Biomedical subjects

Keith H Nuechterlein

Publications and source records attributed to Keith H Nuechterlein.

At least 19 recordsLinked to original sources

PubMed2006

The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes.

The Consortium on the Genetics of Schizophrenia (COGS) is a 7-site collaboration that examines the genetic architecture of quantitative endophenotypes in families with schizophrenia. Here we review the background and rationale for selecting neurocognitive tasks as endophenotypic measures in genetic studies. Criteria are outlined for the potential of measures as endophenotypic vulnerability markers. These include association with illness, state independence (ie, adequate test-retest stability, adequate between-site reliability, impairments in patients not due to medications, impairments observed regardless of illness state), heritability, findings of higher rates in relatives of probands than in the general population, and cosegregation within families. The COGS required that, in addition, the measures be "neurocognitive" and thus linked to neurobiology and that they be feasible in multisite studies. The COGS neurocognitive assessment includes measures of attention, verbal memory, working memory, and a computerized neurocognitive battery that also includes facial processing tasks. Here we describe data demonstrating that these neurobehavioral measures meet criteria for endophenotypic candidacy. We conclude that quantitative neurocognitive endophenotypes need further evidence for efficacy in identifying genetic effects but have the potential of providing unprecedented insight into gene-environment interaction related to dimensions of brain and behavior in health and disease.

Cognition Disorders↗

PubMed2006

The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. METHODS: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. RESULTS: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). DISCUSSION: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.

Cooperative Behavior↗

PubMed2006

Successful multi-site measurement of antisaccade performance deficits in schizophrenia.

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects. Investigators presented 3 blocks of 20 antisaccade stimuli to 143 schizophrenia subjects and 195 comparison subjects. Frequent collaborator communication, standardized training, and ongoing quality assurance optimized testing uniformity. Data were discarded from only 1.2% of subjects due to poor quality, reflecting the high fidelity of data collection and scoring methods. All sites detected a significant difference in the proportion of correct antisaccades between schizophrenia and comparison subjects (p<.02 at all sites); group differences in gain and latency were less robust. Regression analyses to adjust for the effects of group, site, age, gender, smoking, and parental education on the proportion of correct antisaccades revealed a significant effect of group, site, and age but no effect of gender, smoking, or parental education, and no group-by-site interactions. Intraclass correlations between proportion of correct antisaccades across the blocks of stimuli ranged from 0.87 to 0.93, demonstrating good within-session reliability at sites. These results confirm previous findings of antisaccade deficits in schizophrenia subjects and support the use of the antisaccade task as a potential schizophrenia endophenotype in multi-site genetic studies.

Adolescent↗

PubMed2006

Classifying episodes in schizophrenia and bipolar disorder: criteria for relapse and remission applied to recent-onset samples.

Research on predicting and preventing episodes of schizophrenia and mood disorder lacks consistent, specific definitions of episodes. We present an operational system for identifying relapse, exacerbation, and remission of schizophrenia and bipolar disorder within longitudinal studies that involve repeated symptom assessments. Three major classes of episodic outcome are defined: relapse or significant exacerbation, nonrelapse, and stable, severe persisting symptoms. These major classes are further subdivided to distinguish nine categories of episodic outcome. To examine ease of use, interrater reliability, and validity, the classification system was applied to recent-onset samples of schizophrenia patients (N=77) and bipolar mood disorder patients (N=23) followed on medication for 9- to 12-month periods. A range of episodic outcomes were distinguished with high interrater reliability. Despite being prescribed continuous medication, 21% of the recent-onset schizophrenia patients and 61% of bipolar patients met criteria for relapse or significant exacerbation during this follow-up period. Predictive relationships support the validity of this system for classifying episodes. A computer program is available to facilitate its use. Use of these explicit definitions of episodes may help to clarify the relationship between episodic outcome and other fundamental domains of illness outcome, particularly other symptom dimensions, work functioning, and social functioning.

Adult↗

PubMed2006

Exploring the short term visual store in schizophrenia using the attentional blink.

