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Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n = 23), weight-recovered women with a past diagnosis of AN (recAN: n = 23), and age-matched healthy control women (HC: n = 24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxelwise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold-free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Clusterwise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for clusterwise AD and RD. Trait-based increases in diffusivity, changes in which have been associated with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.

Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using unbiased genome-wide methods, recent studies have associated a variety of genes with the disorder. We characterized these genes by projecting them into aggregated gene expression data from reference transcriptomic atlases of the prenatal and adult human brain. We found that genes from an induced stem cell study of anorexia nervosa are expressed at higher levels in the lateral parabrachial and the ventral tegmental areas. The adult expression enrichment of the lateral parabrachial is confirmed with genes from two independent genetic studies. In the fetal brain, enrichment of the ventral tegmental area is also observed for the six genes near the only common variant associated with the disorder (rs4622308). We also observed signals in the adult and fetal pontine raphe, but they were not observed when using the genes from the genetic studies. In addition to signals related to calcitonin gene-related peptide neurons and the tachykinin, we found more than the expected number of microglia marker genes within the gene sets. Using mouse transcriptomic data, we identified several anorexia nervosa associated genes that are differentially expressed during food deprivation. While these genes that respond to fasting are not enriched in the gene sets, we highlightRPS26which is proximal to rs4622308. We did not observe expression enrichment in the cingulate cortex or hypothalamus suggesting other targets for deep brain stimulation should be considered for severe cases. This work improves our understanding of the neurobiological causes of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits.

The mammalian habenula with its medial and lateral complexes has gained much interest in recent years, while knowledge on the detailed biological functions of these nuclei is still scarce. Novel strategies to differentiate and identify habenular cell types are required. Such attempts have largely failed, most likely due to the lack of appropriate molecular markers. One important tool to approach this dilemma is available in form of the Allen Brain Atlas (ABA), which provides detailed expression patterns of many genes in the mouse brain. In the present report, ABA tools in combination with visual inspection of ISH images were used to detect transcripts, which are strongly expressed in medial (MHb) and lateral (LHb) habenular complexes. Against our expectations, most transcripts were differentially distributed throughout the LHb, disregarding boundaries of subnuclear areas. Nine distinct distribution patterns were recognized. Yet, several transcripts could not be attributed to one of these, suggesting a high diversity of neuron types in the LHb. In the MHb, in contrast, many transcripts tended to obey subnuclear boundaries. The differential distribution of others like Adcyap1, Chrna3, or Trp53i11 suggests the presence of a novel subfield adjacent to the region of the MHbVm, which now is termed intermediate field of the ventral MHb. In addition, the localizations of Amigo2, Adcyap1, and a couple of other transcripts suggest a lateral extension of the MHb, which is here, termed HbX area. Apparently, this area is composed of intermingled MHb and LHb neurons and may allow functional interaction between the both habenular complexes.