A multivariate electrophysiological endophenotype, from a unitary cohort, shows greater research utility than any single feature in the Western Australian family study of schizophrenia.

BACKGROUND: Previous studies have found several electrophysiological endophenotypes that each co-varies individually with schizophrenia. This study extends these investigations to compare and contrast four electrophysiological endophenotype, mismatch negativity, P50, P300, and antisaccades, and analyze their covariance on the basis of a single cohort tested with all paradigms. We report a multivariate endophenotype that is maximally associated with diagnosis and evaluate this new endophenotype with respect to its application to genetic analysis. METHODS: Group differences and covariance were analyzed for probands (n = 60), family members (n = 53), and control subjects (n = 44). Associations between individual endophenotypes and diagnostic groups, as well as between the multivariate endophenotype and diagnostic groups, were investigated with logistic regression. RESULTS: Results from all four individual endophenotypes replicated previous findings of deficits in the proband group. The P50 and P300 endophenotypes similarly replicated significant deficits in the family member group, whereas mismatch negativity and antisaccade measures showed a trend. There was minimal correlation between the different endophenotypes. A logistic regression model based on all four features significantly represented the diagnostic grouping (chi(2) = 32.7; p < .001), with 80% accuracy in predicting group membership. CONCLUSIONS: A multivariate endophenotype, based on a weighted combination of electrophysiological features, provides greater diagnostic classification power than any single endophenotype.     

Validating endophenotypes for schizophrenia using statistical modeling of twin data.

The use of endophenotypes (intermediate quantitative traits) is one strategy that may provide valuable information about the neural mechanisms underlying disease etiology and facilitate discovery of susceptibility genes. For a trait to be an appropriate endophenotype, several key features should exist. In this article we discuss validating potential electrophysiological endophenotypes for schizophrenia based on conventionally accepted criteria. We focus on applying a twin study design and model fitting techniques to evaluate whether three event-related potential paradigms (P300, P50, and MMN) meet criteria as valid endophenotypes of schizophrenia.     

Reductions in the N1 and P2 Auditory Event-Related Potentials in First-Hospitalized and Chronic Schizophrenia

The N1 auditory event-related potential (ERP) is reduced in chronic schizophrenia, as is the P2 to attended tones. N1 reduction may be endophenotypic for schizophrenia, being reduced in twins of schizophrenic patients and showing heritability. Results in family members, however, are equivocal, with abnormally small N1 (consistent with an endophenotype) and abnormally large N1 (inconsistent with an endophenotype) reported. P2 has been little studied in schizophrenia or family members. One crucial step in establishing endophenotypes is to rule out causal chronicity factors. We examined schizophrenia patients within 1 year of first hospitalization (most within 2 wk), chronically ill patients, and matched controls to examine N1 and P2 reductions and disease stage. Two active target detection oddball tasks were used, one with 97-dB tones against 70-dB white masking noise, the second with 97-dB tones without noise. Results from 8 samples are reported: first-hospitalized patients and matched controls and chronic patients and matched controls for the 2 tasks. N1 and P2 were measured from the standard stimuli. N1 and P2 were significantly reduced in chronic patients, as expected, and reduced in first-hospitalized patients. Because N1 and P2 are reduced even at the first hospitalization for schizophrenia, they may serve as viable electrophysiological endophenotypes for the disorder. However, deficit early in the disease is necessary but not sufficient to establish these ERPs as endophenotypes. Deficits must next be demonstrated in at least a subset of unaffected family members, a crucial criterion for an endophenotype.     

NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders

Autism is a highly disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors. There are few effective biological treatments for this disorder, partly due to the lack of translational biomarkers. However, recent data suggest that autism has reliable electrophysiological endophenotypes, along with evidence that some deficits may be caused by NMDA receptor (NMDAR) dysfunction. Similarly, the NMDAR antagonist MK801 has been used in behavioral animal models of autism. Since MK801 has also been used as a model of schizophrenia, this paper examines the independent and overlapping ways in which MK801 recreates the electrophysiogical changes present in both diseases. Mouse EEG was recorded in response to auditory stimuli after either vehicle or MK801 and the dose-response relationship for each measure was determined. ERP component amplitude and latency analysis was performed along with time-frequency analysis of gamma frequency inter-trial coherence and evoked power. Evoked gamma power and ITC were decreased by MK801 at the highest dose. P1, N1 latency and gamma baseline power were increased in dose dependent fashion following MK801. There were no amplitude changes in P1 or N1. MK801 caused alterations in evoked gamma activity, gamma ITC, gamma baseline power, P1 and N1 latency similar to findings in autism. These data provide evidence indicating that NMDAR dysfunction may contribute to deficits specific to autism and some that overlap with other disorders such as schizophrenia. Such observations could be important for developing novel therapeutics, as electrophysiological endophenotypes associate with functional measures and may provide early biomarkers for efficacy in clinical trials.     

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part I: Neurophysiology

The neurophysiological components that have been proposed as biomarkers or as endophenotypes for schizophrenia can be measured through electroencephalography (EEG) and magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), polysomnography (PSG), registration of event-related potentials (ERPs), assessment of smooth pursuit eye movements (SPEM) and antisaccade paradigms. Most of them demonstrate deficits in schizophrenia, show at least moderate stability over time and do not depend on clinical status, which means that they fulfil the criteria as valid endophenotypes for genetic studies. Deficits in cortical inhibition and plasticity measured using non-invasive brain stimulation techniques seem promising markers of outcome and prognosis. However the utility of these markers as biomarkers for predicting conversion to psychosis, response to treatments, or for tracking disease progression needs to be further studied.     

Attention-deficit/hyperactivity disorder endophenotypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.     

The utility of neurophysiological markers in the study of alcoholism.

OBJECTIVE: This review attempts to differentiate neuroelectric measures (electroencephalogram (EEG), event-related potentials (ERPs) and event-related oscillations (EROs)) related to acute and chronic effects of alcohol on the brain from those that reflect underlying deficits related to the predisposition to develop alcoholism and related disorders. The utility of these neuroelectric measures as endophenotypes for psychiatric genetics is evaluated. METHODS: This article reviews the main findings of EEG and ERP abnormalities in alcoholics, offspring of alcoholics at high risk to develop alcoholism and the electrophysiological effects of alcohol on high risk compared to low-risk offspring. It highlights findings using EROs, a fast developing tool in examining brain function and cognition. It also reviews evidence of genetic findings related to these electrophysiological measures and their relationship to clinical diagnosis. RESULTS: Many of these abnormal neuroelectric measures are under genetic control, may precede the development of alcoholism, and may be markers of a predisposition toward the development of a spectrum of disinhibitory conditions including alcoholism. Genetic loci underlying some neuroelectic measures that involve neurotransmitter systems of the brain have been identified. CONCLUSIONS: Quantitative neuroelectric measures (EEG, ERPs, EROs) provide valuable endophenotypes in the study of genetic risk to develop alcoholism and related disorders. SIGNIFICANCE: Genetic studies of neuroelectric endophenotypes offer a powerful strategy for identifying susceptibility genes for developing psychiatric disorders, and provide novel insights into etiological factors.     

Evidence of abnormalities in mid-latency auditory evoked responses (MLAER) in cognitive subtypes of patients with schizophrenia

Abnormalities in measures of mid-latency auditory evoked responses (MLAER) have frequently been reported in schizophrenia, while few studies have examined whether these measures could distinguish cognitive subtypes of schizophrenia. The aim of this study was to investigate whether patterns of performance on MLAER measures could differentiate a cognitive subtype of patients characterized by pervasive cognitive deficits (CD) from patients with only mild cognitive deficits (CS) and controls. An auditory paired-click conditioning test was administered to 55 schizophrenia patients (26 CD, 29 CS) and 49 healthy controls. Amplitudes, latencies and sensory gating indices of the P50, N100, and P200 MLAER were analysed. The results showed that CD patients exhibited smaller S1 amplitudes of N100 and P200 than controls, while CS patients were comparable to controls. Binary logistic regression identified the P200 S1 amplitude as a significant predictor of patients' membership in the CD subtype. However, none of the other MLAER measures could differentiate the two subtypes of schizophrenia. These findings suggest that the abnormal pathophysiologic mechanisms underlying the electrophysiological brain responses to auditory stimulation are associated with the pervasive cognitive deficits, which characterize the CD subtype of schizophrenia. This finding might provide additional electrophysiological endophenotypes for future genetic research of schizophrenia.     