Schizophrenia patients exhibit numerous deficits on visual processing tasks, ranging from very early stages of visual processing (e.g., backward masking) to the later working memory stages (e.g., delayed match-to-sample, N-back). However, little is known about deficits in an intermediate stage of visual information processing, namely short term visual memory (STVM). The attentional blink (AB) paradigm is considered to be a valid way to assess the STVM, and recent studies have reported AB deficits in schizophrenia. However, it is not clear whether the reported AB deficit in schizophrenia patients is due to their increased susceptibility to backward masking or increased vulnerability in the STVM. In this study we first found poorer performance in the AB task in 37 schizophrenia patients compared to 26 normal controls. To examine the effects of increasing and decreasing mask strength on AB performance in patients and controls, we next systematically varied the masking effect by varying the length of the distracters immediately following the targets. The manipulation had relatively little effect on the patient--control differences and patients continued to show an enhanced AB effect across conditions. The findings suggest that the enhanced AB effect in schizophrenia reflects an abnormality in their short term visual memory, as opposed to their enhanced susceptibility to visual masking.

Adult↗

PubMed2006

Neurocognitive and social cognitive correlates of formal thought disorder in schizophrenia patients.

The neurocognitive and social cognitive correlates of two types of formal thought disorder (i.e., bizarre-idiosyncratic and concrete thinking) were examined in 47 stable outpatients with schizophrenia. Both types of thinking disturbance were related to impairments in verbal learning, intrusions in verbal memory, immediate auditory memory, sustained attention, and social schema knowledge. Distractibility during an immediate memory task was associated with more frequent bizarre verbalizations but not concreteness. Impaired verbal learning rate and intrusions in verbal memory independently contributed to the prediction of bizarre responses, whereas intrusions in verbal memory and impaired immediate memory independently contributed to concrete thinking. This pattern of findings is consistent with the view that neurocognitive and, possibly, social cognitive deficits underlie these two aspects of formal thinking disturbance in schizophrenia.

Adult↗

PubMed2006

Neurocognitive performance and functional disability in the psychosis prodrome.

OBJECTIVE: This study evaluates the pattern of neuropsychological deficits and their association with clinical symptomatology and social functioning in individuals identified as ultra-high-risk (UHR) for psychosis. METHODS: A sample of 45 UHR individuals was identified using the Structured Interview for Prodromal Syndromes (SIPS) from consecutive referrals to the Staglin Music Festival Center for the Assessment and Prevention of Prodromal States (CAPPS) at UCLA. Participants were administered a neurocognitive test battery, as well as measures of global (Strauss-Carpenter Outcome Scale) and social functioning (UCLA Social Attainment Survey). RESULTS: Participants showed significant deficits in speed of processing, verbal learning and memory, and motor speed. Poorer verbal learning and memory performance was significantly associated with poorer social functioning, and there was a trend for poorer performance on reasoning and problem solving to be associated with poorer global functioning. Verbal memory independently predicted social functioning over and above severity of negative symptoms. Cognitive deficits were not associated with severity of clinical symptomatology. CONCLUSIONS: Despite the absence of fully psychotic symptoms, UHR individuals experience significant cognitive deficits, particularly on tasks requiring speeded information-processing and efficient recall from memory, and these deficits appear to be associated with functional disability in a manner parallel to that observed in patients with established psychotic illness.

Adolescent↗

PubMed2006

Translating basic attentional paradigms to schizophrenia research: reconsidering the nature of the deficits.

Abnormalities in attention have long been viewed as one of the fundamental underlying cognitive deficits in schizophrenia, likely contributing both to formation of some types of symptoms and particularly to the substantial work and social impairments that often accompany schizophrenia. Yet, the precise nature of the attentional deficits in schizophrenia remains poorly understood. Translating advances in cognitive psychology to clinical research brings paradigms with greater analytic power to the study of attention in schizophrenia. In particular, these paradigms should shed light on whether the attentional dysfunction in schizophrenia is best conceptualized as arising from limitations in amount or allocation of processing capacity or from more specific structural bottlenecks that do not allow certain processes to be carried out in two tasks simultaneously. Certain types of dual-task paradigms are particularly well suited to make distinctive predictions, particularly those involving a psychological refractory period paradigm. The background and design of a series of ongoing studies of prodromal, first-episode, and chronic schizophrenia patients are described that are addressing the developmental course of attentional dysfunction in this disorder. These refined paradigms should substantially increase our understanding of the specific forms of attentional impairment characterizing schizophrenia and their connections to symptom development and functional outcome.

