| 1 | Schizophr. Res. 2006 Jul 85: 245-53 |
|---|---|
| PMID | 16730162 |
| Title | Schizophrenia-associated reduction of neuronal and oligodendrocyte numbers in the anterior principal thalamic nucleus. |
| Abstract | The anterior principal thalamic nucleus provides a NODAL link for intralimbic circuits involved in the execution of multiple complex functions that are impaired in schizophrenia (SZ). Using stereologic sampling procedures, we assessed the volume and the number of neurons and oligodendrocytes in this nucleus in well-characterized postmortem material from 23 neuroleptic treated subjects with chronic SZ (SZs) and 12 comparison subjects (Cs) with no psychiatric history. Volume was decreased on average by 17% in SZ, but this difference was not statistically significant. For neuronal number, there was a significant sex by diagnosis interaction with neuronal number being lower in male (p = .002) but not female (p = .374) SZs relative to their respective Cs. For the number of oligodendrocytes, there was a main effect of diagnosis and a diagnosis by sex interaction such that number was significantly reduced in male SZs (p < .001) with a similar trend in female SZs (p = .051) relative to their respective controls. The ratio of oligodendrocytes to neurons was significantly decreased in SZs (p = .045) with no sex by diagnosis interaction. These findings are consistent with a previous report of reduced neuronal number in the anterior principal nucleus of male SZs and add to a growing body of evidence implicating oligodendrocyte abnormalities in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 2 | Neuroimage 2008 Feb 39: 1803-14 |
| PMID | 18061481 |
| Title | Intrinsic and extrinsic analysis in computational anatomy. |
| Abstract | We present intrinsic and extrinsic methods for studying anatomical coordinates in order to perform statistical inference on random physiological signals F across clinical populations. In both intrinsic and extrinsic methods, we introduce generalized partition functions of the coordinates, psi(x), x epsilon M, which are used to construct a random field of F on M as statistical model. In the intrinsic analysis, such partition functions are built intrinsically for individual anatomical coordinate based on Courant's theorem on NODAL analysis via self-adjoint linear elliptic differential operators. In contrast, the extrinsic method needs only one set of partition functions for a template coordinate system, and then applies to each anatomical coordinate system via diffeomorphic transformation. For illustration, we apply both intrinsic and extrinsic methods to a clinical study: cortical thickness variation of the left cingulate gyrus in schizophrenia. Both methods show that the left cingulate gyrus tends to become thinner in schizophrenia relative to the healthy control population. However, the intrinsic method increases the statistical power. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 3 | Acta Neuropathol. 2009 Apr 117: 347-68 |
| PMID | 18604544 |
| Title | The thalamus and schizophrenia: current status of research. |
| Abstract | The thalamus provides a NODAL link for multiple functional circuits that are impaired in schizophrenia (SZ). Despite inconsistencies in the literature, a meta analysis suggests that the volume of the thalamus relative to that of the brain is decreased in SZ. Morphometric neuroimaging studies employing deformation, voxel-based and region of interest methodologies suggest that the volume deficit preferentially affects the thalamic regions containing the anterior and mediodorsal nuclei, and the pulvinar. Postmortem design-based stereological studies have produced mixed results regarding volume and neuronal deficits in these nuclei. This review examines those aspects of thalamic circuitry and function that suggest salience to SZ. Evidence for anomalies of thalamic structure and function obtained from postmortem and neuroimaging studies is then examined and directions for further research proposed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 4 | Curr Top Behav Neurosci 2010 -1 4: 555-83 |
| PMID | 21312413 |
| Title | Integrative circuit models and their implications for the pathophysiologies and treatments of the schizophrenias. |
| Abstract | A preponderance of evidence indicates that the heterogeneous group of schizophrenias is accompanied by disturbances in neural elements distributed throughout multiple levels of interconnected cortico-striato-pallido-thalamic circuitry. These disturbances include a substantial loss of, or failure to develop, both cells and/or appropriate cellular connections in regions that include at least portions of the hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala, prefrontal and anterior cingulate cortex, superior and transverse temporal gyri, and mediodorsal, anterior, and pulvinar nuclei of the thalamus; they appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, that in the opinion of this author cannot be "undone" or even predictably remediated in any physiological manner by existing pharmacotherapies. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and multiple different epigenetic events. Evidence for these complex circuit disturbances has significant implications for many areas of schizophrenia research, and for future efforts toward developing more effective therapeutic approaches for this group of disorders. The conclusion of this chapter is that such future efforts should focus on further developing and refining medications that target NODAL or convergent circuit points within the limbic-motor interface, with the goal of constraining the scope and severity of psychotic exacerbations, to be used in concert with systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements. This strategy should be applied in both preventative and treatment settings, and disseminated for community delivery via an evidence-based manualized format. In contrast to alternative treatment strategies that range from complex polypharmacy to gene therapies to psychosurgical interventions, the use of combined medication plus targeted cognitive and behavioral psychotherapy has both common sense and time-tested documented efficacy with numerous other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 5 | Curr Top Behav Neurosci 2010 -1 4: 555-83 |