Substantial shared genetic influences on schizophrenia and event-related potentials

OBJECTIVE: Several components of event-related potentials--P50 suppression, P300 amplitude and latency, and mismatch negativity--have been proposed as potential endophenotypes for schizophrenia on the basis of family studies. The present study used a twin design to estimate the extent of genetic overlap between these indices and the liability to schizophrenia. METHOD: The authors measured mismatch negativity, P300, and P50 suppression in 16 monozygotic twin pairs concordant for schizophrenia, nine monozygotic twin pairs discordant for schizophrenia, and 78 healthy comparison twin pairs. The study design was based on a power calculation. Structural equation modeling was used to quantify the genetic and environmental contributions to the phenotypic covariance between schizophrenia and each of the event-related potential indices. RESULTS: Significant phenotypic correlation with schizophrenia was found for each of the event-related potential components. Genetic factors were the main source of the phenotypic correlations. P50 suppression had the greatest genetic correlation with schizophrenia, followed by P300 amplitude, P300 latency, and mismatch negativity. CONCLUSIONS: All four event-related potential indices are potentially valid endophenotypes for schizophrenia, but P50 suppression and P300 amplitude show the closest genetic relationship to schizophrenia.     

The concept of endophenotypes in psychiatric diseases meeting the expectations?

Although the prominent role of genetics in psychiatric diseases has been established in various family, twin and adoption studies over the last decades, the identification of concrete contributing genes has been demanding. The reasons for this are manifold, including inconsistencies in psychiatric classification systems, complexity and heterogeneity of psychiatric disorders, epistatic effects and intervening environmental factors. In recent years interest has focused increasingly on the concept of endophenotypes. Genetic analyses have concentrated on discrete phenotypes supposedly linked to a particular psychiatric disorder by common neurobiological pathways, instead of studying the complex disease itself. Several endophenotypes have been established for psychiatric diseases including electrophysiological abnormalities and alterations in structural and functional brain imaging. Although results seem to be getting more consistent and reliable, several concerns have also emerged with the experience gained on the topic. This review will give an overview of the prospects and limitations related to endophenotypes in psychiatric diseases. We will also summarize essential prerequisites for successful endophenotypes in the future as well as applications for psychiatric diseases which have been envisioned.     

Which perspectives can endophenotypes and biological markers offer in the early recognition of schizophrenia?

Summary The early recognition of schizophrenia seems crucial; various studies relate a longer duration-of-untreated-psychosis to a worse prognosis. We give an overview over common psychopathological early recognition instruments (BSABS, CAARMS, SIPS, IRAOS, ERIraos). However, many clinical symptoms of prodromal schizophrenia stages are not sufficiently specific. Thus we review recent contributions of neuroimaging and electrophysiological as well as genetic studies: which new diagnostic perspectives offer endophenotypes (such as P300, P50 sensory gating, MMN, smooth pursuit eye movements; indicating a specific genetic vulnerability) together with a better understanding of schizophrenic pathophysiology (state-dependent biological markers, e.g. aggravated motor neurological soft signs during psychosis) in prodromal schizophrenia when still ambiguous clinical symptoms are present. Several examples (e.g. from COMT polymorphisms to working memory deficits) illustrate more specific underlying neuronal mechanisms behind behavioural symptoms. This way, a characteristic pattern of disturbed cerebral maturation might be distinguished in order to complement clinical instruments of early schizophrenia detection.     