Attention↗

PubMed2006

Electrophysiological analysis of error monitoring in schizophrenia.

In this study, the authors sought to determine whether abnormalities exhibited by schizophrenia patients in event-related potentials associated with self-monitoring--the error-related negativity (ERN) and the correct response negativity (CRN)--persist under conditions that maximize ERN amplitude and to examine relationships between the ERN and behavior in schizophrenia. Participants performed a flanker task under 2 contingencies: one encouraging accuracy and another emphasizing speed. Compared with healthy participants, in schizophrenia patients the ERN was reduced in the accuracy condition, and the CRN was enhanced in the speed condition. The amplitude of a later ERP component, the error positivity, did not differ between groups in either task condition. Reduced self-correction and increased accuracy following errors were associated with larger ERNs in both groups. Thus, ERN generation appears to be abnormal in schizophrenia patients even under conditions demonstrated to maximize ERN amplitude; however, functional characteristics of the ERN appear to be intact.

Adult↗

PubMed2006

Does anhedonia in schizophrenia reflect faulty memory for subjectively experienced emotions?

The authors evaluated whether self-reported trait anhedonia in schizophrenia reflects faulty memory, such that patients are capable of experiencing pleasure while engaged in enjoyable activities but underestimate their pleasure in recalling these experiences. Thirty schizophrenia patients and 31 nonpatient control participants rated their emotional responses to pleasant and neutral foods and film clips and completed a surprise recall task for their emotions after a 4-hr delay. Despite reporting elevated trait anhedonia, patients did not significantly differ from control participants in immediate pleasant emotional responses to the stimuli or in delayed recall for these experiences. In-the-moment pleasure and short-term retention for emotional experiences thus appear to be relatively intact in schizophrenia. Alternative explanations for the hedonic deficit in this disorder are discussed.

Adult↗

PubMed2006

Social perception as a mediator of the influence of early visual processing on functional status in schizophrenia.

OBJECTIVE: The potential of social cognition as a mediator of relations between neurocognition and functional status in schizophrenia has been suggested by correlational studies that link neurocognition to social cognition or link social cognition to functional status. The authors used structural equation modeling to test more directly whether one aspect of social cognition (social perception) mediates relations between basic visual perception and functional status in patients with schizophrenia. METHOD: Seventy-five outpatients with schizophrenia were administered measures of early visual processing (computerized visual masking procedures), social perception (Half Profile of Nonverbal Sensitivity), and functional status (Role Functioning Scale). RESULTS: Structural equation modeling supported social perception as a mediator of relations between early visual processing and functional status in schizophrenia. The mediation model indicated that early visual processing is linked to functional status through social perception, thereby supporting a significant indirect relationship. The direct relationship between early visual processing and functional status was significant in a model that did not include social perception but was not significant in the mediation model that included social perception. CONCLUSIONS: Social cognition appears to be a key determinant of functional status in schizophrenia. Using a very basic measure of visual perception, the present study found that social perception mediates the influence of early visual processing on functional status in schizophrenia.

Ambulatory Care↗

PubMed2006

Do recent-onset schizophrenia patients experience a "social network crisis"?

It has been proposed that the onset of schizophrenia creates a social network crisis, resulting in a dramatic deterioration of social resources during the period immediately following a first hospitalization from essentially normal pre-hospitalization levels. To evaluate this proposal, recent onset patients (n = 89) completed comprehensive assessments that examined their social networks in the 12 months prior to first hospitalization and, in a subset of patients (n = 34), at a 15-month follow-up. Cross-sectional relationships to social functioning and symptoms were examined at both time points. Compared to existing research, at the initial assessment patients were characterized by several network disturbances, including small network size, a high proportion of family members, and highly dense interconnections among network members; these disturbances generally remained moderately to highly stable at follow-up. Smaller social networks were related to poor current and premorbid social functioning and aspects of clinical functioning, particularly at the 15-month follow-up assessment. Thus, this first repeated assessment of social network characteristics in the early course of schizophrenia does not support the social network crisis concept. Instead, results suggest that functionally relevant social network disturbances often exist by the time of first hospitalization in schizophrenia.