| PMID | 21312413 |
| Title | Integrative circuit models and their implications for the pathophysiologies and treatments of the schizophrenias. |
| Abstract | A preponderance of evidence indicates that the heterogeneous group of schizophrenias is accompanied by disturbances in neural elements distributed throughout multiple levels of interconnected cortico-striato-pallido-thalamic circuitry. These disturbances include a substantial loss of, or failure to develop, both cells and/or appropriate cellular connections in regions that include at least portions of the hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala, prefrontal and anterior cingulate cortex, superior and transverse temporal gyri, and mediodorsal, anterior, and pulvinar nuclei of the thalamus; they appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, that in the opinion of this author cannot be "undone" or even predictably remediated in any physiological manner by existing pharmacotherapies. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and multiple different epigenetic events. Evidence for these complex circuit disturbances has significant implications for many areas of schizophrenia research, and for future efforts toward developing more effective therapeutic approaches for this group of disorders. The conclusion of this chapter is that such future efforts should focus on further developing and refining medications that target NODAL or convergent circuit points within the limbic-motor interface, with the goal of constraining the scope and severity of psychotic exacerbations, to be used in concert with systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements. This strategy should be applied in both preventative and treatment settings, and disseminated for community delivery via an evidence-based manualized format. In contrast to alternative treatment strategies that range from complex polypharmacy to gene therapies to psychosurgical interventions, the use of combined medication plus targeted cognitive and behavioral psychotherapy has both common sense and time-tested documented efficacy with numerous other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 6 | Schizophr. Res. 2011 Aug 130: 1-10 |
| PMID | 21645998 |
| Title | Are we studying and treating schizophrenia correctly? |
| Abstract | New findings are rapidly revealing an increasingly detailed image of neural- and molecular-level dysfunction in schizophrenia, distributed throughout interconnected cortico-striato-pallido-thalamic circuitry. Some disturbances appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, resulting in a substantial loss of, or failure to develop, both cells and/or appropriate connectivity across widely dispersed brain regions. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and epigenetic events. Given these complex and variable hard-wired circuit disturbances, it is worth considering how new and emerging findings can be integrated into actionable treatment models. This paper suggests that future efforts towards developing more effective therapeutic approaches for the schizophrenias should diverge from prevailing models in genetics and molecular neuroscience, and focus instead on a more practical three-part treatment strategy: 1) systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements, used in concert with 2) medications that specifically target cognitive mechanisms engaged by these rehabilitative psychotherapies, and 3) antipsychotic medications that target NODAL or convergent circuit points within the limbic-motor interface, to constrain the scope and severity of psychotic exacerbations and thereby facilitate engagement in cognitive rehabilitation. The use of targeted cognitive rehabilitative psychotherapy plus synergistic medication has both common sense and time-tested efficacy with numerous other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 7 | Schizophr. Res. 2011 Aug 130: 1-10 |
| PMID | 21645998 |
| Title | Are we studying and treating schizophrenia correctly? |
| Abstract | New findings are rapidly revealing an increasingly detailed image of neural- and molecular-level dysfunction in schizophrenia, distributed throughout interconnected cortico-striato-pallido-thalamic circuitry. Some disturbances appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, resulting in a substantial loss of, or failure to develop, both cells and/or appropriate connectivity across widely dispersed brain regions. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and epigenetic events. Given these complex and variable hard-wired circuit disturbances, it is worth considering how new and emerging findings can be integrated into actionable treatment models. This paper suggests that future efforts towards developing more effective therapeutic approaches for the schizophrenias should diverge from prevailing models in genetics and molecular neuroscience, and focus instead on a more practical three-part treatment strategy: 1) systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements, used in concert with 2) medications that specifically target cognitive mechanisms engaged by these rehabilitative psychotherapies, and 3) antipsychotic medications that target NODAL or convergent circuit points within the limbic-motor interface, to constrain the scope and severity of psychotic exacerbations and thereby facilitate engagement in cognitive rehabilitation. The use of targeted cognitive rehabilitative psychotherapy plus synergistic medication has both common sense and time-tested efficacy with numerous other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 8 | Biol. Psychiatry 2011 Jan 69: 80-9 |
| PMID | 21035793 |
| Title | Disrupted axonal fiber connectivity in schizophrenia. |
