Axonal myelin increase in the callosal genu in depression but not schizophrenia M. R. Williams 1,2 *, P. Sharma 2,3 , K. L. Fung 4 , R. K. B. Pearce 2 , S. R. Hirsch 2 and M. Maier 5 1 King’s College London, Institute of Psychiatry, De Crespigny Park, London, UK 2 Neuropathology Unit, Division of Experimental Medicine, Imperial College London, Charing Cross Campus, London, UK 3 St George’s University of London, London, UK 4 Li Ka Shing Faculty of Medicine University of Hong Kong, Hong Kong 5 Trust HQ, West London Mental Health NHS Trust, Southall, Middlesex UK Background. Abnormalities in the anterior inter-hemispheric connectivity have previously been implicated in major de- pressive disorder. Disruptions in fractional anisotropy in the callosum and fornix have been reported in schizophrenia and major depressive disorder. Oligodendrocyte density and overall size of the callosum and fornix show no alteration in either illness, suggesting that gross morphology is unchanged but more subtle organizational disruption may exist with- in these brain regions in mood and affective disorders. Method. Using high-resolution oil-immersion microscopy we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath, and using standard high-resolution light microscopy we measured the density of myelinated axons. These measurements were made in the genu of the corpus callosum and the medial body of the fornix at its most dorsal point. Measures were taken in the sagittal plane in the callosal genu and in the coronal plane at the most dorsal part of the fornix body. Results. Cases of major depressive disorder had significantly greater mean myelin cross-sectional area (p = 0.017) and myelin thickness ( p = 0.004) per axon in the genu than in control or schizophrenia groups. There was no significant change in the density of myelinated axons, and no changes observed in the fornix. Conclusion. The results suggest a clear increase of myelin in the axons of the callosal genu in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin. Received 4 July 2014; Revised 13 January 2014; Accepted 14 January 2015 Key words: Axons, callosum, depression, neuropathology. Introduction The corpus callosum (CC) is the largest white-matter (WM) structure in the CNS, running along the midline of the brain and uniting the two cerebral hemispheres (Hofer & Frahm, 2006). The most anterior portion of the CC is termed the genu of the corpus callosum (gCC) which curves ventrally and continues pos- teriorly. Axonal fibres comprising the CC join the cerebral hemispheres by way of homotopic and heterotopic connections, with a majority of commissural fibres uniting symmetrical areas of the hemispheres, although a proportion terminate in different contralat- eral regions from which they emanate. The anterior- most portion of the CC, the genu, connects regions of the frontal cortex (Nolte, 2002). The genu contains the inter-hemispheric axons connecting the frontal lobes, of critical interest in serious mental illness due to the importance of frontal lobe anatomy and func- tionality in these disorders (Nolte, 2002; Hofer & Frahm, 2006, Park et al. 2008). The subgenual region connects the CC to the fornix, and can be located easily as it is positioned directly superior to the amygdala, and is the area containing the gCC (Babcock, 1984). The fornix lies directly beneath the CC and is com- prised mostly of efferent fibres from the hippocampus. Hippocampal fibres project via the fornix to the ventral striatum, septal and preoptic nuclei, the orbitofrontal cortex and anterior cingulate, and less prominent con- nections to the anterior thalamic nucleus and the hypo- thalamus also exist (Griffiths et al. 2009). An examination of this structure is critical in the study of schizophrenia (SZ) and major depressive dis- order (MDD) as there have been extensive reports of functional and structural changes in the frontal lobes * Address for correspondence: Dr M. R. Williams, Francis Fraser Clinic, Hammersmith Hospital, London W12 0NN, UK. (Email: Matthew.r.williams@imperial.ac.uk) Psychological Medicine, Page 1 of 11. © Cambridge University Press 2015 doi:10.1017/S0033291715000136 ORIGINAL ARTICLE