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
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.
"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. "
[Show abstract][Hide abstract] 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.
Frontiers in Genetics 07/2014; 5:239. DOI:10.3389/fgene.2014.00239
"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)]. "
[Show abstract][Hide abstract] 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.
Frontiers in Psychiatry 04/2014; 5:32. DOI:10.3389/fpsyt.2014.00032
"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). "
[Show abstract][Hide abstract] ABSTRACT: CONSIDERING THAT SINGLE LOCATIONS OF STRUCTURAL AND FUNCTIONAL ABNORMALITIES ARE INSUFFICIENT TO EXPLAIN THE DIVERSE PSYCHOPATHOLOGY OF SCHIZOPHRENIA, NEW MODELS HAVE POSTULATED THAT THE IMPAIRMENTS ASSOCIATED WITH THE DISEASE ARISE FROM A FAILURE TO INTEGRATE THE ACTIVITY OF LOCAL AND DISTRIBUTED NEURAL CIRCUITS: the "abnormal neural connectivity hypothesis." In the last years, new evidence coming from neuroimaging have supported and expanded this theory. However, despite the increasing evidence that schizophrenia is a disorder of neural connectivity, so far there are no treatments that have shown to produce a significant change in brain connectivity, or that have been specifically designed to alleviate this problem. Brain-Computer Interfaces based on real-time functional Magnetic Resonance Imaging (fMRI-BCI) are novel techniques that have allowed subjects to achieve self-regulation of circumscribed brain regions. In recent studies, experiments with this technology have resulted in new findings suggesting that this methodology could be used to train subjects to enhance brain connectivity, and therefore could potentially be used as a therapeutic tool in mental disorders including schizophrenia. The present article summarizes the findings coming from hemodynamics-based neuroimaging that support the abnormal connectivity hypothesis in schizophrenia, and discusses a new approach that could address this problem.
Frontiers in Psychiatry 03/2013; 4:17. DOI:10.3389/fpsyt.2013.00017
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