Article

Henseler I, Falkai P, Gruber O. Disturbed functional connectivity within brain networks subserving domain-specific subcomponents of working memory in schizophrenia: relation to performance and clinical symptoms. J Psychiatr Res 44: 364-372

Centre for Translational Research in Systems Neuroscience and Clinical Psychiatry, Department of Psychiatry and Psychotherapy, Georg August University, D-37075 Goettingen, Germany.
Journal of Psychiatric Research (Impact Factor: 4.09). 10/2009; 44(6):364-72. DOI: 10.1016/j.jpsychires.2009.09.003
Source: PubMed

ABSTRACT Disturbed interregional functional connectivity has been hypothesized to be a promising marker of schizophrenia. The relationship between working memory (WM) impairment, disturbed functional connectivity, and the characteristic symptoms of schizophrenia, however, remains elusive.
We used functional MRI (fMRI) to investigate in patients with schizophrenia and matched controls the patterns of functional connectivity during the performance of different tasks selectively engaging subcomponent processes of working memory.
Compared with controls, patients showed reduced connectivity of the prefrontal cortex with the intraparietal cortex and the hippocampus and abnormal negative interactions between the ventrolateral and dorsolateral prefrontal cortex during the non-articulatory maintenance of phonological information. During the maintenance of visuospatial information, patients presented reduced connectivity between regions in the superior parietal and occipital cortex, as well as enhanced positive connectivity of the frontal eye field with visual processing areas.
Our findings suggest complex dysregulations within the networks supporting working memory functions in schizophrenia, which manifest as decreased positive and abnormal negative interactions. Correlations between the connection strength and WM performance suggest that these dysregulations may be neurofunctional correlates of the WM deficits seen in schizophrenia. Altered prefronto-hippocampal and parieto-occipital connectivity was further found to be associated with higher positive symptoms, providing a possible explanation for the development of delusions and disorganization symptoms.
The present findings can help to better understand the relationship between altered patterns of synchronized brain activity and the cognitive and clinical symptoms of schizophrenia.

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    • "With recent advances in neuroimaging, deficits in neural connectivity are being mapped and alterations in neocortical circuitry have been reported in multiple disorders, including ASD, SCZ, and bipolar disorder (Kuperberg et al., 2008; Henin et al., 2009; Henseler et al., 2010; Hall et al., 2013; Zikopoulos and Barbas, 2013). Functional and anatomical imaging studies have also supported neocortical dysfunction in FXS. "
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    • "Deficits in working memory in schizophrenic disorders have been found to be associated with dysfunctions of prefrontal cortices, especially of the dorsolateral prefrontal cortex, of the deep fronto-opercular cortex, and of the anterior cingulate cortex [e.g., Ref. (45–50)]. In the last few years, there have also been several reports of a disturbed connectivity between these prefrontal areas and the medial temporal lobe, particularly the hippocampus [e.g., Ref. (51, 52)]. "
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    ABSTRACT: Schizophrenia is characterized by positive, negative, and cognitive symptoms. While positive symptoms occur periodically during psychotic exacerbations, negative and cognitive symptoms often emerge before the first psychotic episode and persist with low functional outcome and poor prognosis. This review article outlines the importance of modern functional magnetic resonance imaging techniques for developing a stratified therapy of schizophrenic disorders. Functional neuroimaging evidence on the neural correlates of positive and particularly negative symptoms and cognitive deficits in schizophrenic disorders is briefly reviewed. Acute dysregulation of dopaminergic neurotransmission is crucially involved in the occurrence of psychotic symptoms. However, increasing evidence also implicates glutamatergic pathomechanisms, in particular N-methyl-d-aspartate (NMDA) receptor dysfunction in the pathogenesis of schizophrenia and in the appearance of negative symptoms and cognitive dysfunctions. In line with this notion, several gene variants affecting the NMDA receptor's pathway have been reported to increase susceptibility for schizophrenia, and have been investigated using the imaging genetics approach. In recent years, several attempts have been made to develop medications modulating the glutamatergic pathway with modest evidences for efficacy. The most successful approaches were those that aimed at influencing this pathway using compounds that enhance NMDA receptor function. More recently, the selective glycine reuptake inhibitor bitopertin has been shown to improve NMDA receptor hypofunction by increasing glycine concentrations in the synaptic cleft. Further research is required to test whether pharmacological agents with effects on the glutamatergic system can help to improve the treatment of negative symptoms in schizophrenic disorders.
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    • "Results indicated an abnormal unmodulated persistent functional coupling (fMRI time-series correlations) between DLPFC and hippocampus in schizophrenia patients under WM load. Henseler et al. (2010) tested whether abnormal connectivity is present in different functional networks supporting independent components of WM: articulatory rehearsal, non-articulatory maintenance of phonological information, and the maintenance of visuospatial information. Using PPI methodology, it was showed that schizophrenia patients display complex patterns of connectivity compared with healthy controls, with reduced connectivity and abnormal negative connectivity among the regions of interests (ROIs). "
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