Adult↗

PubMed2005

Visual processing in schizophrenia: Structural equation modeling of visual masking performance.

Schizophrenic patients consistently demonstrate performance deficits on visual masking procedures. In visual masking, the subject's ability to process a target stimulus is reduced by another stimulus (mask) presented either before (forward masking) or after (backward masking) the target. Masking procedures employed in schizophrenia research have used several experimental paradigms. Most early studies have used high-energy masks (i.e., the mask is stronger than the target) and spatially overlapping target and mask. More recently, studies have begun to employ relatively weak (i.e., low-energy) masks, as well as masks that surround, but do not spatially overlap, the target. Data for forward and backward masking components of four masking conditions (target location and identification with a high-energy mask, target identification with a low-energy mask, and target identification with equal energy paracontrast/metacontrast) were collected from 75 patients with schizophrenia. Based on theoretical distinctions among masking procedures, we compared four models of visual masking using structural equation modeling. Although high zero-order correlations were found among the masking parameters, a four-factor model, in which factors were separated on the type of response (target location and identification), the shape of the function (monotonic and non-monotonic), and the overlap of the stimuli (overlapping and non-overlapping), provided the best fit for the data. These findings suggest that the four masking procedures used in this study may tap unique aspects of visual processing and are not redundant. The results also support theories of the different mechanisms underlying performance on these measures.

Adult↗

PubMed2005

Distinguishing separable domains of cognition in human and animal studies: what separations are optimal for targeting interventions? A summary of recommendations from breakout group 2 at the measurement and treatment research to improve cognition in schizophrenia new approaches conference.

At the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) New Approaches Conference, a discussion group focused on directions for future research that are critical to enhancing our understanding of the distinctions among key cognitive domains that have relevance for the development of cognition-enhancing interventions. One set of recommendations emphasizes the need for examining and optimizing the psychometric properties of relevant measurement paradigms from cognitive psychology and cognitive neuroscience. This step is critical to translating many notable advances in these basic fields into measures that would be appropriate for clinical trials. A second set of recommendations focuses on key directions for the development and application of animal models of cognitive processes that would greatly aid the discovery and preclinical testing of potential cognition-enhancing agents. As part of this process, the group noted several existing animal paradigms that have particular promise as measures in the key cognitive domains in schizophrenia identified by the MATRICS Neurocognition Committee.

Animals↗

PubMed2005

Forward and backward visual masking in unaffected siblings of schizophrenic patients.

BACKGROUND: Visual masking tasks assess the earliest stages of visual processing. This study examined visual masking performance for forward and backward masking tasks in siblings of schizophrenic patients and healthy comparison subjects. METHODS: A staircase method was used to ensure that unmasked target identification was equivalent across subjects to eliminate differences due to discrimination of simple perceptual inputs. Four computerized visual masking tasks were administered to 43 siblings of patients and 42 normal comparison subjects. The tasks included: 1) locating a target; 2) identifying a target with a high-energy mask; 3) identifying a target with a low-energy mask; and 4) a paracontrast/metacontrast procedure with nonoverlapping target and mask. RESULTS: Across masking conditions, there was a significant group by forward/backward interaction, meaning that siblings showed a larger difference from control subjects in backward versus forward masking. This group difference was more pronounced in the location condition. CONCLUSIONS: These results support the theory that visual masking procedures may be indicators of vulnerability to schizophrenia. The pattern of findings in this report (larger group differences on backward versus forward masking and on the location condition) suggests that the activity of transient visual channels may be particularly linked to vulnerability.

Adult↗

PubMed2005

Stressful life events in recent-onset schizophrenia: reduced frequencies and altered subjective appraisals.

