Wiscosin card sorting task in patients with schizophrenia and thier siblings]

OBJECTIVE: This study's first objective was to confirm that patients with schizophrenia and their nonmentally ill siblings share the same impaired executive function when compared to healthy control subjects. The second objective was to study the relation between Wisconsin card sorting task (WCST) performance and the persistence and severity of clinical symptoms, as well as different clinical dimensions. METHOD: Ninety subjects were involved in this study, divided in 3 groups of 30 each: one group of patients with schizophrenia, one group of their siblings, and a control group. Symptom severity was assessed with the Positive and Negative Syndrome Scale (PANSS), and social functioning was measured by the Global functioning scale (GFS). The WCST was administered to all 3 groups. RESULTS: Patients with schizophrenia and their siblings had a significantly lower WCST performance than control subjects. Statistical analysis showed that the patient group had a significantly greater impaired WCST performance than the 2 other groups. Siblings also had a significantly lower performance than the control subjects. Furthermore, no significant relation was found between WCST performance and other variables, including age, gender, education, illness duration, treatment, and different PANSS and GFS scores. CONCLUSION: Patients with schizophrenia and their nonmentally ill siblings share the same impaired executive function. These findings suggest that WCST performance can be considered a schizophrenia vulnerability marker in siblings of patients with schizophrenia.     

Neurological soft signs in patients with schizophrenia and their unaffected siblings: frequency and correlates in two ethnic and socioeconomic distinct populations

Recent studies have suggested that ethnicity and socioeconomic status may have an impact on the frequency and significance of neurological soft signs (NSS). However, this impact has not been adequately assessed. The objectives were to determine the NSS scores in patients with schizophrenia and their unaffected siblings and to examine the clinical and therapeutic correlates of NSS in two ethnic and socioeconomic distinct populations. Two independent replicate studies were carried out: (1) a French Caucasian sample of 69 patients with schizophrenia, 43 of their unaffected siblings and 108 control subjects; (2) a Tunisian sample of 66 patients with schizophrenia, 31 of their unaffected siblings and 60 control subjects. NSS were assessed with a multidimensional scale, previously validated in drug-naïve and treated samples of patients with schizophrenia. Both patient groups were assessed with the positive and negative syndrome scale (PANSS), the clinical global impressions (CGI) and the global assessment of functioning. NSS total scores were significantly higher in patients with schizophrenia comparatively to siblings and to controls in both studies. The two sibling groups had also higher NSS scores than controls. In addition, NSS total scores were correlated to the PANSS negative and disorganization sub-scores, to the CGI-severity of illness and to a low educational level in both studies. These studies provide a confirmation in two distinct samples of the high prevalence of NSS in patients with schizophrenia, and in their biological relatives, independently of their respective ethnic and socioeconomic origins.     

Prepulse facilitation and prepulse inhibition in schizophrenia patients and their unaffected siblings.

BACKGROUND: Deficits in schizophrenia patients and their first-degree relatives have been reported in prepulse inhibition (PPI), a phenomenon that measures an early stage of information processing (sensorimotor gating). It is less clear whether these information processing deficits extend to prepulse facilitation (PPF), which measures a later stage of generalized alerting or orienting. METHODS: This study examined three separate issues: first, whether schizophrenia patients have deficits in PPI and PPF; second, whether the siblings of patients show deficits in these processes; and third, whether prepulse duration influences the degree of the deficits. These issues were examined in 76 schizophrenia patients, 36 of their siblings, and 41 normal control subjects. RESULTS: Patients and siblings did not differ from control subjects in PPI, perhaps due to the use of different procedural parameters compared with other laboratories that have consistently found PPI deficits in schizophrenia patients. Patients and their siblings produced significantly less PPF than control subjects. For both PPI and PPF, prepulse duration was not a significant factor. CONCLUSIONS: These results imply that PPF deficits reveal a generalized alerting or orienting deficit that is present in both schizophrenia patients and their siblings, suggesting that this deficit may be tapping an endophenotypic vulnerability factor.     