High-resolution fragmentary decomposition--a model-based method of non-stationary electrophysiological signal analysis

Fragmentary decomposition (FD) is a recently developed method of non-stationary electrophysiological signal analysis addressed to mass potentials, such as electromyogram (EMG), event-related potential (ERP), evoked potential, electroencephalogram (EEG), electroretinogram, etc. Being supported by the generally accepted physiological notion that a peak is a functionally meaningful component of a mass potential, FD provides a way to avoid averaging and, instead, quantifies the component composition of complex electrophysiological signals directly from single-trials. The major computational procedures of FD include adaptive segmentation, the frequency domain component identification, and creation of the signal model as a linear aggregation of multiple components, with the generic mass potential (GMP) being the universal component template. This paper presents an improved, high-resolution FD technique which allows the resolution of overlapping sub-components and supports each identified component by an individual model. On the basis of this methodological innovation, we define two fundamental categories of multi-peak component waveforms: complex components (CC), comprised of multiple sub-components (GMPs), versus monolithic components (MC), involving a single GMP. We show that quantification of MCs and CCs from single-trial eyeblink EMG and single-trial ERP provides a more comprehensive analysis of these signals. Given single-trial eyeblink EMG, we find that the stimulus elicits strong though short-term (phasic) effects on MCs and moderate but long-lasting (tonic) effects on CCs. A new realm of single-trial ERP quantification is possible in that the MC appears as a marker of a single cognitive variable whereas the CC appears as a marker of a series of functionally related cognitive variables. The engagement of the brain in a specific cognitive task is accompanied by an increase of CCs in single-trial ERPs, which is especially informative with respect to the P3 cognitive potential. New methodology provides evidence for the three basic types of single-trial P3 sub-components: monolithic P3a, monolithic P3b, and a complex component, P3ab, which includes both P3a and P3b as sub-components.     

Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families

Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2-q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n=1626) allowed replication of linkage on 7q21-32. In a sample of 245 nuclear families (n=1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n=861) of the sample showed significant association to RELN variants for traits related to verbal (P=0.000003) and visual working memory (P=0.002), memory (P=0.002) and executive functioning (P=0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P=0.0004-0.0000000004), memory (P=0.02-0.0001) and executive functioning (P=0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.     

Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs

Autism is a neurodevelopmental syndrome with early childhood onset and deficits in three behavioral and cognitive dimensions: language, social skills and repetitive or restrictive behaviors. We hypothesized that using these endophenotypes would provide more power to detect linkage than the diagnosis of autism. Previously, we reported results for a nonparametric quantitative trait locus (QTL) genome scan in 152 families with autism, which revealed a linkage peak related to spoken language on 7q35. Here, we present the results of a nonparametric QTL scan of autism endophenotypes in 291 multiplex families, including the original 152. The strongest evidence for an 'age at first word' QTL was on chromosomes 3q at 147 cM (Z=3.10, P<0.001), and 17q at 93 cM (Z=2.84, P=0.002), both represent novel susceptibility loci for autism endophenotypes. There was also support for a previously identified autism peak on chromosome 17 at 43 cM (Z=2.22, P=0.013) with 'age at first phrase'. The 7q35 language peak was attenuated (Z=2.05, P=0.02) compared with the original finding. To explore the possibility of increased heterogeneity resulting from the addition of 135 families to the sample, we conducted an Ordered-Subsets Analysis on chromosome 7; these results suggest that the 132 autism families with the earliest average age at first word are responsible for the QTL on 7q35. This locus on 7q35 may harbor a gene contributing variability in spoken language that is not uniquely related to language delay in autism.     

Genetic and environmental influences on sensory gating of mid-latency auditory evoked responses: a twin study

A deficit in sensory gating measured by the suppression of P50 auditory event-related potential (ERP) has been implicated in the biological bases of schizophrenia and some other psychiatric disorders and proposed as a candidate endophenotype for genetic studies. More recently, it has been shown that gating deficits in schizophrenics extend to ERP components reflecting early attentive processing (the N1/P2 complex). However, evidence for heritability of sensory gating in the general population is very limited. Heritability of P50, N1, and P2 amplitudes and gating was estimated in 54 monozygotic and 55 dizygotic twin pairs using a dual-click auditory paradigm. Genetic model-fitting analysis showed high heritability of peak amplitudes of P50, N1, and P2 waves. Genetic influences on P50 gating (S2/S1) were modest, while heritability of N1 and P2 gating was high and significant. The alternative gating measure (S1-S2 difference) showed significant heritability for all three ERP components. Weak genetic influences on P50 gating ratio can be related to its poor test-retest reliability demonstrated in previous studies. These results suggest that gating measures derived from the N1/P2 wave complex may be useful endophenotypes for population-based genetic studies of the sensory gating function and its impairments in psychopathology.     