| Abstract | schizophrenia is believed to result from abnormal functional integration of neural processes thought to arise from aberrant brain connectivity. However, evidence for anatomical dysconnectivity has been equivocal, and few studies have examined axonal fiber connectivity in schizophrenia at the level of whole-brain networks. Cortico-cortical anatomical connectivity at the scale of axonal fiber bundles was modeled as a network. Eighty-two network nodes demarcated functionally specific cortical regions. Sixty-four direction diffusion tensor-imaging coupled with whole-brain tractography was performed to map the architecture via which network nodes were interconnected in each of 74 patients with schizophrenia and 32 age- and gender-matched control subjects. Testing was performed to identify pairs of nodes between which connectivity was impaired in the patient group. The connectional architecture of patients was tested for changes in five network attributes: NODAL degree, small-worldness, efficiency, path length, and clustering. Impaired connectivity in the patient group was found to involve a distributed network of nodes comprising medial frontal, parietal/occipital, and the left temporal lobe. Although small-world attributes were conserved in schizophrenia, the cortex was interconnected more sparsely and up to 20% less efficiently in patients. Intellectual performance was found to be associated with brain efficiency in control subjects but not in patients. This study presents evidence of widespread dysconnectivity in white-matter connectional architecture in a large sample of patients with schizophrenia. When considered from the perspective of recent evidence for impaired synaptic plasticity, this study points to a multifaceted pathophysiology in schizophrenia encompassing axonal as well as putative synaptic mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 9 | Schizophr. Res. 2012 Nov 141: 109-18 |
| PMID | 22981811 |
| Title | Abnormal topological organization of structural brain networks in schizophrenia. |
| Abstract | schizophrenia is a debilitating mental disorder characterized by disturbances of thought and emotion as well as neurocognitive deficits. It is hypothesized that the core symptoms of schizophrenia arise from the inability to integrate neural processes segregated across distributed brain regions. Graph theory allows us to verify this hypothesis at large-scale structural network level. In this study, a sample of 101 schizophrenic patients and 101 healthy controls was included. We sought to investigate the abnormality of network topological organization in patients with schizophrenia by using the cortical thickness measurement from magnetic resonance imaging. Brain networks were constructed by thresholding cortical thickness correlation matrices of 78 regions and analyzed using graph theoretical approaches. Compared to healthy controls, patients showed increased characteristic path length and clustering coefficient in the structural cortical networks. Moreover, schizophrenia patients were associated with reduced NODAL centrality in several regions of the default network and increased NODAL centrality mainly in primary cortex and paralimbic cortex regions. These findings suggest that the structural networks of schizophrenic patients have a less optimal topological organization, resulting in reduced capacity to integrate information across brain regions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 10 | Schizophr. Res. 2012 Nov 141: 109-18 |
| PMID | 22981811 |
| Title | Abnormal topological organization of structural brain networks in schizophrenia. |
| Abstract | schizophrenia is a debilitating mental disorder characterized by disturbances of thought and emotion as well as neurocognitive deficits. It is hypothesized that the core symptoms of schizophrenia arise from the inability to integrate neural processes segregated across distributed brain regions. Graph theory allows us to verify this hypothesis at large-scale structural network level. In this study, a sample of 101 schizophrenic patients and 101 healthy controls was included. We sought to investigate the abnormality of network topological organization in patients with schizophrenia by using the cortical thickness measurement from magnetic resonance imaging. Brain networks were constructed by thresholding cortical thickness correlation matrices of 78 regions and analyzed using graph theoretical approaches. Compared to healthy controls, patients showed increased characteristic path length and clustering coefficient in the structural cortical networks. Moreover, schizophrenia patients were associated with reduced NODAL centrality in several regions of the default network and increased NODAL centrality mainly in primary cortex and paralimbic cortex regions. These findings suggest that the structural networks of schizophrenic patients have a less optimal topological organization, resulting in reduced capacity to integrate information across brain regions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 11 | J. Neurosci. Res. 2013 Mar 91: 374-81 |
| PMID | 23224912 |
| Title | Structural bases for central nervous system malfunction in the quaking mouse: dysmyelination in a potential model of schizophrenia. |
| Abstract | The dysmyelinating mouse mutant quaking (qk) is thought to be a model of schizophrenia based on diminution of CNS myelin (Andreone et al., 2007) and downregulation of the Qk gene (Haroutunian et al., 2006) in the brains of schizophrenic patients. The purpose of this study was to identify specific structural defects in the qk mouse CNS that could compromise physiologic function and that in humans might account for some of the cognitive defects characteristic of schizophrenia. Ultrastructural analysis of qk mouse CNS myelinated fibers shows abnormalities in NODAL, interNODAL, and paraNODAL regions, including marked variation in myelin thickness among neighboring fibers, spotty disruption of paraNODAL junctions, abnormal distribution of NODAL and paraNODAL ion channel complexes, generalized thinning and incompactness of myelin, and on many axonal profiles complete absence of myelin. These structural defects are likely to cause abnormalities in conduction velocity, synchrony of activation, temporal ordering of signals, and other physiological parameters. We conclude that the structural abnormalities described are likely to be responsible for significant functional impairment both in the qk mouse CNS and in the human CNS with comparable myelin pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 12 | J. Neurosci. Res. 2013 Mar 91: 374-81 |
