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The lifetime prevalence of major depressive disorder is 16.5% and, each year, 800 000 individuals worldwide die as a result of suicide, a high proportion of whom suffered from severe depression. Even with treatment, 20% of patients experience chronic symptoms, meaning that major depressive disorder accounts for a greater number of years lived with disability than any other illness. A combination of genetic susceptibility, chronic stress and developmental factors predispose to depression by triggering alterations in neuroplasticity, biochemistry, and brain structure. As illustrated by a recent meta-analysis, structural brain changes predominantly affect the lateral ventricles, basal ganglia, thalamus, hippocampus and frontal lobes (Kempton et al., 2011). In this issue of Brain, Maller et al. (2014) reveal that structural changes also extend to the occipital lobes, with ‘occipital bending’—in which one occipital lobe wraps around the other—three times more prevalent in patients with treatment-resistant major depressive disorder than in healthy controls. Bending or asymmetry of the occipital cortex has not been examined in major depressive disorder before. However, it is worth noting that although the occipital cortex is not among the core regions that exhibit structural changes in major depression, alterations in biochemistry, white matter structure, resting state connectivity and grey matter volume have previously been reported in the occipital lobes in this disorder (Bhagwagar et al., 2007; Grieve et al., 2013; Liao et al., 2013; Meng et al., 2014). A comprehensive meta-analysis identified the right occipital lobe, with the inferior fronto-occipital fasciculus as its major connecting fibre tract, as one of the most consistently reported locations of decreased white matter integrity in patients (Liao et al., 2013). Reductions in the volume of the occipital lobes—particularly midline regions—have also been described (Grieve et al., 2013). Hence, there is reason to believe that the increase in occipital bending in major depressive disorder is related to these previously reported alterations in occipital lobe structure and function; this should be investigated further through studies that combine different imaging modalities. The results of Maller and colleagues raise additional questions. First, what are the mechanisms underlying this increased prevalence of occipital bending in major depressive disorder? And second, what is its clinical relevance? With regards to the first question, Maller et al. (2014) propose that ventricular enlargement may be one mechanism underlying increased occipital bending. Ventricular enlargement is among the most frequently reported structural alterations in major depressive disorder (Kempton et al., 2011) and may exacerbate the natural curvature of occipital cortex. Maller et al. did not measure ventricular volume directly, but they did find CSF volume to be increased in patients, significantly in males and non-significantly in females. Whether increased occipital bending represents a mere ‘sideeffect’ of another pathological process such as ventricular enlargement, or has psychopathological relevance in itself remains, however, to be determined. Notably, increased occipital bending has also been reported in schizophrenia (Deutsch et al., 2000), which is known to feature significant and, most probably, progressive ventricular enlargement. This indicates that the two parameters may be related or may share a common origin. Brain alterations in schizophrenia are thought to reflect in large part disturbed neurodevelopmental processes. Major depression, on the other hand, is not generally seen as a disorder of neurodevelopmental origin. However, studies have linked stress, such as famine during a critical gestational period, to the manifestation of major depressive disorder. For instance, Brown et al. (2000) compared the risk of major affective disorder in birth cohorts who were and were not exposed, in each trimester of gestation, to famine during the Dutch Hunger Winter of 1944–45. They found that the risk of developing a major depressive disorder was significantly increased for those exposed to famine during the third trimester of gestation, which represents a critical period in brain development. These studies indicate that alterations in white and grey matter structure, and potentially gross anatomical changes such as increased occipital bending, may result from early neurodevelopmental alterations. Altered grey matter structure in patients with a first episode of major depressive disorder points to a similar conclusion (Zou et al., 2010). It should not go unnoticed, however, that Maller et al. observed occipital bending in 12% of healthy controls, too. This result, together with the increased prevalence of occipital bending in patients with treatment-resistant major depression, implies that occipital bending could be a vulnerability marker for a predisposition to major depression. This predisposition may result in a manifest illness if further environmental triggers such as chronic stress or adverse developmental conditions doi:10.1093/brain/awu106 Brain 2014: Page 1 of 2 | 1