Electrophysiological correlates of conscious vision: evidence from unilateral extinction

To study the electrophysiological correlates of conscious vision, we recorded event-related potentials (ERPs) in a patient with partial unilateral visual extinction as a result of right-hemisphere damage. When, following bilateral presentations, contralesional stimuli were not perceived, there was an absence of the early attention-sensitive P1 (80-120 msec) and N1 (140-180 msec) components of the ERP response. In contrast, following unilateral presentations, or in those bilateral presentations in which contralesional stimuli were perceived (about 60%), these ERP components were present. These results provide novel evidence that extinction involves the stage of early focusing of attention and that the P1 and N1 components of visual ERPs are reliable physiological correlates of conscious vision.     

The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder.

Psychological functions that are behaviorally and neurally well specified may serve as endophenotypes for attention-deficit/hyperactivity disorder (ADHD) research. Such endophenotypes, which lie between genes and symptoms, may relate more directly to relevant genetic variability than does the clinical ADHD syndrome itself. Here we review evidence in favor of response inhibition as an endophenotype for ADHD research. We show that response inhibition--operationalized by Go/NoGo or Stop-signal tasks--requires the prefrontal cortex (PFC), in particular the right inferior frontal cortex (IFC); that patients with ADHD have significant response inhibition deficits and show altered functional activation and gray matter volumes in right IFC; and that a number of studies indicate that response inhibition performance is heritable. Additionally, we review evidence concerning the role of the basal ganglia in response inhibition, as well as the role of neuromodulatory systems. All things considered, a combined right IFC structure/function/response inhibition phenotype is a particularly good candidate for future heritability and association studies. Moreover, a dissection of response inhibition into more basic components such as rule maintenance, vigilance, and target detection may provide yet better targets for association with genes for neuromodulation and brain development.     

Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder.

Reduced inositol monophosphatase (IMPase) activity and elevated basal intracellular calcium levels ([Ca(2+)](B)) have been reported in B lymphoblast cell lines (BLCLs) from bipolar I affective disorder (BD-I) patients, which may reflect cellular endophenotypes of this disorder. As the PI cycle couples to intracellular Ca(2+) mobilization, these two putative endophenotypes may be related. Using an RT-PCR assay, mRNA levels were estimated for IMPA1 and 2 genes encoding human IMPase 1 and 2, respectively, in BLCLs phenotyped on [Ca(2+)](B), from patients with a DSM-IV diagnosis of BD-I (n = 12 per phenotype) and from age- and sex-matched healthy subjects (n = 12). IMPA2 mRNA levels were significantly lower in BLCLs from male BD-I patients with high [Ca(2+)](B) (n = 6) compared with healthy male subjects (n = 5) (-52%, P = 0.013), male BD-I patients with normal BLCL [Ca(2+)](B) (n = 8) (-42%, P = 0.003) and female BD-I patients with high [Ca(2+)](B) (n = 6) (-59%, P = 0.0004). A significant negative correlation was observed between IMPA2 mRNA levels and [Ca(2+)](B) in BLCLs from male (P = 0.046), but not female BD-I patients. Sex-dependent differences were also evident in postmortem temporal cortex IMPA2 mRNA levels which, in contrast to BLCLs, were significantly higher in male BD-I subjects compared with male controls (P = 0.025, n = 4/group). Collectively, these observations suggest a potential sex-dependent link between abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD.     

The endophenotype concept in psychiatry: etymology and strategic intentions

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.     

酒依赖的事件相关电位P300实验研究

目的　事件相关电位P30 0是一种特殊的脑诱发电位。本研究探讨酒依赖患者事件相关电位P30 0的基本特征。方法　使用丹麦丹迪SEEG 16道技术系统 ,以及听觉靶—非靶刺激序列为诱发事件 ,检测 2 6例男性酒依赖患者 ,并与 31例正常男性进行比较。结果　与正常男性相比 ,酒依赖患者ERP/P30 0波形有变异 ,稳定性差。酒依赖患者P30 0靶和非靶主成分潜伏期延迟 ,波幅下降 (P <0 0 5或P <0 0 1)。结论　提示长期大量饮酒对脑功能有损害。P30 0若干指标或许可以作为酒依赖的检测手段。