Alterations of Superficial White Matter in Schizophrenia and Relationship to Cognitive Performance

Kimel Family Translational Imaging-Genetics Laboratory.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.83). 04/2013; 38(10). DOI: 10.1038/npp.2013.93
Source: PubMed

ABSTRACT Post-mortem studies have demonstrated alterations in superficial white matter (SWM) in schizophrenia patients. Diffusion tensor imaging (DTI) can be used to assess SWM in vivo, and compare SWM fractional anisotropy (FA) in schizophrenia patients vs. healthy controls. The assessment of SWM in vivo also provides an opportunity to identify novel neural correlates of cognitive performance, and potential cognitive impairment in schizophrenia. Forty-four patients with schizophrenia and 44 matched healthy controls underwent neuroimaging and cognitive protocols. Using an SWM mask, and Tract-Based Spatial Statistics differences in SWM-FA were examined between groups. SWM-FA clusters different between groups were then used to predict cognitive performance with multiple linear regression. The relative contribution of SWM fiber subtypes (deep white matter extensions vs. U-fibers and intraregional fibers) from significantly different clusters was examined. Compared to controls, patients with schizophrenia had reduced FA in five SWM clusters: the largest a left posterior parieto-occipital cluster, followed by four clusters in the left frontal lobe. SWM-FA in frontal lobe clusters predicted attention, working memory, and processing speed performance in healthy controls, but not in patients with schizophrenia. The majority of streamlines tracked from these clusters were restricted to U-fibers and intraregional fibers, rather than deep white matter extensions. Our analyses revealed prominent SWM disruption in patients with schizophrenia compared to controls. SWM-cognition relationships shown in healthy individuals, were disrupted in patients with schizophrenia. SWM may be an important neurobiological substrate of cognitive performance and a novel cortical treatment target for cognitive deficits in schizophrenia.Neuropsychopharmacology accepted article preview online, 16 April 2013; doi:10.1038/npp.2013.93.