Effects of lithium on saccadic eye movements in healthy subjects in a ten-day double-blind placebo-controlled cross-over pilot study

INTRODUCTION: Although previous studies have shown that lithium modifies eye movements or psychomotor speed, no studies have ever explored the predictive saccades or memory guided saccades during lithium administration. We took the objective to determine the influence of lithium in pseudo-random, predictive or memory-guided saccades in healthy subjects with a view to detect reduced psychomotor speed, inability to anticipate incoming events, or working memory deficits. METHODS: A ten day lithium-placebo randomized double-blind cross-over pilot study was carried out with 12 healthy male volunteers. The cognitive assessment included pseudo-random, predictive and memory guided saccades before and after lithium and placebo periods. A biological assay substantiated the lithium effect on TSH and thyroid hormones. RESULTS: There was no change in pseudo-random or memory guided saccades when comparing lithium or placebo administration. However the ratio of anticipated saccades decreased under the lithium sequence while it remained stable under placebo. Also, subjects having lithium serum levels of > 0.5 meq/l had longer latencies in anticipated saccades. CONCLUSION: The findings do not support a major effect of lithium on alertness or on working memory, although the dosage and duration of lithium was sufficient to modify TSH blood level. Nevertheless, lithium treatment was associated with decreased anticipation in predictive saccades, suggesting this could reflect a reduced ability to anticipate quick motor movements and could be related to the well-known effect of lithium as an anti-impulsive medication.     

Smooth pursuit performance in families with multiple occurrence of schizophrenia and nonpsychotic families.

BACKGROUND: Eye tracking dysfunction (ETD) has been put forward as a trait marker for biological susceptibility to schizophrenia with the hope of identifying a link to specific cerebral lesions. METHODS: Eye movements were recorded using infrared oculography in 8 families (67 members) showing multiple occurrence of schizophrenia and in 9 nonpsychotic families (80 members). Triangle wave stimuli at 15 degrees/s and 30 degrees/s were used and gains (eye velocity/target velocity), rates and amplitudes of different saccade categories (catch-up, back-up, anticipatory saccades, and squarewave-jerks) were determined. RESULTS: In the relatives, the same deficit in maintenance of smooth pursuit performance was found as was seen in the schizophrenic patients. This deficit, which was not observed in the nonpsychotic families, consisted of lower gains for leftward as compared to rightward pursuit. This was emphasized most clearly at 30 degrees/s and was associated with an excess of catch-up saccades in the schizophrenic patients, whereas in the relatives a tendency to exhibit more and larger anticipatory saccades was observed. CONCLUSIONS: The results confirm the hypothesis that eye-tracking dysfunction is a phenotypic marker for genetic liability to schizophrenia. Neurophysiologically, a cerebral dysfunction which includes one or more of the oculomotor centers can be assumed in subjects who carry a genetic susceptibility to schizophrenia.     

Physiology of schizophrenia, bipolar disorder, and schizoaffective disorder

OBJECTIVE: Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder. METHOD: Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance. RESULTS: Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings. CONCLUSION: A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups.     

Focal and global brain measurements in siblings of patients with schizophrenia

Background: It remains unclear whether structural brain abnormalities in schizophrenia are caused by genetic and/or disease-related factors. Structural brain abnormalities have been found in nonpsychotic first-degree relatives of patients with schizophrenia, but results are inconclusive. This large magnetic resonance imaging study examined brain structures in patients with schizophrenia, their nonpsychotic siblings, and healthy control subjects using global and focal brain measurements. Methods: From 155 patients with schizophrenia, their 186 nonpsychotic siblings, and 122 healthy controls (including 25 sibling pairs), whole-brain scans were obtained. Segmentations of total brain, gray matter (GM), and white matter of the cerebrum, lateral and third ventricle, and cerebellum volumes were obtained. For each subject, measures of cortical thickness and GM density maps were estimated. Group differences in volumes, cortical thickness, and GM density were analyzed using Structural Equation Modeling, hence controlling for familial dependency of the data. Results: Patients with schizophrenia, but not their nonpsychotic siblings, showed volumetric differences, cortical thinning, and reduced GM density as compared with control subjects. Conclusions: This study did not reveal structural brain abnormalities in nonpsychotic siblings of patients with schizophrenia compared with healthy control subjects using multiple imaging methods. Therefore, the structural brain abnormalities observed in patients with schizophrenia are for the largest part explained by disease-related factors.     

Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia

OBJECTIVE: The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition and working memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified. METHOD: The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizophrenic, cognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects. RESULTS: In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia. CONCLUSIONS: These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contribute to inefficient prefrontal information processing will increase risk for schizophrenia.     

Obstetric complications in patients with schizophrenia and their unaffected siblings.

OBJECTIVE: We sought to explore whether obstetric complications (OCs) are more likely to occur in the presence of familial/genetic susceptibility for schizophrenia or whether they themselves represent an independent environmental risk factor for schizophrenia. METHODS: The presence of OCs was assessed through maternal interview on 216 subjects, comprising 36 patients with schizophrenia from multiply affected families, 38 of their unaffected siblings, 31 schizophrenic patients with no family history of psychosis, 51 of their unaffected siblings and 60 normal comparison subjects. We examined the familiality of OCs and whether OCs were commoner in the patient and sibling groups than in the control group. RESULTS: OCs tended to cluster within families, especially in multiply affected families. Patients with schizophrenia, especially those from multiply affected families, had a significantly higher rate of OCs compared to normal comparison subjects, but there was no evidence for an elevated rate of OCs in unaffected siblings. CONCLUSION: Our data provides little evidence for a link between OCs and genetic susceptibility to schizophrenia. If high rates of OCs are related to schizophrenia genes, this relationship is weak and will only be detected by very large sample sizes.     

Familial aggregation of eye-tracking endophenotypes in families of schizophrenic patients

BACKGROUND: Abnormal smooth pursuit eye movements (SPEMs) are some of the most reproducible biological changes associated with the susceptibility for schizophrenia. Recent studies have suggested that deficit in predictive pursuit, a specific component of the SPEMs, marks schizophrenia susceptibility. OBJECTIVE: To test whether predictive pursuit contains less extraneous noise and may be under more direct genetic control than the traditional measure of overall pursuit performance using maintenance pursuit gain. DESIGN: Familial aggregation estimation of the predictive pursuit measure and the traditional maintenance pursuit measure in sibling pairs from families of schizophrenic patients. SETTING: Outpatient clinics. PARTICIPANTS: Patients with schizophrenia and their full siblings were recruited, provided that at least 1 sibling pair could be formed per family. Ninety-two siblings were recruited into the study. They formed 70 sibling pairs. Ninety healthy control subjects were also recruited using targeted local community advertisements based on patients' county of residence, aiming to capture the basic demographics of the regions from which the patients were recruited. MAIN OUTCOME MEASURES: Familial correlations and heritability estimates of 2 SPEM measures: maintenance pursuit gain and predictive pursuit gain. RESULTS: The sibling intraclass correlation coefficient of the predictive pursuit gain (r = 0.45-0.48) was significantly higher than that of maintenance pursuit gain (r = 0.02-0.20) (P = .005-.007). Variance component analysis suggested a high genetic loading for predictive pursuit (heritability = 0.90, SE = 0.22; P<.001) but relatively low heritability in the traditional maintenance pursuit measure (heritability = 0.27, SE = 0.21; P = .08). CONCLUSION: These results suggest that predictive pursuit may index stronger genetic effect and may be better suited for genetic studies than the traditional SPEM measure of maintenance pursuit gain.     

Poor performance in smooth pursuit and antisaccadic eye-movement tasks in healthy siblings of patients with schizophrenia

This study examines the area of eye movement dysfunctions as an indicator of vulnerability to schizophrenia. Eye movement performance was investigated with three different paradigms: Smooth Pursuit Eye Movements (SPEM); Visually Guided Saccades (VGS); and Antisaccades (AS) in 21 clinically stable patients with schizophrenia, 21 of their healthy, biological full siblings and 21 healthy control subjects. The three groups did not differ on VGS performance, whereas both patients and their siblings showed lower SPEM gain, an increased catch-up Saccades (CUS) rate, reduced AS accuracy and an increased number of AS errors in comparison to control subjects. In addition, patients with schizophrenia exhibited increased AS latency. Among the patients with schizophrenia, eye movement abnormalities did not correlate with age, gender, clinical state or duration of illness. These data suggest that abnormalities of SPEM and AS may represent neurobiological markers of the vulnerability to schizophrenia in individuals at high genetic risk for the disease.     

Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia

Smooth pursuit eye movement (SPEM) and antisaccade deficits have been proposed as endophenotypes in the search for schizophrenia genes. We assessed these measures in 24 schizophrenia patients, 24 of their healthy siblings, and 24 healthy controls closely matched to the siblings. Between-group differences were assessed using a random effects regression model taking into account the relatedness between patients and siblings. Patients showed reduced SPEM gain, increased frequency of saccades during pursuit, increased antisaccade error rate, and reduced antisaccade gain compared to controls. Siblings performed intermediate, i.e. between patients and controls, on most measures, but were particularly characterised by reduced antisaccade gain. SPEM gain at one target velocity was significantly correlated between patients and siblings, highlighting the necessity of taking into account within-family correlations in the statistical analysis of between-group differences. It is concluded that subtle SPEM and antisaccade deficits are observed in clinically unaffected siblings of schizophrenia patients; these deficits may be useful markers of genetic liability to schizophrenia.     

Evidence from increased anticipation of predictive saccades for a dysfunction of fronto-striatal circuits in obsessive-compulsive disorder

In obsessive-compulsive disorder (OCD), a dysfunction of neuronal circuits involving prefrontal areas and the basal ganglia is discussed that implies specific oculomotor deficits. Performance during reflexive and predictive saccades, antisaccades and predictive smooth pursuit was compared between patients with OCD (n=22), patients with schizophrenia (n=21) and healthy subjects (n=24). Eye movements were recorded by infrared reflection oculography. In both patient groups, higher frequencies of anticipatory saccades with reduced amplitudes in the predictive saccade task were observed. Additionally, reduced smooth pursuit eye velocity and increased frequencies of saccadic intrusions during smooth pursuit as well as increased error rates in the antisaccade task were demonstrated for patients suffering from schizophrenia. Patients with OCD and schizophrenia revealed different patterns of oculomotor impairment: whereas increased anticipation of predictive saccades provides evidence for a dysfunction of the circuit between the frontal eye field and the basal ganglia in both groups, results from the antisaccade task imply additional deficits involving the dorsolateral prefrontal cortex in schizophrenic patients. Furthermore, the cortical network for smooth pursuit (especially the frontal eye field) is also assumed to be disturbed in schizophrenia.     

Hippocampal deformities in the unaffected siblings of schizophrenia subjects.

BACKGROUND: Neuroanatomical abnormalities have been reported in schizophrenia subjects and their relatives and may be related to genetic vulnerability. The objective of this study was to further elucidate hippocampal deformities as a marker of genetic vulnerability for schizophrenia. METHODS: Magnetic resonance scans were collected in 13 pairs of schizophrenics and their unaffected siblings from families with multiple affected members, in 12 schizophrenics from families without another affected member, and in 10 healthy controls. Hippocampal volume and shape were compared using large-deformation high-dimensional brain mapping. RESULTS: Decreases in hippocampal volume, covaried for total cerebral volume, were observed in the schizophrenia subjects from families with multiple affected members, as well as in their unaffected siblings. Shape analysis demonstrated that both groups of schizophrenia subjects, as well as the unaffected siblings, could be distinguished from the controls; however, no significant difference in hippocampal shape was found between the schizophrenia subjects and their unaffected siblings. Visualization of the pattern of hippocampal shape deformity in both groups of schizophrenia subjects and in the unaffected siblings showed inward deformities of the head of the hippocampus. CONCLUSIONS: Deformations of hippocampal anatomy may be related to the genetic vulnerability of acquiring schizophrenia.     

