Introduction to the Special Section: Myelin and oligodendrocyte abnormalities in schizophrenia

Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, USA.
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 09/2007; 10(4):499-502. DOI: 10.1017/S1461145706007449
Source: PubMed

ABSTRACT A central tenet of modern views of the neurobiology of schizophrenia is that the symptoms of schizophrenia arise from a failure of adequate communication between different brain regions and disruption of the circuitry that underlies behaviour and perception. Historically this disconnectivity syndrome has been approached from a neurotransmitter-based perspective. However, efficient communication between brain circuits is also contingent on saltatory signal propagation and salubrious myelination of axons. The papers in this Special Section examine the neuroanatomical and molecular biological evidence for abnormal myelination and oligodendroglial function in schizophrenia through studies of post-mortem brain tissue and animal model systems. The picture that emerges from the studies described suggests that although schizophrenia is not characterized by gross abnormalities of white matter such as those evident in multiple sclerosis, it does involve a profound dysregulation of myelin-associated gene expression, reductions in oligodendrocyte numbers, and marked abnormalities in the ultrastructure of myelin sheaths.

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    • "Given myelin’s critical role in brain communication, processes that disrupt its development may result in reduced brain connectivity and inefficient interneuronal communication. In turn, this may lead to altered neuronal functioning, and may contribute to some neurodevelopmental and psychiatric disorders, including autism and attention deficit and hyperactivity disorder (Courchesne, 2004; Haroutunian and Davis, 2007; Konrad and Eickhoff, 2010). "
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    ABSTRACT: An emerging hypothesis in developmental and behavioral disorders is they arise from disorganized brain messaging or reduced connectivity. Given the importance of myelin to efficient brain communication, characterization of myelin development in infancy and childhood may provide salient information related to early connectivity deficits. In this work, we investigate regional and whole brain growth trajectories of the myelin water fraction, a quantitative magnetic resonance imaging measure sensitive and specific to myelin content, in data acquired from 122 healthy male children from 3 to 60months of age. We examine common growth functions to find the most representative model of myelin maturation and subsequently use the best of these models to develop a continuous population-averaged, four-dimensional model of normative myelination. Through comparisons with an independent sample of 63 male children across the same age span, we show that the developed model is representative of this population. This work contributes to understanding the trajectory of myelination in healthy infants and toddlers, furthering our knowledge of early brain development, and provides a model that may be useful for identifying developmental abnormalities.
    NeuroImage 10/2013; 84(100). DOI:10.1016/j.neuroimage.2013.09.058 · 6.36 Impact Factor
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    • "These findings also concur with previous neuropathologic investigations in schizophrenia that have reported reduced density and numbers of oligodendrocytes, the myelinating cells, in white matter in schizophrenia (Uranova et al., 2004; Tkachev et al., 2007). Furthermore, prominent dysregulation of myelin-associated gene expression and marked abnormalities in the ultrastructure of myelin sheaths have been identified in schizophrenia (e.g., Haroutunian and Davis, 2007). Besides the structural analysis of this frontostriatal pathway, we further investigated correlations between white matter and executive function and symptom severity. "
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    ABSTRACT: Previous studies have shown that frontostriatal networks, especially those involving dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) mediate cognitive functions some of which are abnormal in schizophrenia. This study examines white matter integrity of the tracts connecting DLPFC/VLPFC and striatum in patients with first-episode schizophrenia (FESZ), and their associations with cognitive and clinical correlates. Diffusion tensor and structural magnetic resonance images were acquired on a 3T GE Echospeed system from 16 FESZ and 18 demographically comparable healthy controls. FreeSurfer software was used to parcellate regions of interest. Two-tensor tractography was applied to extract fibers connecting striatum with rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC respectively. DTI indices, including fractional anisotropy (FA), trace, axial diffusivity (AD) and radial diffusivity (RD), were used for group comparisons. Additionally, correlations were evaluated between these diffusion indices and the Wisconsin Card Sorting Task (WCST) and the Brief Psychiatric Rating Scale (BPRS). FA was significantly reduced in the left IFG-striatum tract, whereas trace and RD were significantly increased in rMFG-striatum and IFG-striatum tracts, bilaterally. The number of WCST categories completed correlated positively with FA of the right rMFG-striatum tract, and negatively with trace and RD of right rMFG-striatum and right IFG-striatum tracts in FESZ. The BPRS scores did not correlate with these indices. These data suggest that white matter tract abnormalities between rMFG/IFG and striatum are present in FESZ and appear to be significantly associated with executive dysfunction but not with symptom severity.
    Schizophrenia Research 04/2013; 145(1-3):1-10. DOI:10.1016/j.schres.2012.11.028 · 3.92 Impact Factor
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    • "White matter abnormalities have been proposed to be central to the pathophysiology of schizophrenia (Haroutunian and Davis, 2007; Takahashi et al., 2011), but the neurobiological substrates of these abnormalities remain elusive. Recent evidence suggests that dysfunction in myelination and altered oligodendrocytes (OLG) number and function may contribute to schizophrenia (Flynn et al., 2003; Vostrikov et al., 2007; Katsel et al., 2008), and myelin and fatty-acid biosynthesis dysfunction was reported on post-mortem brain (prefrontal cortex) of schizophrenia utilizing parallel metabolic and transcriptomics investigations (Tkachev et al., 2007). "
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    ABSTRACT: Schizophrenia is a common, severe, and chronically disabling mental illness of unknown cause. Recent MRI studies have focused attention on white matter abnormalities in schizophrenia using diffusion tensor imaging (DTI). Indices commonly derived from DTI include (1) mean diffusivity, independent of direction, (2) fractional anisotropy (FA) or relative anisotropy (RA), (3) axial diffusivity, and (4) radial diffusivity. In cerebral white matter, contributions to these indices come from fiber arrangements, degree of myelination, and axonal integrity. Relatively pure deficits in myelin result in a modest increase in radial diffusivity, without affecting axial diffusivity and with preservation of anisotropy. Although schizophrenia is not characterized by gross abnormalities of white matter, it does involve a profound dysregulation of myelin-associated gene expression, reductions in oligodendrocyte numbers, and marked abnormalities in the ultrastructure of myelin sheaths. Since each oligodendrocyte myelinates as many as 40 axon segments, changes in the number of oligodendrocytes (OLG), and/or in the integrity of myelin sheaths, and/or axoglial contacts can have a profound impact on signal propagation and the integrity of neuronal circuits. Whereas a number of studies have revealed inconsistent decreases in anisotropy in schizophrenia, we and others have found increased FA in key subcortical tracts associated with the circuits underlying symptom generation in schizophrenia. We review data revealing increased anisotropy in dopaminergic tracts in the mesencephalon of schizophrenics and their unaffected relatives, and discuss the possible biological underpinnings and physiological significance of this finding.
    Frontiers in Integrative Neuroscience 03/2013; 7:9. DOI:10.3389/fnint.2013.00009
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