We first provide a brief overview of longitudinal case-control studies in bipolar disorder, then discuss factors that might contribute to structural brain changes, and subsequently, we provide a more detailed outline of studies reporting mania-related structural changes. We review and summarize longitudinal structural magnetic resonance imaging studies that relate imaging outcomes to manic episodes. The aim of this narrative review was therefore to advance our understanding of the consequences manic episodes might have on neuroanatomical structures. Not only is the occurrence of manic episodes the hallmark of bipolar disorder, but the number of manic episodes has also been associated with worsening illness severity over time. While the causes of abnormal brain changes remain undetermined, medication use, genetic factors, and the occurrence of mood episodes have been hypothesized as probable contributing factors. However, bipolar disorder patients did show an accelerated enlargement of ventricles compared with healthy controls. Notably, however, the largest longitudinal imaging study in bipolar disorder to date-a multi-center effort conducted by the ENIGMA bipolar disorder working group-found no decrease in cortical measures over time, but in fact slower thinning of specific cortical measures in some brain areas than controls. Single-center studies, multi-center studies, and recent reviews have observed structural changes mainly in the prefrontal and temporal cortices. These do in fact indicate that aberrant brain changes occur. Recently, however, a few longitudinal studies of brain morphology that enable conclusions about possible brain changes in bipolar disorder have been performed. It is still disputed, however, whether bipolar disorder entails such neuroprogression, mainly because longitudinal studies investigating brain changes over time are scarce. Such progressive deterioration of illness has-along with hypothesized neuroanatomical changes over time-been denoted ‘neuroprogression’ and has also been described in bipolar disorder. Some observations suggest that brain abnormalities might be related to worsening along the course of illness and decline in general functioning, at least in some patients with bipolar disorder. The causes of these findings remain unknown and the question whether the observed brain aberrancies presage disease onset or are consequences of disease processes cannot be resolved due to inherent limitations of cross-sectional study designs. Finally, enlarged ventricles have been observed in bipolar disorder. Subcortical abnormalities have been observed in amygdala, hippocampus, and thalamus in bipolar disorder patients. Large-scale studies from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) bipolar disorder working group found the most pronounced cortical alterations in pars opercularis and rostral middle frontal and fusiform cortex. Finally, we discuss potential mechanisms at play, remaining limitations, and future directions.Ĭross-sectional neuroimaging studies show that bipolar disorder is associated with structural brain abnormalities, predominantly observed in prefrontal and temporal cortex, cingulate gyrus, and subcortical regions, and less consistently in insula and visual cortex. We further propose a model of prefrontal cortical trajectories in relation to the occurrence of manic episodes. The findings stress the importance of preventing manic episodes. Importantly, evidence also suggests that in contrast to healthy controls, who in general show age-related cortical decline, brain metrics remain stable or increase during euthymic periods in bipolar disorder patients, potentially reflecting structural recovering mechanisms. Second, we conclude that manic episodes have been related to accelerated cortical volume and thickness decreases, with the most consistent findings occurring in prefrontal brain areas. First, we conclude that longitudinal brain imaging studies suggest an association of bipolar disorder with aberrant brain changes, including both deviant decreases and increases in morphometric measures. Here, we narratively review and summarize longitudinal structural magnetic resonance imaging studies that relate imaging outcomes to manic episodes. However, longitudinal studies are needed to elucidate whether these abnormalities presage disease onset or are consequences of disease processes, and to identify potential contributing factors. Cross-sectional neuroimaging studies show that bipolar disorder is associated with structural brain abnormalities, predominantly observed in prefrontal and temporal cortex, cingulate gyrus, and subcortical regions.
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