White Matter Injury, Neural Connectivity and the Pathophysiology of Psychiatric Disorders

Department of Psychiatry and The Neuropsychiatric Institute, University of California, Los Angeles, Calif 90024, USA.
Developmental Neuroscience (Impact Factor: 2.7). 02/2002; 24(4):255-61. DOI: 10.1159/000066746
Source: PubMed


Psychiatric disorders are characterized by diverse clinical manifestations that include deficits in cognition, perception, mood and arousal. These complex processes are not mediated by any specific brain region but require the coordinated activity of several areas that are anatomically connected. Impairments in these neural circuits may therefore be expected to result in an attenuation of the functions regulated by them. The white matter provides the structural and physiological substrate of neural circuits in the central nervous system. We propose that injury to the white matter, from diverse biological sources, may compromise neural connectivity by associated axonal injury or impaired conductivity. Either mechanism could result in clusters of signs and symptoms that are currently recognized as psychiatric disorders. The role of white matter impairment in the pathophysiology of psychiatric illness is under-appreciated in the neurosciences. Focused translational research aimed at identifying the links between white matter compromise and specific behaviors are necessary for a more thorough understanding of the etiology of mental illness to emerge.

3 Reads
  • Source
    • "The current study investigated the relationship between biological measures of stress and brain structure in first episode patients in comparison to matched healthy controls. Despite indications that complex brain processes depend on networks including white matter interconnections (Kumar and Cook, 2002), and suggestions that changes in both grey and white matter volume are associated with increased levels of perceived stress (Li et al., 2014), existing research has focussed on grey matter structure. Given that the first episode of psychosis is associated with progressive brain changes in frontal, temporal as well as parietal areas, the relationship between biological measures of stress and whole brain measures of cortical thickness and white matter volume was examined. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stress and abnormal hypothalamic-pituitary-adrenal axis functioning have been implicated in the early phase of psychosis and may partly explain reported changes in brain structure. This study used magnetic resonance imaging to investigate whether biological measures of stress were related to brain structure at baseline and to structural changes over the first 12 weeks of treatment in first episode patients (n=22) compared with matched healthy controls (n=22). At baseline, no significant group differences in biological measures of stress, cortical thickness or hippocampal volume were observed, but a significantly stronger relationship between baseline levels of cortisol and smaller white matter volumes of the cuneus and anterior cingulate was found in patients compared with controls. Over the first 12 weeks of treatment, patients showed a significant reduction in thickness of the posterior cingulate compared with controls. Patients also showed a significant positive relationship between baseline cortisol and increases in hippocampal volume over time, suggestive of brain swelling in association with psychotic exacerbation, while no such relationship was observed in controls. The current findings provide some support for the involvement of stress mechanisms in the pathophysiology of early psychosis, but the changes are subtle and warrant further investigation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research: Neuroimaging 11/2014; 231(2). DOI:10.1016/j.pscychresns.2014.11.004 · 2.42 Impact Factor
  • Source
    • "The white matter (WM) abnormalities constitute one element of the pathogenesis of MDD.15–17 Various fiber tract alterations have been seen in MDD patients.18–22 Magnetic resonance imaging (MRI) is a noninvasive method used to examine WM abnormalities. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. These results suggest an association between the COMT gene Val158Met and the white matter abnormalities found in the temporal lobe of patients with MDD.
    Neuropsychiatric Disease and Treatment 06/2014; 10:1183-90. DOI:10.2147/NDT.S61275 · 1.74 Impact Factor
  • Source
    • "Some structurally connected networks of brain regions are known to modulate higher-order brain functions, such as executive function and complex behaviors (Fuster, 2001). Diminished integrity of these networks, through damage or failure to develop normally, may disrupt these functions, resulting in profiles of symptoms that may involve mood, learning, perception, or memory, and may be diagnosed as mental illness (Kumar and Cook, 2002). Genetic factors may also affect brain connectivity and white matter integrity in these networks (Jahanshad et al., 2013; Thompson et al., 2010; Tost et al., 2012), possibly increasing the risk for carriers of certain genetic variants to develop mental illness. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3'-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults related to genetic variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain. To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6±2.2 years; range: 20-29 years) with 105-gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) - a DTI measure of white matter integrity. FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p=0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders.
    NeuroImage 05/2013; 82. DOI:10.1016/j.neuroimage.2013.05.095 · 6.36 Impact Factor
Show more