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: 3.96). 10/2009; 44(6):364-72. DOI: 10.1016/j.jpsychires.2009.09.003
Source: PubMed


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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    • "Another important outstanding question is how alterations in hippocampal-prefrontal connectivity contribute to the symptoms of schizophrenia. Some of the studies reviewed here have reported a correlation between hippocampalprefrontal connectivity and disease symptoms as well as cognitive performance (Henseler et al., 2010). Abnormal connectivity between frontal and temporal lobes has also been found to correlate with hallucinations in schizophrenia patients (Lawrie et al., 2002). "
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    ABSTRACT: The hippocampus and prefrontal cortex have long been known to play a central role in various behavioral and cognitive functions. More recently, electrophysiological and functional imaging studies have begun to examine how interactions between the two structures contribute to behavior during various tasks. At the same time, it has become clear that hippocampal-prefrontal interactions are disrupted in psychiatric disease and may contribute to their pathophysiology. These impairments have most frequently been observed in schizophrenia, a disease that has long been associated with hippocampal and prefrontal dysfunction. Studies in animal models of the illness have also begun to relate disruptions in hippocampal-prefrontal interactions to the various risk factors and pathophysiological mechanisms of the illness. The goal of this review is to summarize what is known about the role of hippocampal-prefrontal interactions in normal brain function and compare how these interactions are disrupted in schizophrenia patients and animal models of the disease. Outstanding questions for future research on the role of hippocampal-prefrontal interactions in both healthy brain function and disease states are also discussed.
    Full-text · Article · Jan 2016 · Frontiers in Systems Neuroscience
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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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    ABSTRACT: A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.
    Full-text · Article · Jul 2014 · Frontiers in Genetics
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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.
    Full-text · Article · Apr 2014 · Frontiers in Psychiatry
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