted lower integrated and peak P300 amplitude during the novel but not the standard oddball paradigm. The effect on integrated P300 amplitude was localized to anterior leads after novel stimuli. Negative symptoms predicted lower WCST performance, lower integrated P300 amplitude, and smaller GFP after novel stimuli. Positive symptoms predicted reduced overall GFP and specific but inconsistent reductions in parietal P300 amplitude. The results suggest relationships between dorsolateral prefrontal competence, P300 activity in response to stimulus novelty, and negative symptoms in schizophrenic patients, paralleling findings obtained from blood flow and other measures of brain activity.

N-acetylaspartate reductions in the mediodorsal and anterior thalamus in men with schizophrenia verified by tissue volume corrected proton MRSI.

OBJECTIVE: Deficits in the mediodorsal and anterior nuclei of the thalamus may contribute to the psychopathological symptoms of schizophrenia. These thalamic nuclei have been found to be abnormal in schizophrenia and have close connections with other brain structures implicated in the disorder. We therefore examined schizophrenia-related alterations in brain metabolite levels specifically in the mediodorsal and anterior thalamic subregions. METHOD: We used in vivo proton magnetic resonance spectroscopic imaging ((1)H MRSI) to measure N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine+phosphocreatine (Cr) in the mediodorsal and anterior thalamus in 22 male patients with schizophrenia and 22 male controls. Magnetic resonance imaging (MRI) tissue segmentation and thalamic volume mask techniques were performed to distinguish the thalamus, extrathalamic gray and white matter, and CSF within the spectroscopic voxels. RESULTS: Compared to healthy subjects, patients with schizophrenia had significantly lower NAA in the mediodorsal and anterior thalamus bilaterally. No significant differences in Cho or Cr levels were seen. NAA was significantly higher in the left thalamus relative to the right in both groups. We found a strong negative correlation between left thalamic NAA and duration of illness, even after partialling out the effect of age. Tissue segmentation and thalamic volume mask techniques detected no group or lateralized differences in tissue type or CSF percentages, demonstrating that the metabolite reductions were not an artifact of spectroscopic voxel heterogeneity. CONCLUSIONS: These findings suggest diminished function and/or structure in the mediodorsal and anterior thalamus in male patients with schizophrenia and support earlier research demonstrating schizophrenia-related abnormalities in the thalamus and its circuitry.

Decreased cortical gray and cerebral white matter in male patients with familial bipolar I disorder.

BACKGROUND: Previous MRI studies of bipolar disorder have failed to consistently demonstrate cortical gray or cerebral white matter tissue loss, as well as sulcal or ventricular enlargement. The inconsistencies are most likely due to the clinical and gender heterogeneity of the study populations as well as the different MRI acquisition and processing techniques. The objective of this study was to determine if there was a cortical gray matter and cerebral white matter deficit as well as sulcal and ventricular enlargement in a homogeneous sample of euthymic male patients with familial bipolar I disorder. METHODS: MRI tissue segmentation was utilized to obtain cortical gray matter, cerebral white matter, ventricular cerebrospinal fluid (CSF), and sulcal CSF volumes in 22 euthymic males with familial bipolar I disorder and 32 healthy male control subjects. RESULTS: Relative to the controls, the familial bipolar I patients demonstrated: (1) significant reductions of both cortical gray matter and cerebral white matter volumes; and (2) significant increases in both sulcal and ventricular CSF volumes. In the bipolar group, there was a significant negative correlation between cortical gray matter volume and sulcal CSF volume. LIMITATIONS: Small sample size, retrospective interviews, possible medication effects. CONCLUSIONS: These results provide evidence for significant cortical gray matter and cerebral white matter deficits and associated sulcal and ventricular enlargement in euthymic males with familial bipolar I disorder.

Lower concentration of hippocampal N-acetylaspartate in familial bipolar I disorder.

