Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling Ralf Schlo ¨sser, a,c, * Thomas Gesierich, a Bettina Kaufmann, a Goran Vucurevic, b Stefan Hunsche, b Joachim Gawehn, b and Peter Stoeter b a Department of Psychiatry, University of Mainz, Mainz, Germany b Department of Neuroradiology, University of Mainz, Mainz, Germany c Department of Psychiatry, University of Jena, Jena, Germany Received 26 March 2002; revised 22 October 2002; accepted 23 December 2002 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. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Schizophrenia; fMRI; Frontal cortex; Antipsychotics; Connectivity Introduction Aside from the characteristic psychopathology including positive and negative symptoms, deficits in a number of cognitive domains including working memory and execu- tive functions have been described in schizophrenic patients (Goldberg and Gold, 1995). Initial fMRI studies demon- strated 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 pre- frontal 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 * Corresponding author. Department of Psychiatry, University of Jena, Philosophenweg 3, 07740 Jena, Germany. Fax: +49(0)3641-9-35444. E-mail address: Ralf.Schloesser@uni-jena.de (R. Schlo ¨sser). NeuroImage 19 (2003) 751–763 www.elsevier.com/locate/ynimg 1053-8119/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1053-8119(03)00106-X