The relationship between eye movement and brain structural abnormalities in patients with schizophrenia and their unaffected relatives

Schizophrenia is associated with subtle eye movement and brain structural abnormalities, but the extent to which these abnormalities occur in the same individuals is unclear. The relationship between quantitative measures of eye movement task performance (smooth pursuit and antisaccade) and MRI volumetric measurements (whole brain volume, prefrontal region, lateral ventricles, third ventricle, hippocampus, and cerebellum) was assessed in 70 patients with schizophrenia or schizoaffective disorder, 105 of their unaffected first-degree relatives and 68 controls. There was a lack of correlation between eye movement and morphometric abnormalities suggesting largely separable neurobiological pathways underlying the morphological and the eye movement deviations that have previously been identified in these patients. However, in the total sample, smaller prefrontal lobe volume was significantly associated with longer latency of correct antisaccades (partial correlation r=-0.22, p=0.01) in line with previous studies demonstrating the importance of frontal lobe structures in performance of the antisaccade task. Also larger third ventricular volume was associated with larger mean amplitude of intrusive saccades during smooth pursuit (r=0.28, p=0.01). There were no significant between-group differences in the relationship between measures of eye movement and morphometry.     

Speed,Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research?

Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD. Edited by Irwin Waldman.     

Eye movement abnormality suggestive of a spatial working memory deficit is present in parents of autistic probands

Autistic probands exhibit impaired spatial accuracy and impaired response suppression errors during a delayed oculomotor response task. Family members of autistic probands, and thus the possible familial nature of these deficits, have not been assessed. Eleven parents of autistic probands and 17 adults from unaffected families, ages 25–50 years, completed oculomotor delayed-response tasks. Parents of autistic probands demonstrated poorer spatial accuracy than the comparison group (p = .002), with no significant differences between groups on percentage of premature saccades or latency of remembered saccades. Spatial working memory deficits, as measured by the delayed oculomotor response task, appear to be familial in families with an autistic proband. These deficits deserve further evaluation as a potential endophenotypic marker for genetic risk for autism.     

Meta-analysis of the P300 and P50 waveforms in schizophrenia

Objective: To determine whether patients with schizophrenia have abnormalities in the P300 and P50 waves and to quantify the magnitude of any differences from controls. Method: We conducted a systematic search for articles published between January 1994 and August 2003 that reported P50 or P300 measures in schizophrenic patients and controls. Metaregression analyses were performed using a random effects model. The pooled standardised effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation. Results: We identified 46 studies suitable for analysis of P300 measures, including 1443 patients and 1251 controls. There were 20 P50 studies including 421 patients and 401 controls. The PSES for the P300 amplitude was 0.85 (95% CI: 0.65 to 1.05; p<0.001), and for the P300 latency was −0.57 (95% CI: −0.75 to −0.38; p<0.001). The PSES of the P50 ratio was −1.56 (95% CI: −2.05 to −1.06; p<0.001). There were no significant differences between patients and controls in P50 latency. Across-study variations in filters, task difficulty, antipsychotic medication and duration of illness did not influence the PSES significantly. Conclusions: This meta-analysis confirms the existence of ERP deficits in schizophrenia. The magnitude of these deficits is similar to the most robust findings reported in neuroimaging and neuropsychology in schizophrenia.     

Identification of quantitative trait loci for prepulse inhibition in rats

Abstract Introduction. Schizophrenia is a common and debilitating psychiatric disorder that is partially under genetic control. Because of difficulties in mapping the genes that influence susceptibility to schizophrenia in humans, there has been substantial interest in mapping genes that control endophenotypes for schizophrenia in both human and rodent populations. Deficient prepulse inhibition (PPI) of the startle response has shown promise as an endophenotype for schizophrenia, as well as several other psychiatric disorders. Methods. Brown Norway (BN/SsNHsd) and Wistar Kyoto (WKY/lj-cr) rats were used because they show a large, unconfounded difference in PPI. We used interval mapping methods to identify quantitative trait loci (QTL) for PPI in a backcross population. Results. We identified a QTL on chromosome 2 with a LOD score of 3.63 and a suggestive QTL on chromosome 18 with a LOD score of 2.71. Conclusions. Both of the identified regions contain several candidate genes. Furthermore, the implicated rat chromosomes are syntenic with human chromosomal regions that have been reported to contain QTL for schizophrenia, bipolar disorder, and Tourette's syndrome. These results identify the chromosomal location of gene(s) that modulate an endophenotype for schizophrenia, and other psychiatric disorders, and may provide a shortcut to identifying specific genes and/or biochemical pathways involved in human psychiatric diseases. Electronic Publication     

Selective Breeding of Reduced Sensorimotor Gating in Wistar Rats

Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is reduced in some neuropsychiatric disorders (e.g. schizophrenia). Animal models have revealed insight into the neuronal and pharmacological underpinnings of PPI-deficits. Recent work has shown that a PPI-deficit can be selectively bred in Wistar rats and is already stable in the second filial generation. We here report on developmental and parametric characteristics of sensorimotor gating deficits in the 4th and 6th filial generation of male rats selectively bred for low PPI (low PPI) compared to rats with normal levels of PPI (high PPI). Low PPI rats showed significantly reduced PPI and variable startle magnitude (in pulse alone trials) along with reduced short-term habituation of startle as adults. Reduced PPI in the low PPI rats was found throughout development (tested on postnatal days 21, 35, 49, 70). PPI-deficits in the low PPI rats were evident at prepulse intensities ranging from 62–86 dB and for interstimulus intervals ranging between 30–1000 ms. These behavioral data add to a growing body of knowledge about the genetic basis of sensorimotor gating deficits and suggest that low PPI rats have potential use as an intermediate phenotype in schizophrenia research. The stable phenotype of breeding-induced PPI-deficits and reduced startle habituation indicates that PPI has strong genetic determinants and that selectively bred rats can be used for future neurophysiological, anatomical, pharmacological, and genomic analyses. Edited by Stephen Maxson.     

Cortical Serotonin Type-2 Receptor Density in Parents of Children with Autism Spectrum Disorders

Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [¹⁸F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [¹⁸F]setoperone intensity in regions of interest (ROI) to cerebellar intensity. Cortical 5-HT2 BPs were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD. Further research should examine the relationship of reduced 5-HT2 receptor expression to underlying causation and to clinical and neurochemical correlates of autistic behavior.