| PMID | 23224912 |
| Title | Structural bases for central nervous system malfunction in the quaking mouse: dysmyelination in a potential model of schizophrenia. |
| Abstract | The dysmyelinating mouse mutant quaking (qk) is thought to be a model of schizophrenia based on diminution of CNS myelin (Andreone et al., 2007) and downregulation of the Qk gene (Haroutunian et al., 2006) in the brains of schizophrenic patients. The purpose of this study was to identify specific structural defects in the qk mouse CNS that could compromise physiologic function and that in humans might account for some of the cognitive defects characteristic of schizophrenia. Ultrastructural analysis of qk mouse CNS myelinated fibers shows abnormalities in NODAL, interNODAL, and paraNODAL regions, including marked variation in myelin thickness among neighboring fibers, spotty disruption of paraNODAL junctions, abnormal distribution of NODAL and paraNODAL ion channel complexes, generalized thinning and incompactness of myelin, and on many axonal profiles complete absence of myelin. These structural defects are likely to cause abnormalities in conduction velocity, synchrony of activation, temporal ordering of signals, and other physiological parameters. We conclude that the structural abnormalities described are likely to be responsible for significant functional impairment both in the qk mouse CNS and in the human CNS with comparable myelin pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 13 | Front Hum Neurosci 2013 -1 7: 402 |
| PMID | 24046733 |
| Title | Graph theory reveals dysconnected hubs in 22q11DS and altered nodal efficiency in patients with hallucinations. |
| Abstract | schizophrenia is postulated to be the prototypical dysconnection disorder, in which hallucinations are the core symptom. Due to high heterogeneity in methodology across studies and the clinical phenotype, it remains unclear whether the structural brain dysconnection is global or focal and if clinical symptoms result from this dysconnection. In the present work, we attempt to clarify this issue by studying a population considered as a homogeneous genetic sub-type of schizophrenia, namely the 22q11.2 deletion syndrome (22q11.2DS). Cerebral MRIs were acquired for 46 patients and 48 age and gender matched controls (aged 6-26, respectively mean age = 15.20 ± 4.53 and 15.28 ± 4.35 years old). Using the Connectome mapper pipeline (connectomics.org) that combines structural and diffusion MRI, we created a whole brain network for each individual. Graph theory was used to quantify the global and local properties of the brain network organization for each participant. A global degree loss of 6% was found in patients' networks along with an increased Characteristic Path Length. After identifying and comparing hubs, a significant loss of degree in patients' hubs was found in 58% of the hubs. Based on Allen's brain network model for hallucinations, we explored the association between local efficiency and symptom severity. Negative correlations were found in the Broca's area (p < 0.004), the Wernicke area (p < 0.023) and a positive correlation was found in the dorsolateral prefrontal cortex (DLPFC) (p < 0.014). In line with the dysconnection findings in schizophrenia, our results provide preliminary evidence for a targeted alteration in the brain network hubs' organization in individuals with a genetic risk for schizophrenia. The study of specific disorganization in language, speech and thought regulation networks sharing similar network properties may help to understand their role in the hallucination mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 14 | Front Comput Neurosci 2013 -1 7: 93 |
| PMID | 23874288 |
| Title | Graph theoretical analysis of resting magnetoencephalographic functional connectivity networks. |
| Abstract | Complex networks have been observed to comprise small-world properties, believed to represent an optimal organization of local specialization and global integration of information processing at reduced wiring cost. Here, we applied magnitude squared coherence to resting magnetoencephalographic time series in reconstructed source space, acquired from controls and patients with schizophrenia, and generated frequency-dependent adjacency matrices modeling functional connectivity between virtual channels. After configuring undirected binary and weighted graphs, we found that all human networks demonstrated highly localized clustering and short characteristic path lengths. The most conservatively thresholded networks showed efficient wiring, with topographical distance between connected vertices amounting to one-third as observed in surrogate randomized topologies. NODAL degrees of the human networks conformed to a heavy-tailed exponentially truncated power-law, compatible with the existence of hubs, which included theta and alpha bilateral cerebellar tonsil, beta and gamma bilateral posterior cingulate, and bilateral thalamus across all frequencies. We conclude that all networks showed small-worldness, minimal physical connection distance, and skewed degree distributions characteristic of physically-embedded networks, and that these calculations derived from graph theoretical mathematics did not quantifiably distinguish between subject populations, independent of bandwidth. However, post-hoc measurements of edge computations at the scale of the individual vertex revealed trends of reduced gamma connectivity across the posterior medial parietal cortex in patients, an observation consistent with our prior resting activation study that found significant reduction of synthetic aperture magnetometry gamma power across similar regions. The basis of these small differences remains unclear. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 15 | Neuroscience 2014 Sep 276: 135-47 |
