Hypo-activation in the executive core of the sustained attention network in adolescent offspring of schizophrenia patients mediated by premorbid functional deficits

Abstract

Adolescent offspring of schizophrenia patients (SCZ-Off) are vulnerable to psychiatric disorders. Assessing relationships between clinical and biological measures (such as functional magnetic resonance imaging, fMRI) may elucidate pathways of vulnerability in this group. Here we assessed the relationship between clinically assessed premorbid function, and cortico-striatal activity during sustained attention in controls (HC: with no family history of psychosis) and SCZ-Off. Subjects (n = 39) were assessed using the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Symptoms. Based on the Global Assessment of Functioning (GAF) score, SCZ-Off were cleaved into "high" or “low” clinically functioning sub-groups (SCZ-Off_HF, SCZ-Off_LF respectively). During fMRI, subjects participated in a modified continuous performance task (CPT-IP). fMRI was conducted on a Bruker MedSpec 4 T system (345 EPI scans; TR = 2 s; 24 slices; 3.8 × 3.8 × 4 mm). Results show SCZ-Off_LF evinced less activation than both HC and SCZ-Off_HF in the executive core of the brain's attentional system (anterior cingulate, dorsal prefrontal cortex and caudate), but not visuo-spatial regions such as primary visual or superior parietal cortex. Differences were independent of behavioral performance, and reduction in activity was related to GAF score in a dose-dependent manner. Assessing the relationship between clinical measures and brain activity in domains such as attention provides a window into mechanisms of vulnerability in the developing adolescent brain.

Introduction

Sustained attention, or the ability to remain consistently (as opposed to transiently) focused on an ongoing task, is one of the most basic of cognitive domains and has been the subject of intense research scrutiny (Posner and Rothbart, 1998). In vivo imaging studies suggest that higher order mechanisms in sustained attention, relating to control and vigilance, are particularly dependent on the brain's fronto-striatal resources (Kelley et al., 2008). Sustained attention generally underlies many basic cognitive processes, and itself depends on the development of fronto-striatal regions including the prefrontal cortex, the anterior cingulate cortex and the basal ganglia, regions that lie within the “executive core” of the brain's attention system (Rueda et al., 2005) and that rapidly connect during adolescence (Barnea-Goraly et al., 2005).

In the schizophrenia spectrum, attention deficits have been hypothesized not only as a marker of the illness itself, but also of risk for schizophrenia (Rutschmann et al., 1977, Cornblatt et al., 1988, Chen and Faraone, 2000). Thus, consistent with neurodevelopmental models of schizophrenia (Rapoport et al., 2005), deficits in sustained attention have been documented in larger cohorts of child and adolescent offspring of schizophrenia parents (SCZ-Off), presumably resulting from developmentally mediated impairments in essential fronto-striatal neuro-circuitry (Keshavan et al., 2009). The abnormalities associated with risk may in fact result from altered development of critical neuro-circuitry during adolescence. In general, rapid changes in functional development during adolescence relate to rapid changes in the functional organization of cortical and sub-cortical structures. As networks rapidly evolve under a combination of genetic and environmental influences, their susceptibility to developmental deviations in both pre-natal and post-natal periods becomes increasingly acute (Rakic, 1999). The combination of developmental brain changes and psychosocial stressors, together, increases adolescent susceptibility to psychiatric disease resulting in estimated peak onsets of any lifetime mental health disorder as early as 14 years of age (Kessler et al., 1994). Therefore, the altered trajectory of neurodevelopment hypothesized in the schizophrenia diathesis may significantly impact vulnerable groups such as SCZ-Off. Through adolescence, the expansion of functional competence is particularly marked in the domain of sustained attention, which is relatively immature early in childhood, but rapidly develops through adolescence (Rubia et al., 2006). This ascent in attention-related competence appears closely related to the development of well-orchestrated interactions in fronto-parietal and basal-ganglia circuitry (Haber and Calzavara, 2009).

