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    • Changes in FA in relation to changes in RD

    2018-11-05

    Changes in FA in relation to changes in RD and AD suggest that the greatest change in white matter microstructure was a reduction in RD that led to an increase in FA values. FA is an aggregate index of white matter integrity. It essentially reflects the prominence of diffusion along sirtuins relative to diffusion perpendicular to the wall of the axon. It thus reflects complex tissue properties such as intra- and extra-cellular volume, fiber coherence, axonal density and degree of myelination, and thus interpretation about any specific alteration in white matter from FA measures must be made with caution (Jones et al., 2013). Analysis of axial and radial diffusivities can help define the neurobiological determinants of altered white matter microstructure. Data from animal studies suggest that AD is primarily an axonal marker and RD is primarily a myelin marker (Song et al., 2003; Song et al., 2002; Song et al., 2005). In the region of increased FA in the left superior and middle frontal gyri in PTSD, we saw a decrease both in AD and in RD relative to controls. Thus, the pattern of effects we observed is likely the manifestation of complex microstructural changes affecting both axon and myelin. This is consistent with our DTI study in children with PTSD that also identified both AD and RD alterations (Lei et al., 2015b). While interpretation needs to be made with caution, the findings from the present study are most consistent with a pattern of decreased axonal density or disturbed intracellular structure suggested by the reduced AD, and increased glial cell density or higher myelination suggested by the reduced RD. The increase in FA appeared to be primarily a result of increased myelination (lower RD), which could be induced by increased oligodendrocyte growth or migration through a glial-axonal communication mechanism activated by increased rates of action potentials in fibers of passage forming affected fiber tracts (Demerens et al., 1996; Schlegel et al., 2012). The increased oligodendrocytes could account for both increased myelin (lower RD) and reduced axonal density (lower AD) (Caprihan et al., 2015). The pattern of MRI findings in the present study contrast with findings from studies of patients with several years duration of illness in which diminished neuronal plasticity appears to represent the more prominent deficit (Schuff et al., 2011). We note that in our cross-sectional clinical study it is not possible to exclude the possibility that more myelin preexists in those at risk to develop PTSD. Other possibilities and factors also require consideration. For example, an FA increase can result from greater directional coherence of diffusion resulting from more coherent fiber tract organization and less neuronal branching (van Ewijk et al., 2012). A mechanism such as this might explain the increased FA we observed in the forceps major of the corpus callosum. Tractography shows that the increased FA in left forceps major is at the intersection of crossing fibers from the splenium of the corpus callosum and the inferior longitudinal fasciculus. FA increase at locations where fibers cross can reflect increased thickness of a dominant tract or degeneration of the non-dominant crossing fibers (Radua et al., 2014). PFC dysfunction has been linked to stress-related disorders such as PTSD in animal models as well as patient studies (Arnsten, 2009). The DLPFC is critical for “top-down” cognitive control, working memory, control of attention, and mood regulation (Aupperle et al., 2012; Goldman-Rakic, 1996; Stein, 2008), and has reciprocal connections to limbic system regions such as the amygdala and hippocampus via projections from ventromedial PFC (Hartley and Phelps, 2010). Studies have shown the crucial role of these regions and their functional relationships in fear extinction learning (Maren and Quirk, 2004; Milad et al., 2006), and thus our finding of white matter alterations in DLPFC is consistent with the idea that abnormalities in these regions are pivotal in PTSD (Lyoo et al., 2011; Rauch et al., 2006).