Cingulate gyrus neuroanatomy in schizophrenia subjects and their non-psychotic siblings

BACKGROUND AND METHODS: In vivo neuroimaging studies have provided evidence of decreases in the gray matter volume of the cingulate gyrus in subjects with schizophrenia as compared to healthy controls. To investigate whether these changes might be related to heritable influences, we used high-resolution magnetic resonance imaging and labeled cortical mantle distance mapping to measure gray matter volume, as well as thickness and the area of the gray/white interface, in the anterior and posterior segments of the cingulate gyrus in 28 subjects with schizophrenia and their non-psychotic siblings, and in 38 healthy control subjects and their siblings. RESULTS: There was a significant effect of group status on posterior cingulate cortex (PCC) gray matter volume (p=0.02). Subjects with schizophrenia and their non-psychotic siblings showed similar reductions of gray matter volume (~10%) in the PCC compared to healthy control subjects and their siblings. In turn, trend level effects of group status were found for thickness (p=0.08) and surface area (p=0.11) of the PCC. In the combined group of schizophrenia subjects and their siblings, a direct correlation was observed between PCC gray matter volume and negative symptoms. However, the reduction in PCC gray matter volume in schizophrenia subjects and their siblings was proportionate to an overall reduction in whole cerebral volume, i.e., the effect of group on the volume of the PCC became non-significant when cerebral volume was included as a covariate (p=0.4). There was no significant effect of group on anterior cingulate cortex volume, thickness, or area. CONCLUSIONS: Our findings suggest that decreases in the gray matter volume of the PCC occur in schizophrenia subjects and their siblings. The presence of such decreases in the non-psychotic siblings of schizophrenia subjects suggests that heritable factors may be involved in the development of cortical abnormalities in schizophrenia.     

Visual scan paths in first-episode schizophrenia and cannabis-induced psychosis

OBJECTIVE: Patterns of successive saccades and fixations (scan paths) that are made while viewing images are often spatially restricted in schizophrenia, but the relation with cannabis-induced psychosis has not been examined. We used higher-order statistical methods to examine spatiotemporal characteristics of scan paths to determine whether viewing behaviour was distinguishable on a continuum. METHODS: Patients with early acute first-episode paranoid schizophrenia (SCH; n = 11), cannabis-induced psychosis (CIP; n = 6) and unaffected control subjects (n = 22) undertook a task requiring free viewing of facial, fractal and landscape images for 5 seconds while their eye movements were recorded. Frequencies and distributions of saccades and fixations were calculated in relation to image regions examined during each trial. RESULTS: Findings were independent of image category, indicating generalized scanning deficits. Compared with control subjects, patients with SCH and CIP made fewer saccades and fewer fixations of longer duration. In turn, the spatial distribution of fixations in CIP patients was more clustered than in SCH and control subjects. The diversity of features fixated in subjects with CIP was also lower than in SCH patients and control subjects. CONCLUSION: A continuous approach to characterizing scan path changes in different phenotypes suggests that CIP shares some of the abnormalities of SCH but can be distinguished with measures that are sensitive to cognitive strategies active or inhibited during visual exploration.     

Neuronal substrate of the saccadic inhibition deficit in schizophrenia investigated with 3-dimensional event-related functional magnetic resonance imaging

BACKGROUND: Several studies have shown that the ability to suppress automatic saccadic eye movements is impaired in patients with schizophrenia as well as in their first-degree relatives, and suggest that this impairment is a potential vulnerability marker for schizophrenia. The neurobiological mechanisms underlying normal saccade production and inhibition, revealed in primate studies, indicate that the impairment may result from a failure of the oculomotor system to effectively exert inhibitory control over brainstem structures. Functional localization of the affected brain structure(s) potentially provides a physiological measure for the investigation of vulnerability markers in schizophrenia. METHODS: The hemodynamic response to discrete visual stimuli was measured during prosaccades (saccades toward a peripheral stimulus), antisaccades (saccades toward a position opposite to a peripheral stimulus), and active fixation (holding fixation and ignoring a peripheral stimulus) in 16 patients with schizophrenia receiving atypical neuroleptics and 17 healthy control subjects using an event-related functional magnetic resonance imaging task design. RESULTS: Brain responses were detected in the frontal and parietal regions of the oculomotor system in all 3 tasks. Patients made more errors during inhibition tasks and exhibited a selective failure to activate the striatum during the inhibition of saccades. In other regions that were active during inhibition, specifically the supplementary and frontal eye fields, no difference was found between patients and control subjects. CONCLUSIONS: A frontostriatal network is engaged in the suppression of automatic eye movements. The results indicate that abnormalities in this network, rather than the selective dysfunction of prefrontal brain regions, underlie the saccade inhibition deficit in schizophrenia.     

