Auditory working memory impairments in individuals at familial high risk for schizophrenia.

OBJECTIVES: The search for predictors of schizophrenia has accelerated with a growing focus on early intervention and prevention of psychotic illness. Studying nonpsychotic relatives of individuals with schizophrenia enables identification of markers of vulnerability for the illness independent of confounds associated with psychosis. The goal of these studies was to develop new auditory continuous performance tests (ACPTs) and evaluate their effects in individuals with schizophrenia and their relatives. METHODS: We carried out two studies of auditory vigilance with tasks involving working memory (WM) and interference control with increasing levels of cognitive load to discern the information-processing vulnerabilities in a sample of schizophrenia patients, and two samples of nonpsychotic relatives of individuals with schizophrenia and controls. Study 1 assessed adults (mean age = 41), and Study 2 assessed teenagers and young adults age 13-25 (M = 19). RESULTS: Patients with schizophrenia were impaired on all five versions of the ACPTs, whereas relatives were impaired only on WM tasks, particularly the two interference tasks that maximize cognitive load. Across all groups, the interference tasks were more difficult to perform than the other tasks. Schizophrenia patients performed worse than relatives, who performed worse than controls. For patients, the effect sizes were large (Cohen's d = 1.5), whereas for relatives they were moderate (d = ~0.40-0.50). There was no age by group interaction in the relatives-control comparison except for participants <31 years of age. CONCLUSIONS: Novel WM tasks that manipulate cognitive load and interference control index an important component of the vulnerability to schizophrenia.

Auditory verbal working memory load and thalamic activation in nonpsychotic relatives of persons with schizophrenia: an fMRI replication.

First-degree relatives of persons with schizophrenia are at genetic risk for the illness and show deficits on high-load information-processing tasks. In a prior study of auditory working memory (WM) using functional MRI (fMRI), the authors demonstrated that adult relatives had significantly increased activation in the dorsomedial (DM) thalamus, anterior cingulate, and prefrontal cortex (H. W. Thermenos et al., 2004). In this study, the authors extended this work using a parametric WM task designed for fMRI in an independent, unmedicated sample. Twelve nonpsychotic relatives of persons with schizophrenia and 13 healthy controls were administered multiple versions of an auditory continuous performance test during fMRI. Data were analyzed using Statistical Parametric Mapping software. Compared with controls, relatives showed significantly greater task-elicited activation in the DM thalamus. When fMRI signal change was modeled as a function of increasing WM load, there was a significant Group x Load interaction, with relatives showing significantly greater task-elicited activation in the right DM thalamus compared with controls. Greater DM thalamic activation in the relatives remained significant when WM performance, vocabulary score, and education were controlled. This replication suggests that altered thalamic activation is a feature of neurobiological risk for schizophrenia.

Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study.

BACKGROUND: First-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness and show deficits on high-load information processing tasks. We used functional magnetic resonance imaging (fMRI) to test whether nonpsychotic relatives show altered functional activation in the prefrontal cortex (PFC), thalamus, hippocampus, and anterior cingulate during a working memory task requiring interference resolution. METHODS: Twelve nonpsychotic relatives of persons with schizophrenia and 12 healthy control subjects were administered an auditory, verbal working memory version of the Continuous Performance Test during fMRI. An asymmetric, spin-echo, T2*-weighted sequence (15 contiguous, 7-mm axial slices) was acquired on a full-body MR scanner. Data were analyzed by Statistical Parametric Mapping (SPM). RESULTS: Compared with control subjects, relatives showed greater task-elicited activation in the PFC and the anterior and dorsomedial thalamus. When task performance was controlled, relatives showed significantly greater activation in the anterior cingulate. When effects of other potentially confounding variables were controlled, relatives generally showed significantly greater activation in the dorsomedial thalamus and anterior cingulate. CONCLUSIONS: This pilot study suggests that relatives of persons with schizophrenia have subtle differences in brain function in the absence of psychosis. These differences add to the growing literature identifying neurobiological vulnerabilities to schizophrenia.