Very early assessments of SCZ-Off recognized the increased incidence of cognitive and behavioral impairments (Marcus, 1974), and several decades of subsequent research have pointed to increasingly reliable deficits in brain structure, behavior and function. Behavioral deficits are generally observed in domains including attention (Rosenberg et al., 1997, Cornblatt and Malhotra, 2001), executive function (Erlenmeyer-Kimling, 2000) and working memory (Diwadkar et al., 2001) and appear to be broadly associated with impairments in fronto-striatal structure and neurochemistry (Diwadkar et al., 2006, Keshavan et al., 2009). Specifically of these, deficits in attention appear to be the centerpiece of impairment in adolescence and the expansion in attention-related competence that is generally observed in controls is absent or attenuated in SCZ-Off (Cornblatt and Keilp, 1994, Cornblatt et al., 1999).

Only recently have studies used functional magnetic resonance imaging (fMRI) to investigate the correlates of sustained attention in groups at risk for schizophrenia. Adult siblings of schizophrenia patients (Sepede et al., 2010) showed hypo-activation (or less activation) in frontal circuitry (in the absence of behavioral deficits); differences from controls are amplified under conditions of increased attention demand. These results of impaired frontal recruitment suggest a relationship between vulnerability to schizophrenia and cortical recruitment. The study of child and adolescent SCZ-Off offers particularly unique advantages. This is a sub-group in whom the interactive effects of genetic and developmental vulnerabilities (Lewis and Levitt, 2002) can be assessed. Furthermore, it is also possible to observe potential premorbid precursors of the illness in terms of fMRI measures of brain function. Finally, SCZ-Off also offer the opportunity of studying the vulnerable adolescent brain in a medication naïve state, thus providing potentially valuable insights into how the developing, yet vulnerable brain may respond to attention challenges.

In addition to assessing sustained attention-related processing in the brain, we were particularly interested in investigating the relationship between the fMRI response and measures of premorbid clinical function in SCZ-Off using structured interviews such as the Structured Interview for Prodromal Syndromes (SIPS) (Miller et al., 2003). In SCZ-Off, the degree of risk and vulnerability for the onset of disorders is highly variable, suggesting significant heterogeneity in vulnerability markers. Understanding the relationship between clinical assessments and the fMRI response may advance understanding of the relationship between clinical symptoms and brain function. Characterizing these brain–behavior correlates of vulnerability in SCZ-Off may significantly assist in the objective parcellation of vulnerability in this heterogeneous sample (Diwadkar et al., 2006).

Here we used fMRI to study mechanisms of sustained attention using a modified continuous performance task (Cornblatt et al., 1989, Salgado-Pineda et al., 2004) in a group of controls (with no family history of psychosis to the 2nd degree) and adolescent offspring of schizophrenia patients. Independent from the fMRI analyses, subjects were administered the Structured Interview for the Assessment of Prodromal Syndromes (Miller et al., 2002, Miller et al., 2003). The assessment of clinical function in SCZ-Off was based on the Global Assessment of Function (GAF) sub-scale of the SIPS. The GAF is an index of the psychological, social, and occupational functioning of individuals, providing a measure of the extent of their clinical impairment. This sub-scale is valuable as it allows for the categorical division of subjects into low- (scores < 80) and high- (scores > 80) functioning sub-groups. Based on this approach, we attempted to a) separately evaluate each of the sub-groups (relative to controls) for differences in activation and b) investigate the continuous relationship between this clinical measure and fMRI measures across the entire SCZ-Off sample. We hypothesized that if general clinical function impacted the engagement of sustained attention-related regions, subjects with greater clinical impairments would show hypo-responsivity of the fMRI response. The regional specificity of the response can provide evidence of the specificity of the impact of clinical impairments on brain function.

The analyses of fMRI data focused on the regions that collectively conform to the brain's attention network. Among these were regions such the prefrontal cortex (BA 9/46), the dorsal anterior cingulate cortex and the caudate (Corbetta et al., 1998, Gregoriou et al., 2009, Reynolds et al., 2009), all implicated in higher order supervisory processes in attention, and the superior parietal and primary visual cortices (Offen et al., 2009, Thakral and Slotnick, 2009), implicated in sensory and spatial orienting mechanisms in sustained attention.