    • "ocytes to oligodendrocytes , as oligo - dendrocytes are involved in myelination . The oligodendro - cyte changes thought to be accompanied by altered gene expression and abnormal myelination ( Uranova et al . , 2011 ) are a possible source of the white matter alterations detected by DTI studies ( Whitford et al . , 2011 ; Nakamura et al . , 2012 ; Nazeri et al . , 2013 ) . Since oligodendrocytes are known to express excitatory glutamate receptors , the putative deficits in glutamatergic neurotransmission in schizophrenia ( see Harrison and Weinberger , 2005 for review ) may reflect oligodendroglial changes . Disruption of the glutamate – glutamine cycle , or changes in perineuronal nets in late develo"
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    ABSTRACT: Schizophrenia is a devastating mental illness. Although its aetiology is still largely unknown, strides have been taken throughout the last several decades to elucidate the nature of the neuropathology behind this disorder. The advent of neuroimaging technologies such as CT and MRI have progressed knowledge about the macroscopic brain changes that occur in schizophrenia, including the characteristic reduced ventricle size and reductions in gray matter volume, whole brain volume, and white matter anisotropy. Although this review presents a broad outline of current and historical neuropathological research in research, the focus is primarily on the quantitative neuropathology of the cerebral cortex in schizophrenia, which may underlie many of the larger scale changes observed. The reduced neuropil hypothesis has been suggested as a microanatomical explanation to account for these macroscopic changes, although the present review finds that evidence does not always support this. A quantitative summary of these studies, focused on neuron density, provides support for the finding of increased neuron density in schizophrenia, with variation dependent on age. This is consistent with neuroimaging data and implicates an altered aging trajectory as a factor in the pathogenesis of schizophrenia. Combined with evidence from other neuroanatomical studies reviewed here, as well as studies in childhood-onset schizophrenia the evidence converges on a progressive neurodevelopmental model of schizophrenia related to altered neuroplasticity. The evidence also supports a particular vulnerability of inhibitory cortical circuits with markers of interneurons showing some of the more consistent reductions in schizophrenia. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 06/2015; 303. DOI:10.1016/j.neuroscience.2015.06.028 · 3.33 Impact Factor
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    • "Diffusion tensor imaging (DTI) is widely used for quantification of cerebral white matter (WM) integrity in disorders that affect cerebral connectivity including schizophrenia (Friedman et al., 2008; Jones et al., 2006; Kanaan et al., 2005; Kochunov et al., 2013; Mori et al., 2007; Nazeri et al., 2013) and other psychiatric and neurological disorders (Allan et al., 2011; Blood et al., 2011; Kanaan et al., 2005; Kieseppa et al., 2011; Korgaonkar et al., 2011; White et al., 2008; Zhang et al., 2012). DTI-derived fractional anisotropy (FA) of water diffusion (Basser and Pierpaoli, 1996; Kochunov et al., 2007; Pfefferbaum et al., 2000; Song et al., 2003, 2005) has emerged as one of the more sensitive imaging biomarkers in schizophrenia research (Friedman et al., 2008; Glahn et al., 2011; Mori et al., 2007). "
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    ABSTRACT: Diffusion tensor imaging (DTI) assumes a single pool of anisotropically diffusing water to calculate fractional anisotropy (FA) and is commonly used to ascertain white matter (WM) deficits in schizophrenia. At higher b-values, diffusion-signal decay becomes bi-exponential, suggesting the presence of two, unrestricted and restricted, water pools. Theoretical work suggests that semi-permeable cellular membrane rather than the presence of two physical compartments is the cause. The permeability-diffusivity (PD) parameters measured from bi-exponential modeling may offer advantages, over traditional DTI-FA, in identifying WM deficits in schizophrenia. Imaging was performed in N = 26/26 patients/controls (age = 20-61 years, average age = 40.5 ± 12.6). Imaging consisted of fifteen b-shells: b = 250-3800 s/mm(2) with 30 directions/shell, covering seven slices of mid-sagittal corpus callosum (CC) at 1.7 × 1.7 × 4.6 mm. 64-direction DTI was also collected. Permeability-diffusivity-index (PDI), the ratio of restricted to unrestricted apparent diffusion coefficients, and the fraction of unrestricted compartment (Mu) were calculated for CC and cingulate gray matter (GM). FA values for CC were calculated using tract-based-spatial-statistics. Patients had significantly reduced PDI in CC (p ≅ 10(- 4)) and cingulate GM (p = 0.002), while differences in CC FA were modest (p ≅ .03). There was no group-related difference in Mu. Additional theoretical-modeling analysis suggested that reduced PDI in patients may be caused by reduced cross-membrane water molecule exchanges. PDI measurements for cerebral WM and GM yielded more robust patient-control differences than DTI-FA. Theoretical work offers an explanation that patient-control PDI differences should implicate abnormal active membrane permeability. This would implicate abnormal activities in ion-channels that use water as substrate for ion exchange, in cerebral tissues of schizophrenia patients.
    Clinical neuroimaging 07/2013; 3:18-26. DOI:10.1016/j.nicl.2013.06.019 · 2.53 Impact Factor
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    ABSTRACT: Antipsychotic drugs have thus far focused on dopaminergic antagonism at the D2 receptors, as counteracting the hyperdopaminergia in nigrostriatal and mesolimbic projections has been considered mandatory for the antipsychotic action of the drugs. Current drugs effectively target the positive symptoms of psychosis such as hallucinations and delusions in the majority of patients, whereas effect sizes are smaller for negative symptoms and cognitive dysfunctions. With the understanding that neurocognitive dysfunction associated with schizophrenia have a greater impact on functional outcome than the positive symptoms, the focus in pharmacotherapy for schizophrenia has shifted to the potential effect of future drugs on cognitive enhancement. A major obstacle is, however, that the biological underpinnings of cognitive dysfunction remain largely unknown. With the availability of increasingly sophisticated techniques in molecular biology and brain imaging, this situation is about to change with major advances being made in identifying the neuronal substrates underlying schizophrenia, and putative pro-cognitive drug targets may be revealed. In relation to cognitive effects, this review focuses on evidence from basic neuroscience and clinical studies, taking two separate perspectives. One perspective is the identification of previously under-recognized treatment targets for existing antipsychotic drugs, including myelination and mediators of inflammation. A second perspective is the development of new drugs or novel treatment targets for well-known drugs, which act on recently discovered treatment targets for cognitive enhancement, and which may complement the existing drugs. This might pave the way for personalized treatment regimens for patients with schizophrenia aimed at improved functional outcome. The review also aims at identifying major current constraints for pro-cognitive drug development for patients with schizophrenia.
    Frontiers in Psychiatry 02/2014; 5:11. DOI:10.3389/fpsyt.2014.00011
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