OBJECTIVE: Previous studies attempting to identify neuropathological alterations in the hippocampus in bipolar disorder have been inconclusive. The objective of this study was to determine if the concentration of N-acetylaspartate, a neuronal and axonal marker, was lower in subjects with familial bipolar I disorder than in healthy comparison subjects, suggesting possible neuronal loss, neuronal dysfunction, or neuropil reduction in bipolar I disorder. METHOD: N-acetylaspartate, choline, and creatine in the right and left hippocampus were measured in 15 euthymic male patients with familial bipolar I disorder and 20 healthy male comparison subjects by using proton magnetic resonance spectroscopy ((1)H-MRS). RESULTS: Relative to the comparison group, the patients with bipolar I disorder demonstrated significantly lower concentrations of N-acetylaspartate and creatine but normal choline concentration in both the right and left hippocampus. There were no group or lateralized differences in the percentages of different tissue types within the MRS voxels, suggesting that the hippocampal N-acetylaspartate and creatine alterations were not an artifact of variations in tissue types represented in the voxels. There was also a significant negative correlation between N-acetylaspartate concentration in the right hippocampus and illness duration, after adjustment for the effects of age. CONCLUSIONS: This preliminary study provides support for the existence of neuronal loss, neuronal metabolic dysfunction, or interneuronal neuropil reduction in the hippocampal region in male patients with familial bipolar I disorder. The finding of normal hippocampal choline levels in these patients does not provide support for ongoing myelin breakdown or glial cell proliferation in this brain region in familial bipolar I disorder. The significant association between illness duration and N-acetylaspartate concentration in the right hippocampus supports the idea that neuronal pathology may increase with disease progression and that this effect may be lateralized, involving the right but not the left hippocampus.

Anterior hippocampal volume reduction in male patients with schizophrenia.

Quantitative high resolution magnetic resonance imaging (MRI) was utilized to measure anterior, posterior, and total hippocampal volumes in 27 male patients with chronic schizophrenia and 24 male controls. To optimize measurement techniques, hippocampal volumes were: (1) acquired with 1.4-mm slices; (2) excluded with the amygdala; (3) normalized for position; and (4) corrected for total intracranial volume (ICV). The results of a linear mixed effects regression analysis, which made it possible to analyze total anterior and total posterior hippocampal volumes separately, indicated that the anterior hippocampus was significantly smaller in the schizophrenic group relative to the control group. There were no significant group differences with respect to posterior hippocampal volumes, and no significant correlations between hippocampal volumes and illness duration. A significant lateralized asymmetry was also noted in both groups with the right hippocampal volume being larger than the left. These preliminary findings support a significant anterior hippocampal volume reduction in men with schizophrenia as well as a similar hippocampal volume asymmetry in both male controls and schizophrenics.

Magnetic resonance imaging of the thalamus in male patients with schizophrenia.

Thalamic abnormalities have been hypothesized to explain much of the psychopathology in schizophrenia, however, quantitative magnetic resonance imaging (MRI) studies have yielded discrepant results as to whether there are thalamic volume alterations. The current study utilized high resolution MRI and an axial voluming protocol to determine if there was a significant reduction in the volume of the thalamus in patients with schizophrenia. Quantitative analysis was performed on magnetic resonance images of the brain in 41 male medicated schizophrenic patients and 39 male normal control subjects similar in age, education and handedness. There were no group differences in thalamic volumes between controls and patients with schizophrenia, even after adjusting for intracranial volume, total brain tissue volume, and gray matter volume. There were also no significant correlations between thalamic volume and either current neuroleptic dose or illness duration. However, there was a significant right greater than left thalamic volume asymmetry in schizophrenics and controls, and the degree of thalamic volume asymmetry was similar in both groups. The failure to detect any significant difference in thalamic volumes may be due to the heterogeneity of the schizophrenic population and as yet undetermined chronic effects of neuroleptic medication on the thalamus. However, another reasonable explanation for the study findings is that quantitative MRI voluming of the entire thalamus may not be sensitive enough to detect more subtle regional neuropathology within the thalamus.