Cerebral changes and cognitive dysfunctions in medication-free schizophrenia – An fMRI study

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Abstract

Proposing cognitive impairment in working memory (wm) functions as a cognitive core deficit in schizophrenia, 23 first episode, medication-free schizophrenic patients in a comparison of healthy adults have been investigated by fMRI. Additionally, the effects of different attentional demands in wm tasks were analysed.

A wm paradigm was applied, in which stimuli were presented in a 2-back and a 0-back condition in a non-degraded and degraded version.

As hypothesized in healthy controls increased activity during both 2-back tasks was found in the ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), parietal regions, the thalamus and the cerebellum. Different activation patterns were found for the cingulate cortex in the 2-back degraded conditions. The comparison between healthy controls and schizophrenic patients revealed decreased activity in the right VLPFC in patients as well as increased activity in temporal regions. Furthermore patients’ task performance quality was significantly lower for 2-back conditions.

Schizophrenic patients use different cognitive strategies to solve working memory tasks, reflected in significantly altered cerebral activity. However, the different fMRI working memory correlates found in schizophrenic patients seem to be insufficient in terms of overall task performance.

Introduction

Previous neuropsychological investigations found a diversity of cognitive impairments in schizophrenic patients, especially with regard to working memory (wm) (Hutton et al., 1998, Krieger et al., 2005, Nestor et al., 1998), in which the prefrontal cortex plays a crucial role (Rainer et al., 1999, Watanabe, 1996). The lateral prefrontal cortex can be divided into the ventrolateral prefrontal cortex (VLPFC, BA 44,45,47 in the inferior frontal gyrus) and the dorsolateral prefrontal cortex (DLPFC, regions superior to the inferior frontal gyrus, i.e. BA 46,9). To find a link between prefrontal deficits, underlying disturbed wm functions and schizophrenic symptoms, it can be hypothesized that disturbed wm functions are the basis for many other cognitive deficits in schizophrenia, in the sense of a failure to handle behaviour on the basis of schematas or ideas (Cohen et al., 1996). This would lead to event-related, repetitive reactions which are uncoupled from the context. Formal thought disorders, the incapability to understand correct associative coherences or organizing the world into conclusive schemes can be regarded as possible consequences of such dysfunctions like attentional and wm deficits.

It is now a decade since first fMRI studies were reported in schizophrenic patients, in which numerous of these investigations applied wm paradigms (Weinberger and Berman, 1996, Callicott et al., 1998, Callicott et al., 2000, Callicott et al., 2003, Volz et al., 1999, Honey et al., 1999, Manoach et al., 2000, Barch et al., 2001, Barch et al., 2002, Menon, 2001, Perlstein et al., 2003, Quintana et al., 2003, Schlösser et al., 2003, Kindermann et al., 2004, Mendrek et al., 2004, Thermenos et al., 2005). Whereas some found decreased activation in the DLPFC (Volz et al., 1999, Menon, 2001, Barch et al., 2001, Barch et al., 2002, Perlstein et al., 2003), other researchers detected the inverse effects during wm performance (Callicott et al., 2000, Manoach et al., 2000). In healthy subjects DLPFC activities increases with task difficulty. When wm capacity is exceeded, activity decreases. Reduced signals in prefrontal areas can thus be regarded as a diminished wm capacity in schizophrenic patients, an interpretation which is supported by lower wm task performance of schizophrenic patients. Additionally, Callicott (Callicott et al., 2003) found that schizophrenic patients only showed decreased frontal activity when they performed poorly and that high performance was correlated with increased activity.

But not only frontal or parietal regions are involved in complex cognitive functions such as wm. Cerebral circuits, including lateral PFC, premotor cortex, the intraparietal sulcus, the caudate nucleus, the thalamus, the hippocampus and occipitotemporal regions (Gazzaley et al., 2004) build the underlying neuronal network for wm performance. Evidence for cerebellar attendance came from studies which analyzed the consequences of cerebellar lesions on wm functions (Ravizza et al., 2006, Hokkanen et al., 2006).

A possible explanation of heterogeneous findings are potential clinical subgroups of schizophrenic patients, different motivational states or the psychopharmacological treatment. Previous studies mostly scanned medicated patients or small samples of unmedicated patients. To avoid confounds from psychopharmacological treatment we studied 23 untreated schizophrenic patients and matched healthy controls with fMRI, performing a modified 2-back paradigm of the continuous performance test (CPT). Additionally, the aim of this study was to investigate the effect of distinct attentional demands in wm tasks. We hypothesized involvement of the VLPFC, DLPFC, parietal regions, thalamus and cerebellum in healthy controls during wm tasks. Furthermore, we anticipated worse task performance and altered cerebral activation patterns in schizophrenic patients, especially in the sense of a prefrontal decreased activity.

Section snippets

Subjects

Twenty-three healthy controls and 23 untreated schizophrenic inpatients recruited from the Department of Psychiatry of the Ludwig-Maximilians-University of Munich with the diagnosis of schizophrenia according to DSMIV criteria were included. All participants were right-handed according to the modified version of the Edinburgh Handedness Inventory (Oldfield, 1971). Twenty patients were drug-naive, three patients were scanned after a wash-out period of 3 days, receiving haloperidol (10 mg/d),

Task performance

Significant differences in task performance were detected at a statistical threshold of p < 0.05. Patients made significantly more errors in 2-back (T = −2.6, df = 34, p = 0.01) and 2-back degraded (T = −3.4, df = 33, p = 0.002) conditions, but there were no error differences in 0-back trials (0-back: T = −1.7, df = 34, p = 0.09; 0-back degraded: T = −1.4, df = 34, p = 0.16). There were no significant differences between reaction times (0-back: T = 1.6, df = 34, p < 0.12, 0-back degraded:T = 1.5, df = 34, p = 0.15, 2-back: T = 1.7, df

Healthy controls

The first aim of this study was to gain a better understanding of functional circuits during higher cognitive functions such as wm. In accordance to a model proposed by Petrides (Petrides, 1994, Petrides, 2000) we found more activation in the DLPFC, the VLPFC and parietal regions in healthy controls. The difference between the 2-back and 2-back degraded conditions is due to the demand of attention, degraded trials requiring a higher effort. Previous studies emphasized that activity in the DLPFC

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