| PMID | 24291730 |
| Title | Role of myelin plasticity in oscillations and synchrony of neuronal activity. |
| Abstract | Conduction time is typically ignored in computational models of neural network function. Here we consider the effects of conduction delays on the synchrony of neuronal activity and neural oscillators, and evaluate the consequences of allowing conduction velocity (CV) to be regulated adaptively. We propose that CV variation, mediated by myelin, could provide an important mechanism of activity-dependent nervous system plasticity. Even small changes in CV, resulting from small changes in myelin thickness or NODAL structure, could have profound effects on neuronal network function in terms of spike-time arrival, oscillation frequency, oscillator coupling, and propagation of brain waves. For example, a conduction delay of 5ms could change interactions of two coupled oscillators at the upper end of the gamma frequency range (?100Hz) from constructive to destructive interference; delays smaller than 1ms could change the phase by 30°, significantly affecting signal amplitude. Myelin plasticity, as another form of activity-dependent plasticity, is relevant not only to nervous system development but also to complex information processing tasks that involve coupling and synchrony among different brain rhythms. We use coupled oscillator models with time delays to explore the importance of adaptive time delays and adaptive synaptic strengths. The impairment of activity-dependent myelination and the loss of adaptive time delays may contribute to disorders where hyper- and hypo-synchrony of neuronal firing leads to dysfunction (e.g., dyslexia, schizophrenia, epilepsy). |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 16 | Mol. Psychiatry 2015 Sep 20: 1091-100 |
| PMID | 25330739 |
| Title | Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia. |
| Abstract | Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-? (RPTP?) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13?394 cases and 34?676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a NODAL point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 17 | Cereb. Cortex 2015 Oct -1: -1 |
| PMID | 26503264 |
| Title | Reduced Hemispheric Asymmetry of Brain Anatomical Networks Is Linked to Schizophrenia: A Connectome Study. |
| Abstract | Despite convergent evidence indicating a variety of regional abnormalities of hemispheric asymmetry in schizophrenia, patterns of wider neural network asymmetry remain to be determined. In this study, we investigated alterations in hemispheric white matter topology in schizophrenia and their association with clinical manifestations of the illness. Weighted hemispheric brain anatomical networks were constructed for each of 116 right-handed patients with schizophrenia and 66 matched healthy participants. Graph theoretical approaches were then employed to estimate the hemispheric topological properties. We found that although small-world properties were preserved in the hemispheric network, a significant hemispheric-independent deficit of global integration was found in schizophrenia. Furthermore, a significant group-by-hemisphere interaction was revealed in the characteristic path length and global efficiency, attributing to significantly reduced hemispheric asymmetry of global integration in patients compared with healthy controls. Specifically, we found reduced asymmetric NODAL efficiency in several frontal regions and the hippocampus. Finally, the abnormal hemispheric asymmetry of brain anatomical network topology was associated with clinical features (duration of illness and psychotic psychopathology) in patients. Our findings provide new insights into lateralized nature of hemispheric dysconnectivity and highlight the potential for using brain network measures of hemispheric asymmetry as neural biomarkers for schizophrenia and its clinical features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 18 | Schizophr. Res. 2015 Oct 168: 345-52 |
| PMID | 26299706 |
| Title | Nodal centrality of functional network in the differentiation of schizophrenia. |
| Abstract | A disturbance in the integration of information during mental processing has been implicated in schizophrenia, possibly due to faulty communication within and between brain regions. Graph theoretic measures allow quantification of functional brain networks. Functional networks are derived from correlations between time courses of brain regions. Group differences between SZ and control groups have been reported for functional network properties, but the potential of such measures to classify individual cases has been little explored. We tested whether the network measure of betweenness centrality could classify persons with schizophrenia and normal controls. Functional networks were constructed for 19 schizophrenic patients and 29 non-psychiatric controls based on resting state functional MRI scans. The betweenness centrality of each node, or fraction of shortest-paths that pass through it, was calculated in order to characterize the centrality of the different regions. The nodes with high betweenness centrality agreed well with hub nodes reported in previous studies of structural and functional networks. Using a linear support vector machine algorithm, the schizophrenia group was differentiated from non-psychiatric controls using the ten nodes with the highest betweenness centrality. The classification accuracy was around 80%, and stable against connectivity thresholding. Better performance was achieved when using the ranks as feature space as opposed to the actual values of betweenness centrality. Overall, our findings suggest that changes in functional hubs are associated with schizophrenia, reflecting a variation of the underlying functional network and neuronal communications. In addition, a specific network property, betweenness centrality, can classify persons with SZ with a high level of accuracy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 19 | Schizophr. Res. 2015 Oct 168: 345-52 |