While research strongly supports the notion that stressful life events may trigger the exacerbation of psychotic symptoms in schizophrenia, the mechanisms through which affected individuals respond to life events during the early course of this disorder have received limited attention. This 12-month longitudinal study compared the frequencies, qualitative characteristics, and subjective appraisals of life events in recent-onset schizophrenia patients (n=78) and a nonpatient comparison sample (n=63). Negative and positive life events were assessed using a semi-structured interview every 4 weeks among patients and approximately every 4 months among controls, and participants appraised each event they experienced in terms of emotional impact, controllability, and effectiveness in handling the event. Schizophrenia patients reported significantly lower rates of life events than their nonpsychiatric counterparts across nearly every type of negative and positive event examined. In the context of generally lower event frequencies, patients appraised the negative and positive events they did experience as less controllable and more poorly handled than controls, and also appraised positive events as less desirable. Results are discussed in terms of their implications for understanding susceptibility to stress during the early course of schizophrenia.

Adaptation, Psychological↗

PubMed2005

A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia.

OBJECTIVE: On April 23, 2004, a joint meeting of the FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop guidelines for the design of clinical trials of cognitive-enhancing drugs for neurocognitive impairments in patients with schizophrenia. METHOD: Experts were asked to address specific questions relating to clinical trial design of adjunctive/co-treatment and broad spectrum agents. At the workshop, experts reviewed relevant evidence before offering the discussion panel proposed guidelines for a given subset of questions. The discussion panel, which consisted of presenters and representatives from FDA, NIMH, academia, and industry, deliberated to reach consensus on suggested guidelines. When evidence was insufficient, suggested guidelines represent the opinion of a cross-section of the presenters and discussion panel. RESULTS: Guidelines were developed for inclusion criteria, the use of co-primary outcome measures, and statistical approaches for study design. Consensus was achieved regarding diagnostic and concomitant medication inclusion criteria and on the use of cognitive screening measures. A key guideline was to limit the trial to patients in the residual phase of their illness, who have a predefined level of positive, negative, and affective symptoms. The most difficult issues were the feasibility of including a co-primary measure of functional improvement and the choice of comparator agent for a trial of a broad spectrum agent (with antipsychotic and cognitive-enhancing effects). CONCLUSIONS: The suggested guidelines represent reasonable starting points for trial design of cognitive-enhancing drugs, with the understanding that new data, subsequent findings, or other methodological considerations may lead to future modifications.

Antipsychotic Agents↗

PubMed2005

Is unawareness of psychotic disorder a neurocognitive or psychological defensiveness problem?

We examined whether deficits in attention and perceptual encoding as well as psychological defensiveness were associated with impaired awareness of disorder in schizophrenia. The Scale for Unawareness of Mental Disorder (SUMD) was administered to 52 outpatients with a recent onset of schizophrenia approximately 1-2 months following hospital discharge. Two versions of the Continuous Performance Test (CPT) were used to measure attentional impairment--the Degraded Stimulus CPT (DS-CPT) and a memory-load version (3-7 CPT). Three scales from the Minnesota Multiphasic Personality Inventory were used as indicators of psychological defensiveness: Scales L (Lie), K (Correction), and R (Repression). The Classification and Regression Tree (CART) program, a nonparametric statistical method, was used to identify relationships among multiple predictor variables and to provide optimal splitting scores for each predictor variable. Different combinations of poor target discrimination (d') on the 3-7 CPT and a cautious response style on the DS-CPT were associated with the three levels of overall unawareness of having a mental disorder. For nonpsychotic patients, better target discrimination (d') on the 3-7 CPT tended to be associated with better awareness of having a mental disorder. In contrast, unawareness among the patients who were psychotic at the time of the SUMD administration was not discriminated by attentional measures, but was associated with a combination of two measures of psychological defensiveness from the MMPI reflecting guardedness, psychological suppression, attempting to present oneself in a socially desirable light, and social acquiescence. Generally similar associations were found for two other dimensions of poor insight: unawareness of the beneficial effects of antipsychotic medication, and inability to attribute unusual thoughts and hallucinatory experiences to a mental disorder.

Adult↗