The executive control of attention differentiates patients with schizophrenia, their first-degree relatives and healthy controls

Abstract

Attentional and executive impairments have been reported in patients with schizophrenia and in their healthy first-degree relatives. However, its nature remains unclear and discrepancies between studies have been observed. These might be due to differences in the clinical severity of the illness or in sociodemographic factors. The objective of the present work was to explore the efficiency of three attention networks: alerting, orienting and executive control (conflict inhibition) defined anatomically, using patients, their relatives and controls, assessing the possibility to use them as endophenotypes. We used three tests, the Attention Network Test (ANT), the Wisconsin Card Sorting Test (WCST) and the Stroop Test, and compared 52 patients with schizophrenia, 55 of their first-degree relatives and 53 unrelated healthy controls, taking into account demographic variables (age, sex and years of education) and clinical symptoms of schizophrenia. Patients had a longer overall mean reaction-time (p < 0.001), and took longer to resolve the ANT conflict (ANTc) (p = 0.04) than the control group. In the schizophrenia group, the SSPI disorganization score was significantly correlated to the ANTc performance. Additionally, first-degree relatives of patients with schizophrenia also performed significantly worse than controls in attention performance test. Our findings support a specific deficit in executive control of attention in patients with schizophrenia. This deficit was shown to be correlated with the intensity of the disorganization score in patients. Relative presented an intermediate phenotype between patients and controls; the ANT reaction time (but not the ANTc) may thus be considered as possible endophenotype marker for schizophrenia.

Introduction

Cognitive deficits in executive performance, working memory and attention are considered to be core features in patients with schizophrenia, because these deficits are present from the first psychotic episode (Bilder et al., 2000, Ma et al., 2007). As they are also observed in relatives of patients, they are attractive as potential endophenotypes for studying the genetic background of schizophrenia (Gottesman and Shields, 1973, Leboyer, 2003). Most of the studies of neuropsychological deficits in patients with schizophrenia (see meta-analyses by Heinrichs and Zakzanis, 1998, Johnson-Selfridge and Zalewski, 2001) and their first-degree relatives (see meta-analyses by Snitz et al., 2006, Szöke et al., 2005) lead to the convergent conclusion that these two populations display cognitive deficits affecting the same cognitive functions (attention, executive functions and memory), and that less profound impairments of the same type are also observed in first-degree relatives. The Stroop test and the Wisconsin Card Sorting Test (WCST) have both been shown to be particularly sensitive to these deficits. However, there are discrepancies between studies investigating attentional and executive functions, which might be in part explained by differences in the inclusion criteria for patients (age at onset, duration and severity of illness, type of treatment received), for first-degree relatives (age at inclusion, which might be related to differences in the risk of developing schizophrenia) and for controls (not identical compared to relatives, and with unknown psychiatric family history). In this study, we used homogenous strict inclusion criteria for patients, relatives and controls to compare the neuropsychological impairment of attention and of executive functions avoiding such inclusion criteria confonding factors.

Attention is defined as reflecting the efficiency of three anatomically-distinct, organized networks (alerting, orienting and executive control) that are widely distributed across frontal, parietal and thalamic sites (Posner & Peterson, 1990). The alerting component involves the capacity to sustain an alert cognitive state and can be assessed with continuous performance and vigilance task, whereas the orienting network involves the focused identification and selection of sensory information and can be tested with cue task. The executive control of attention governs the capacity to decide among conflicting responses and to give a response to one aspect of a stimuli by ignoring a dominant aspect. Several previous studies have found a deficit in one of the alerting, orienting and executive control components of attention in schizophrenia using different employed experimental manipulations. An approach of attention impairment has been developed to assess the three attention network within one test.

The attention network test (ANT) is a recent paradigm designed to investigate attention efficiencies of alerting, orienting, and executive control of attention (Fan, McCandliss, Sommer, Raz, & Posner, 2002), on the basis of a concept of an integrative selective attention system (Posner & Peterson, 1990). It is a combination of a cued reaction time task (Posner, 1980) and a flanker task (Eriksen & Eriksen, 1974). Validation study in a healthy population showed sufficient independence of the three networks and gave reliable single subject estimates of alerting, orienting and executive function. In particular, the assessment of executive functions seems to reveal robust conflict effects reflected in the reaction time (RT) (Fan et al., 2002). In healthy subjects, orienting is not influenced by age, executive function remained stable after the age of seven and alerting is improved with age (Rueda et al., 2004). Given prior findings of impaired performances by schizophrenia patients on the measure of executive functioning and attention with the Wisconsin Card Sorting Test (WCST) (Grant and Berg, 1948, Heaton, 1981) and the Stroop Word-Color Test (Stroop WC) (Stroop, 1935), we selected these two well established tests as external validated tests in our samples.

Wang et al. (2005) firstly administrated ANT to a large sample of inpatients with schizophrenia compared to controls and found that schizophrenia patients showed impairments of the executive and orienting networks. Gooding, Braun, and Studer (2006) also found an increased ANT conflict (ANTc) effect in schizophrenia outpatients, with no significant difference for the alertness and orientation metrics compared to controls, suggesting a specific deficit of the executive control of attention in schizophrenia. Other studies have produced controversial results and have reported significantly lower conflict effect scores in individuals with schizophrenia (Neuhaus et al., 2007, Opgen-Rhein et al., 2008), or similar levels of executive controls (Nestor et al., 2007, Urbanek et al., 2009), suggesting discrepancies with the ANT studies in schizophrenia. Schizophrenia is a heterogeneous disorder that is likely the result of diversity in the underlying pathophysiological processes in different forms of schizophrenia. Factorial analytic studies lead to a tri-syndromic model of schizophrenia, including a negative, a positive and a disorganization factor (Liddle, 1987). Each syndrome has been associated with distinct patterns of neuropsychological deficits and a distinct pattern of aberrant cerebral activity. For example, thought disorders, a cardinal feature of disorganization, can influence performance in attention-dependent functions (Braff & Light, 2004). Some studies report an association between the disorganized syndrome and defective performance in tasks involving executive and attentional functions (Basso et al., 1998, Daban et al., 2003, Ngan and Liddle, 2000). These associations have been consistently demonstrated in patients with persistent symptoms, but may differ in patients with remitting illness. It seems possible that the inconsistencies between previous studies may be attributable, at least in part, to differences in socio-demographic factors or in the clinical severity of the illness between patient samples.

Furthermore, the efficiency of the executive control of ANT was previously found to be highly heritable (Fan, Wu, Fossella, & Posner, 2001), which may make it an attractive potential endophenotype in schizophrenia. The present study thus evaluated for the first time whether the executive control of attention deficit measured using ANT is characteristic of a specific liability to schizophrenia or may represent an endophenotype.

In this study, we tested the hypothesis that patients with schizophrenia and their first-degree relatives would perform less well in the conflict task and/or display longer reaction times (RTs) than healthy controls. To do this, we first compared executive control of attention using the Attention Network test in patients affected with schizophrenia and in a group of healthy volunteers to find out whether these impairments constitute a feature of schizophrenia. We then compared the performance of their healthy first-degree relatives to that of healthy controls to find out whether executive control of attention, like that of other executive functions or attention, has a familial component. We also evaluated whether the deficits are related to variations on clinical characteristics of patients, such as symptoms scores, age, duration of the illness, age at onset and other deficits known to involve executive function.