| PMID | 26299706 |
| Title | Nodal centrality of functional network in the differentiation of schizophrenia. |
| Abstract | A disturbance in the integration of information during mental processing has been implicated in schizophrenia, possibly due to faulty communication within and between brain regions. Graph theoretic measures allow quantification of functional brain networks. Functional networks are derived from correlations between time courses of brain regions. Group differences between SZ and control groups have been reported for functional network properties, but the potential of such measures to classify individual cases has been little explored. We tested whether the network measure of betweenness centrality could classify persons with schizophrenia and normal controls. Functional networks were constructed for 19 schizophrenic patients and 29 non-psychiatric controls based on resting state functional MRI scans. The betweenness centrality of each node, or fraction of shortest-paths that pass through it, was calculated in order to characterize the centrality of the different regions. The nodes with high betweenness centrality agreed well with hub nodes reported in previous studies of structural and functional networks. Using a linear support vector machine algorithm, the schizophrenia group was differentiated from non-psychiatric controls using the ten nodes with the highest betweenness centrality. The classification accuracy was around 80%, and stable against connectivity thresholding. Better performance was achieved when using the ranks as feature space as opposed to the actual values of betweenness centrality. Overall, our findings suggest that changes in functional hubs are associated with schizophrenia, reflecting a variation of the underlying functional network and neuronal communications. In addition, a specific network property, betweenness centrality, can classify persons with SZ with a high level of accuracy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 20 | Neuroimage 2015 Feb 107: 345-55 |
| PMID | 25514514 |
| Title | Assessing dynamic brain graphs of time-varying connectivity in fMRI data: application to healthy controls and patients with schizophrenia. |
| Abstract | Graph theory-based analysis has been widely employed in brain imaging studies, and altered topological properties of brain connectivity have emerged as important features of mental diseases such as schizophrenia. However, most previous studies have focused on graph metrics of stationary brain graphs, ignoring that brain connectivity exhibits fluctuations over time. Here we develop a new framework for accessing dynamic graph properties of time-varying functional brain connectivity in resting-state fMRI data and apply it to healthy controls (HCs) and patients with schizophrenia (SZs). Specifically, nodes of brain graphs are defined by intrinsic connectivity networks (ICNs) identified by group independent component analysis (ICA). Dynamic graph metrics of the time-varying brain connectivity estimated by the correlation of sliding time-windowed ICA time courses of ICNs are calculated. First- and second-level connectivity states are detected based on the correlation of NODAL connectivity strength between time-varying brain graphs. Our results indicate that SZs show decreased variance in the dynamic graph metrics. Consistent with prior stationary functional brain connectivity works, graph measures of identified first-level connectivity states show lower values in SZs. In addition, more first-level connectivity states are disassociated with the second-level connectivity state which resembles the stationary connectivity pattern computed by the entire scan. Collectively, the findings provide new evidence about altered dynamic brain graphs in schizophrenia, which may underscore the abnormal brain performance in this mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 21 | Hum Brain Mapp 2015 Jan 36: 354-66 |
| PMID | 25213204 |
| Title | Characterizing the connectome in schizophrenia with diffusion spectrum imaging. |
| Abstract | schizophrenia is a complex psychiatric disorder characterized by disabling symptoms and cognitive deficit. Recent neuroimaging findings suggest that large parts of the brain are affected by the disease, and that the capacity of functional integration between brain areas is decreased. In this study we questioned (i) which brain areas underlie the loss of network integration properties observed in the pathology, (ii) what is the topological role of the affected regions within the overall brain network and how this topological status might be altered in patients, and (iii) how white matter properties of tracts connecting affected regions may be disrupted. We acquired diffusion spectrum imaging (a technique sensitive to fiber crossing and slow diffusion compartment) data from 16 schizophrenia patients and 15 healthy controls, and investigated their weighted brain networks. The global connectivity analysis confirmed that patients present disrupted integration and segregation properties. The NODAL analysis allowed identifying a distributed set of brain nodes affected in the pathology, including hubs and peripheral areas. To characterize the topological role of this affected core, we investigated the brain network shortest paths layout, and quantified the network damage after targeted attack toward the affected core. The centrality of the affected core was compromised in patients. Moreover the connectivity strength within the affected core, quantified with generalized fractional anisotropy and apparent diffusion coefficient, was altered in patients. Taken together, these findings suggest that the structural alterations and topological decentralization of the affected core might be major mechanisms underlying the schizophrenia dysconnectivity disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 22 | Brain Struct Funct 2015 Mar 220: 1145-59 |
