Elsevier

NeuroImage

Volume 19, Issue 3, July 2003, Pages 751-763
NeuroImage

Regular article
Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling

https://doi.org/10.1016/S1053-8119(03)00106-XGet rights and content

Abstract

The present study aimed to explore altered effective connectivity in schizophrenic patients while performing a 2-back working memory task. Twelve right-handed, schizophrenic patients treated with typical or atypical antipsychotics and 6 healthy control subjects were studied with fMRI while performing a “2-back” working memory task. Effective connectivity within a cortical-subcortical-cerebellar network for mnemonic information processing was assessed and compared between both groups. The path model included cortico-cortical connections comprising the parietal association cortex, ventrolateral prefrontal cortex (VLPFC), and the dorsolateral prefrontal cortex (DLPFC) as well as a cortico-cerebellar feedback loop comprising prefrontal cortex, contralateral cerebellum, and thalamus. Group differences were analyzed with a stacked models approach. Relative to normal controls, both patient groups revealed a pattern of reduced connectivity within the prefrontal-cerebellar and the cerebellar-thalamic limbs but enhanced connectivity in the thalamo-cortical limb of the cortical-cerebellar circuit. Moreover, a direct comparison of both treatment groups revealed enhanced connectivity in the interhemispheric connections between the cortical association areas in patients treated with atypical antipsychotics. However, right prefrontal and left parieto-frontal path coefficients were lower in the patient group receiving atypical antispychotic drugs. The findings suggest that the relationship between pathology in cortical-subcortical cerebellar networks and associated functional connectivity is complex and may include aspects of increased and decreased levels of connectivity consistent with the notion of “cognitive dysmetria” in schizophrenia. The observed pronounced connectivity within thalamo-cortical projections could be attributed to a compensatory increase of thalamic input in the presence of disrupted effective connectivity within the preceding limb of the cortical-cerebellar circuitry. The study demonstrated the feasibility of structural equation modeling for the investigation of group and treatment-related differences in effective connectivity and provides a promising approach to further disentangle the relationship between altered functional capacity and associated fMRI signal changes.

Introduction

Aside from the characteristic psychopathology including positive and negative symptoms, deficits in a number of cognitive domains including working memory and executive functions have been described in schizophrenic patients (Goldberg and Gold, 1995). Initial fMRI studies demonstrated that schizophrenic patients exhibited less prefrontal cortical activation than normal controls while performing working memory and executive tasks Callicott et al 1998, Volz et al 1999, Stevens et al 1998. These findings suggesting “hypofrontality,” however, have recently been challenged by studies indicating a relatively increased prefrontal cortical activation pattern in schizophrenic patients in comparison to normal controls (Manoach et al., 1999). This difference between groups was present even when the schizophrenic patients were matched for (Manoach et al., 2000) or demonstrated impaired task performance (Callicott et al., 2000) relative to normal controls. The findings indicate a compensatory recruitment of neural circuits in the presence of impaired integrity of the main neural systems subserving working memory functions.

Whereas the major component of working memory has traditionally been ascribed to prefrontal brain areas (Goldman Rakic, 1994), functional brain imaging approaches provided information about widespread networks including frontal and parietal association areas involved in the performance of working memory tasks (Cohen, 1997).

Petrides 1994, Petrides 1996, Petrides 2000 has proposed a model of cortico-cortical functional interactions underlying mnemonic information processing according to which information is first processed in the parietal cortex. The posterior association areas are connected with the ventrolateral prefrontal cortex (VLPFC), where decision making, comparison, and reproduction of information held in working memory takes place. The dorsolateral prefrontal cortex (DLPFC), which is connected with the VLPFC, is additionally recruited when a higher order control of mnemonic processing such as monitoring and manipulation of information in working memory is required. This organization-by-process model could be confirmed in subsequent imaging studies. There is evidence that the dorsolateral prefrontal cortex is predominantly subserving executive control functions, whereas preprocessing and maintenance of information are mainly associated with activation of the ventrolateral frontal and also the parietal association cortex D’Esposito et al 2000, Postle et al 2000, Stern et al 2000.

Additionally, there is mounting evidence that, aside from cortical structures, cerebellar (Schmahmann and Pandya, 1997b) and thalamic (Alexander et al., 1986) areas are involved in higher cognitive functions in terms of a cortical-subcortical-cerebellar circuitry. It has been proposed that psychopathology and cognitive deficits in schizophrenia are associated with disruptions of defined information processing pathways in the brain Friston and Frith 1995, McGuire and Frith 1996. The concept of “cognitive dysmetria” has been introduced to characterize a disintegration at the system level of cortical-subcortical-cerebellar circuitry (Andreasen et al., 1998). A complex pattern of existing deficits and compensatory adaptation is likely to involve separate network components in a differential way.

Previous studies investigating schizophrenic patients with working memory tasks employed mostly univariate statistical approaches aiming at a functional segregation of distinct areas of activation. In dealing with issues of concerted network operations, the analysis of cerebral activation data provided by functional imaging has more recently moved to the search for connectivity within activated networks. Models of information processing for higher cognitive task have to address the interaction within large-scale neuronal networks. The notion of effective connectivity between brain areas involves model-based assumptions about the effect which one neural systems exerts over another (Mclntosh et al., 1999). Statistical approaches addressing effective connectivity such as structural equation modeling (SEM) have been successfully adopted to functional brain imaging data previously (Büchel and Friston, 1997).

In addition to existing pathological alterations, neuropsychological functions and related cognitive brain activation patterns can be modulated by antipsychotic treatment. Atypical antipsychotic agents appear to exert a more favorable effect on cognitive functions and in particular working memory than treatment with conventional neuroleptics (Green et al., 1997). In a comparison study of typical and atypical antipsychotic drugs, cognitive brain activation patterns as studied with fMRI and a working memory task were enhanced after switching from conventional to atypical agents (Honey et al., 1999). However, the effect of antipsychotic treatment on measures of effective connectivity has not been studied yet.

The present study was aimed to model information processing within defined cortical-subcortical-cerebellar circuitry subserving working memory functions. It was hypothesized that schizophrenic patients demonstrate a disruption in effective connectivity measures, possibly paralleled by the compensatory strengthening of other pathways, and that this dysfunction might be differentially modulated by treatment with typical and atypical antipsychotic drugs.

Section snippets

Subjects

Twelve patients were recruited from the inpatient service of a University Hospital. The patients fulfilled the diagnostic criteria for schizophrenia, either paranoid or undifferentiated type (DSM IV). All schizophrenic subjects were clinically stabilized with either typical or atypical antipsychotics for at least 2 weeks. In the typical antipsychotic group, 6 patients received haloperidol (mean dose = 4.67 mg/day) at the time of the fMRI investigation. Within the atypical antipsychotic group, 5

Psychometric performance

There was a significant difference in task performance A′ among the 3 groups (χ2(2) = 8.91, P < 0.05). The highest performance A′ was reached by the normal controls followed by the group of patients treated with atypical antipsychotics and finally the group receiving typical antipsychotics (Table 1). The difference in performance between controls and patients with typical antipsychotics received statistical significance (P < 0.05), whereas all other pairwise group differences were not

Discussion

The results of the present study suggest differences in connectivity strengths within a cortical-subcortical-cerebellar network between healthy controls and schizophrenic patients treated with typical and atypical antipsychotics. In patients treated with typical antipsychotics compared to normal controls, reduced connectivity strength could be observed in a left prefrontal/right cerebellar network and in interhemispheric connections whereas increased connectivity strength was found in

Acknowledgements

We thank the staff of the Department of Neuroradiology, University of Mainz, for performing the functional MRI scans.

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