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Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

The Apolipoprotein E (APOE) ɛ4 allele is the best-established genetic risk factor for sporadic Alzheimer's disease, and is also associated with structural gray matter and functional brain changes in healthy young, middle-aged and elderly subjects. Because APOE is implicated in brain mechanisms associated with white matter (WM) development and repair, we investigated the potential role played by the APOE polymorphism on WM structure in healthy younger (aged 20-35 years) and older (aged 50-78 years) adults using diffusion tensor imaging. General reduction of fractional anisotropy and increase in mean diffusivity values was found in carriers of the APOE ɛ4 allele relative to non-carriers. No significant interactions between genotype and age were observed, suggesting that differences in WM structure between APOE ɛ4-carriers and non-carriers do not undergo significant differential changes with age. This result was not explained by differences in brain morphology or cognitive measures. The APOE ɛ4 allele modulates brain WM structure before any clinical or neurophysiological expression of impending disease.

Recent neuropsychological studies in healthy volunteers suggest that antidepressants enhance the processing of positive emotional information. However, the neural substrates underpinning these changes have not been fully elucidated. The current study, therefore, used functional magnetic resonance imaging (fMRI) to map brain systems activated during successful categorization and subsequent recognition of self-referent positive and negative personality characteristics in healthy volunteers following short-term (7 days) repeated administration of the selective noradrenergic reuptake inhibitor reboxetine. Twenty-four healthy volunteers were randomly assigned to 7-day double-blind intervention with reboxetine or placebo. On day 7, neural responses during the categorization and subsequent recognition of positive and negative characteristics were assessed using fMRI. Questionnaires monitoring mood, hostility and anxiety were given before and during this intervention. During categorization, reboxetine was associated with greater activation to positive words, relative to negative words, in left precuneus and right inferior frontal gyrus. By contrast, at subsequent recognition reboxetine was associated with reduced response to positive words, relative to negative words, in left precuneus, anterior cingulate and medial frontal gyrus. These changes in the neural processing of positive and negative words occurred in the absence of significant differences in ratings of mood and anxiety. Such adaptations in the neural processing of emotional information support the hypothesis that antidepressants have early effects on emotional processing in a manner which would be expected to reverse negative biases in depression.