| PMID | 24449342 |
| Title | Disrupted brain anatomical connectivity in medication-naïve patients with first-episode schizophrenia. |
| Abstract | Previous studies suggested that the topological properties of brain anatomical networks may be aberrant in schizophrenia (SCZ), and most of them focused on the chronic and antipsychotic-medicated SCZ patients which may introduce various confounding factors due to antipsychotic medication and duration of illness. To avoid those potential confounders, a desirable approach is to select medication-naïve, first-episode schizophrenia (FE-SCZ) patients. In this study, we acquired diffusion tensor imaging datasets from 30 FE-SCZ patients and 34 age- and gender-matched healthy controls. Taking a distinct gray matter region as a node, inter-regional connectivity as edge and the corresponding streamline counts as edge weight, we constructed whole-brain anatomical networks for both groups, calculated their topological parameters using graph theory, and compared their between-group differences using nonparametric permutation tests. In addition, network-based statistic method was utilized to identify inter-regional connections which were impaired in the FE-SCZ patients. We detected only significantly decreased inter-regional connections in the FE-SCZ patients compared to the controls. These connections were primarily located in the frontal, parietal, occipital, and subcortical regions. Although small-worldness was conserved in the FE-SCZ patients, we found that the network strength and global efficiency as well as the degree were significantly decreased, and shortest path length was significantly increased in the FE-SCZ patients compared to the controls. Most of the regions that showed significantly decreased NODAL parameters belonged to the top-down control, sensorimotor, basal ganglia, and limbic-visual system systems. Correlation analysis indicated that the NODAL efficiency in the sensorimotor system was negatively correlated with the severity of psychosis symptoms in the FE-SCZ patients. Our results suggest that the network organization is changed in the early stages of the SCZ disease process. Our findings provide useful information for further understanding the brain white matter dysconnectivity of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 23 | Sci Rep 2016 -1 6: 23577 |
| PMID | 27032817 |
| Title | Distinct disruptions of resting-state functional brain networks in familial and sporadic schizophrenia. |
| Abstract | Clinical and brain structural differences have been reported between patients with familial and sporadic schizophrenia; however, little is known about the brain functional differences between the two subtypes of schizophrenia. Twenty-six patients with familial schizophrenia (PFS), 26 patients with sporadic schizophrenia (PSS) and 26 healthy controls (HC) underwent a resting-state functional magnetic resonance imaging. The whole-brain functional network was constructed and analyzed using graph theoretical approaches. Topological properties (including global, NODAL and edge measures) were compared among the three groups. We found that PFS, PSS and HC exhibited common small-world architecture of the functional brain networks. However, at a global level, only PFS showed significantly lower normalized clustering coefficient, small-worldness, and local efficiency, indicating a randomization shift of their brain networks. At a regional level, PFS and PSS disrupted different neural circuits, consisting of abnormal nodes (increased or decreased NODAL centrality) and edges (decreased functional connectivity strength), which were widely distributed throughout the entire brain. Furthermore, some of these altered network measures were significantly correlated with severity of psychotic symptoms. These results suggest that familial and sporadic schizophrenia had segregated disruptions in the topological organization of the intrinsic functional brain network, which may be due to different etiological contributions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 24 | Neuroimage Clin 2016 -1 10: 239-49 |
| PMID | 26870660 |
| Title | An affected core drives network integration deficits of the structural connectome in 22q11.2 deletion syndrome. |
| Abstract | Chromosome 22q11.2 deletion syndrome (22q11DS) is a genetic disease known to lead to cerebral structural alterations, which we study using the framework of the macroscopic white-matter connectome. We create weighted connectomes of 44 patients with 22q11DS and 44 healthy controls using diffusion tensor magnetic resonance imaging, and perform a weighted graph theoretical analysis. After confirming global network integration deficits in 22q11DS (previously identified using binary connectomes), we identify the spatial distribution of regions responsible for global deficits. Next, we further characterize the dysconnectivity of the deficient regions in terms of sub-network properties, and investigate their relevance with respect to clinical profiles. We define the subset of regions with decreased NODAL integration (evaluated using the closeness centrality measure) as the affected core (A-core) of the 22q11DS structural connectome. A-core regions are broadly bilaterally symmetric and consist of numerous network hubs - chiefly parietal and frontal cortical, as well as subcortical regions. Using a simulated lesion approach, we demonstrate that these core regions and their connections are particularly important to efficient network communication. Moreover, these regions are generally densely connected, but less so in 22q11DS. These specific disturbances are associated to a rerouting of shortest network paths that circumvent the A-core in 22q11DS, "de-centralizing" the network. Finally, the efficiency and mean connectivity strength of an orbito-frontal/cingulate circuit, included in the affected regions, correlate negatively with the extent of negative symptoms in 22q11DS patients, revealing the clinical relevance of present findings. The identified A-core overlaps numerous regions previously identified as affected in 22q11DS as well as in schizophrenia, which approximately 30-40% of 22q11DS patients develop. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 25 | Mol. Cell. Neurosci. 2016 Jun 73: 63-83 |