Basic parameters of saccadic eye movements – differences between unmedicated schizophrenia and affective disorder patients

Background Smooth pursuit eye movement (SPEM) dysfunctions are considered a biological marker for schizophrenia and have been studied widely. In contrast, saccadic eye movements have received less attention, although disturbances have been described previously. Basic neurophysiologic parameters of saccades in schizophrenics, especially in unmedicated patients, have not been studied extensively. Methods Saccadic eye movements of 38 unmedicated schizophrenic patients, 32 patients with major depression and 42 non-psychiatric controls were examined using high-resolution infrared oculography. Two large-amplitude saccadic tasks were presented. The groups were compared on peak velocity, reaction time and accuracy. Results Peak velocity was significantly increased in schizophrenic patients. Depressive patients had a significantly longer reaction time. Both patient groups needed more corrective saccades to reach the target than controls. Conclusions Peak velocity distinguishes unmedicated schizophrenic patients from depressive patients and normal controls. This could be explained by deficits of the prefrontal cortex in the inhibitory control of saccades. Our findings suggest that schizophrenia affects not only SPEM but also saccadic eye movements. Received: 30 November 2000 / Accepted: 28 June 2001     

Alteration of event related potentials in siblings discordant for schizophrenia

This study was aimed at confirming that auditory event related potential (ERP) abnormalities are indicators of vulnerability to schizophrenia. Auditory ERP performances were assessed at Fz, Cz, and Pz, with an oddball paradigm, in 21 clinically stable patients with schizophrenia, 21 of their healthy biological full siblings and 21 control subjects. The evoked response did not differ between the three groups on N200 waves. Compared to controls, patients with schizophrenia exhibited reduced amplitudes of N100 and P300, and prolonged latency of P300, while their siblings showed prolonged latency of P200 and P300. Among the patients with schizophrenia, ERP abnormalities did not correlate with age, clinical state, duration of illness or antipsychotic treatments. Although other conditions also accounted for alterations of the same type, ERP abnormalities may represent a neurobiological marker of the genetic vulnerability to schizophrenia, independent of phenotypic expression.     

P300 subcomponent abnormalities in schizophrenia: III. Deficits In unaffected siblings of schizophrenic probands.

BACKGROUND: Reduced P300 amplitude is a robust finding in patients with schizophrenia. In previous investigations, we reported reductions of specific subcomponents of the auditory oddball P300 that were independent of acute symptomatology and persistent over time, consistent with a trait abnormality. To clarify whether these stable deficits represented genetic markers of vulnerability to schizophrenia, event-related brain potentials (ERPs) from patients were compared to those from their own healthy siblings and unrelated control subjects. METHODS: Auditory P300 ERPs were acquired from 11 schizophrenic patients, 12 healthy siblings and 23 matched control subjects. Five P300 subcomponents were identified using current source density measures: frontal, bilateral parietal, and bilateral temporal. RESULTS: Consistent with previous reports, patients had reduced parietal and frontal P300 amplitudes. The healthy siblings of the schizophrenic probands had an isolated reduction of the frontal P300. CONCLUSIONS: Frontal P300 amplitude is a potential endophenotypic marker of genetic vulnerability to schizophrenia in individuals who otherwise show no evidence of clinical symptomatology. Given the functional interpretation of the frontal P300 as a physiological correlate of cognitive orienting, this supports the hypothesis that impairments of the neural substrate underlying attentional mechanisms are selective indicators of genetic susceptibility to schizophrenia in high-risk individuals.