Inefficient executive cognitive control in schizophrenia is preceded by altered functional activation during information encoding: An fMRI study

Abstract

Working memory deficits are a core feature of schizophrenia. Previous working memory studies suggest a load dependent storage deficit. However, explicit studies of higher executive working memory processes are limited. Moreover, few studies have examined whether subcomponents of working memory such as encoding and maintenance of information are differentially affected by these deficits.

Therefore, the aim of the present study was to examine the neural substrates of working memory subprocesses requiring stimulus encoding, maintenance and higher executive processing.

Using functional magnetic resonance imaging a modified Sternberg working memory task involving verbal stimulus material was applied. The event-related design enabled the segregation of encoding, active maintenance and executive manipulation of information. Forty-one patients with schizophrenia and 41 healthy subjects were included.

Relative to normal controls, schizophrenic patients demonstrated a significantly stronger activation pattern in a fronto-parietal network during executive information manipulation. Additionally, significant relative hypoactivity was detectable in the thalamus. Conversely, during stimulus encoding the patients demonstrated lower activation relative to controls in the prefrontal cortex and the anterior cingulate gyrus.

The present findings indicate a pronounced prefrontal functional hyperactivation within the neural network subserving higher executive working memory control processes in schizophrenia. Moreover, they suggest that these altered activations during executive control are related to a preceding abnormality of information encoding. During encoding, a reduced activation in mainly dorsolateral prefrontal and anterior cingulate regions was observed. These results could be explained by increased top-down control processing from prefrontal cortex as a compensation for functional deficits occurring during encoding.

Introduction

Converging lines of evidence suggest that cognitive deficits are a core feature of schizophrenia. In particular, schizophrenic patients exhibit dysfunctions in complex working memory (WM) tasks demanding a high amount of cognitive control. WM enables the short-term storage of information and manipulation of this information while being kept in storage. In the classical WM model of Baddeley a central executive is residing above a verbal and a visuo-spatial sketchpad (Repovs & Baddeley, 2006). According to this model, the sketchpad “slave” systems mainly support short-term maintenance of information. The central executive exerts cognitive control and allows for higher mnemonic processes such as manipulation of information.

Functional imaging studies have provided evidence that the neural substrates underlying short-term maintenance might be partially dissociable from those systems responsible for executive control. Maintenance of verbal information has been shown to be associated with mainly ventrolateral prefrontal cortex activation while executive processing has been ascribed to predominantly dorsolateral regions of the PFC (for a review, see Smith & Jonides, 1999). However, several other studies which found the VLPFC also to be involved in processes of stimulus manipulation and executive control challenge this clear-cut functional differentiation (Glahn et al., 2002; Veltman, Rombouts, & Dolan, 2003; Wagner, Maril, Bjork, & Schacter, 2001).

Although activation abnormalities during working memory processing in mainly dorsolateral and ventrolateral prefrontal regions have frequently been reported in patients with schizophrenia (Callicott et al., 2003, Manoach, 2003; Perlstein, Carter, Noll, & Cohen, 2001; Schneider et al., 2007) few working memory studies have specifically examined functional activation patterns during executive control processes in patients (Cannon et al., 2005; Kim, Glahn, Nuechterlein, & Cannon, 2004; Perry et al., 2001; Tan, Choo, Fones, & Chee, 2005). Applying a delayed-response task, Kim et al. (2004) found that simultaneous maintenance and manipulation of verbal and spatial material was associated with significantly worse performance than mere maintenance in patients with schizophrenia. Cannon et al. (2005) used a Sternberg item recognition task (Sternberg, 1966) to compare maintenance and manipulation of spatial stimuli with mere maintenance processing. In this study, patients exhibited significantly stronger deficits in the combined task in association with activation abnormalities in mainly dorsolateral prefrontal regions. Similar results have been reported in a verbal working memory study by Tan et al. (2005) who contrasted maintenance and manipulation related activation with mere maintenance. Tan et al. (2005) detected relative hyperactivity in the left VLPFC (BA 45, 44) in combination with a significantly reduced signal in the anterior cingulate cortex (ACC; BA 32) and the left dorsolateral prefrontal cortex (DLPFC; BA 9) in patients. The authors concluded from their findings that manipulation of information or executive processing is the subprocess which is most seriously impaired in schizophrenia.

It is, however, still a matter of debate which temporal subcomponents of WM are predominantly impaired by the disorder. Recent results suggest that working memory deficits in patients might occur particularly during the encoding phase of WM (Johnson et al., 2006). Utilizing a Sternberg design which allowed the separate analysis of encoding and retrieval processing Johnson et al. found activation abnormalities in terms of significantly reduced activations in the ACC, the left DLPFC, and several subcortical regions in patients already during encoding of verbal stimulus material. These results add to the vast amount of episodic memory studies which show deficits in verbal encoding in association with a reduced cerebral activation in patients (Hofer et al., 2003, Jessen et al., 2003, Ragland et al., 2001, Ragland et al., 2004). Hence, there is reason to assume that working memory deficits in patients might manifest already during encoding of information.

The present fMRI study focused on the executive cognitive control functions in schizophrenia and sought to differentially examine which of the WM subprocesses are affected in schizophrenia. To achieve this goal, a modified Sternberg task arranged as an event-related design differentiating between encoding, active maintenance and executive processing was employed. In order to acquire stable and representative data, relatively large samples of patients and controls were examined. In correspondence with results by Johnson et al. (2006) we expected to find activation differences in terms of hypoactivations in task-related regions (predominantly anterior cingulate and dorsolateral prefrontal) in the patient group already during encoding of stimulus material.

We hypothesized that these encoding-related activation abnormalities, predominantly in the ACC, might be related to the integrity of the subsequent manipulation-associated activation during executive control processing.