| PMID | 26608002 |
| Title | Neurodevelopmental origins of bipolar disorder: iPSC models. |
| Abstract | Bipolar disorder (BP) is a chronic neuropsychiatric condition characterized by pathological fluctuations in mood from mania to depression. Adoption, twin and family studies have consistently identified a significant hereditary component to BP, yet there is no clear genetic event or consistent neuropathology. BP has been suggested to have a developmental origin, although this hypothesis has been difficult to test since there are no viable neurons or glial cells to analyze, and research has relied largely on postmortem brain, behavioral and imaging studies, or has examined proxy tissues including saliva, olfactory epithelium and blood cells. Neurodevelopmental factors, particularly pathways related to nervous system development, cell migration, extracellular matrix, H3K4 methylation, and calcium signaling have been identified in large gene expression and GWAS studies as altered in BP. Recent advances in stem cell biology, particularly the ability to reprogram adult somatic tissues to a pluripotent state, now make it possible to interrogate these pathways in viable cell models. A number of induced pluripotent stem cell (iPSC) lines from BP patient and healthy control (C) individuals have been derived in several laboratories, and their ability to form cortical neurons examined. Early studies suggest differences in activity, calcium signaling, blocks to neuronal differentiation, and changes in neuronal, and possibly glial, lineage specification. Initial observations suggest that differentiation of BP patient-derived neurons to dorsal telencephalic derivatives may be impaired, possibly due to alterations in WNT, Hedgehog or NODAL pathway signaling. These investigations strongly support a developmental contribution to BP and identify novel pathways, mechanisms and opportunities for improved treatments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 26 | Neuropsychologia 2016 Apr 84: 205-12 |
| PMID | 26921480 |
| Title | The PCSK6 gene is associated with handedness, the autism spectrum, and magical ideation in a non-clinical population. |
| Abstract | Common polymorphisms in the gene PCSK6, whose protein product mediates the development of brain and body asymmetry through the NODAL pathway, have recently been associated with handedness in three studies, making it a key candidate gene for understanding the developmental and expression of human lateralization. We tested the hypothesis that the PCSK6 VNTR polymorphism rs1053972 influences the expression of handedness and aspects of dimensional schizotypy and autism. For a sample of 709 healthy individuals, rs1053972 genotype was significantly associated with categorical measures of handedness, and with dimensional handedness in subsets of the population with high schizotypy and magical ideation or a lack of strong right-handedness. Both findings showed evidence of stronger or exclusive effects among females, compared to males. Genotypes of PCSK6 also showed significant sex-limited associations with magical ideation, a component of positive schizotypal cognition measured using the schizotypal Personality Questionnaire, and total autism score, measured using the Autism Spectrum Quotient. These results partially replicate previous studies on effects of PCSK6 rs1053972 genetic variation on handedness phenotypes, link the PCSK6 gene with the dimensional expression of neurodevelopmental conditions in healthy individuals, and show that associations of this gene with handedness and psychological phenotypes exhibit evidence of sex-limited effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |
| 27 | Neuropsychologia 2016 Apr 84: 205-12 |
| PMID | 26921480 |
| Title | The PCSK6 gene is associated with handedness, the autism spectrum, and magical ideation in a non-clinical population. |
| Abstract | Common polymorphisms in the gene PCSK6, whose protein product mediates the development of brain and body asymmetry through the NODAL pathway, have recently been associated with handedness in three studies, making it a key candidate gene for understanding the developmental and expression of human lateralization. We tested the hypothesis that the PCSK6 VNTR polymorphism rs1053972 influences the expression of handedness and aspects of dimensional schizotypy and autism. For a sample of 709 healthy individuals, rs1053972 genotype was significantly associated with categorical measures of handedness, and with dimensional handedness in subsets of the population with high schizotypy and magical ideation or a lack of strong right-handedness. Both findings showed evidence of stronger or exclusive effects among females, compared to males. Genotypes of PCSK6 also showed significant sex-limited associations with magical ideation, a component of positive schizotypal cognition measured using the schizotypal Personality Questionnaire, and total autism score, measured using the Autism Spectrum Quotient. These results partially replicate previous studies on effects of PCSK6 rs1053972 genetic variation on handedness phenotypes, link the PCSK6 gene with the dimensional expression of neurodevelopmental conditions in healthy individuals, and show that associations of this gene with handedness and psychological phenotypes exhibit evidence of sex-limited effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizophrenias, schizotypal |