Altered intracortical myelin staining in the dorsolateral prefrontal cortex in severe mental illness

Abstract

Imaging and postmortem studies into the severe mental illnesses of major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have revealed deficiencies in the myelination of deep white matter tracts of the brain. Recent studies have further suggested that deficits could extend to myelinated fibers running through the cortex in those illnesses. Disruptions in this intracortical myelin may underlie functional symptomology in MDD, BD, and SZ; thus, in this study, we hypothesized that individuals with these illnesses may have reduced myelin staining relative to controls in the cerebral cortex. We stained 60 sections of dorsolateral prefrontal cortex for myelin with Luxol fast blue in four groups: 15 BD, 15 MDD, 15 SZ, and 15 controls with no psychiatric illness. We digitally measured optical tissue attenuation reflecting the amount of myelin staining across six cortical depths in the middle frontal gyrus (MFG), in superficial white matter in the crown of the MFG, and in deep white matter. We found that a diagnosis of MDD or SZ meant that optical tissue attenuation was significantly reduced in the shallowest depths of the cortex. Furthermore, there was a trend toward reduced optical tissue attenuation in all illnesses across all myelinated regions we studied. These results encourage future studies into potential reductions in intracortical myelin in severe mental illness.

Altered hippocampal centrality and dynamic anatomical covariance of intracortical microstructure in first episode psychosis

“…Intriguingly, these regions are enriched for genes associated with schizophrenia risk. Our works suggests that previously reported alterations in intracortical myelination of higher-order association areas in psychotic disorders (Lake et al, 2017;Tishler et al, 2018;Wei et al, 2017) may be influenced by altered covariation with hippocampal microstructure, driven by hippocampal output regions or "hubs," and this may underlie the noted observations with negative symptoms and verbal memory. (Harvey et al, 2013;Riedel et al, 2010;Sumiyoshi et al, 2007), and may even have potential to decrease negative symptoms (Ogasa, Kimura, Nakamura, & Guarino, 2013).…”

“…Path c 0 between HC centrality and change in negative symptoms is no longer significant when taking into account Δ verbal memory, indicating that Δ verbal memory statistically mediates the relationship between hippocampal centrality and Δ negative symptoms. Note that hippocampal centrality denotes the mean PC of the hippocampal module in relation to DAC with intracortical microstructure, adjusted for age and sex [Color figure can be viewed at wileyonlinelibrary.com] et al, DeLisi, 2008;Olabi et al, 2011;Pantelis, 2005); (b) there is empirical evidence for direct connectivity between the hippocampus and medial temporal lobe, as well as between the hippocampus and prefrontal cortex (Simons & Spiers, 2003); (c) altered intracortical myelin has been noted in patients with enduring schizophrenia and other psychotic disorders within the prefrontal cortex (Lake et al, 2017;Tishler et al, 2018;Wei et al, 2017); and (d) HC-medial temporal lobe and hippocampus-PFC subserve memory, emotional expression and motivational behaviors (Pier, Marin, Wilsnack, & Goodman, 2016;Schulze, Schmahl, & Niedtfeld, 2016;Squire, Stark, & Clark, 2004), which underlie verbal memory deficits and negative symptoms. Indeed, altered frontal connectivity has previously been linked to negative symptom severity (Luck et al, 2011).…”

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

“…Pathology of oligodendrocytes and myelin is considered to be a biological basis for dysconnectivity in schizophrenia (2,8). Reduced oligodendrocyte density (9)(10)(11)(12), ultrastructural alterations of oligodendrocytes and myelinated fibers (13)(14)(15), altered intracortical myelin staining (16) and impaired differentiation of oligodendrocyte precursors (17) have been reported in the PFC in schizophrenia. Abnormalities of myelination, reduced expression and dysregulation of oligodendrocyte and myelin-related genes (18)(19)(20) have been detected in the PFC in schizophrenia.…”

Age-related deficits in intracortical myelination in young adults with bipolar disorder type I

“…8,9 Intracortical myelin consists of myelinated axons in the cortical grey matter; deeper layers of the cortex contain greater amounts of myelin. 10,11 Importantly, animal studies have begun to link ICM with changes in behaviour and show that neuronal activity stimulates proliferation of oligodendrocyte precursor cells in the cortex and promotes oligodendrogenesis. This thickening of the myelin sheath enhances motor learning in mice.…”