Larger hypothalamic volume in narcolepsy type 1.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is a neurological sleep disorder. Postmortem studies have shown 75%-90% loss of the 50 000-70 000 hypocretin-producing neurons and 64%-94% increase in the 64 000-120 000 histaminergic neurons and conflicting indications of gliosis in the hypothalamus of NT1 patients. The aim of this study was to compare MRI-based volumes of the hypothalamus in patients with NT1 and controls in vivo. METHODS: We used a segmentation tool based on deep learning included in Freesurfer and computed the volume of the whole hypothalamus, left/right part of the hypothalamus, and 10 hypothalamic subregions. We included 54 patients with post-H1N1 NT1 (39 females, mean age 21.8 ± 11.0 years) and 114 controls (77 females, mean age 23.2 ± 9.0 years). Group differences were tested with general linear models using permutation testing in Permutation Analysis of Linear Models and evaluated after 10 000 permutations, yielding two-tailed P-values. Furthermore, a stepwise Bonferroni correction was performed after dividing hypothalamus into smaller regions. RESULTS: The analysis revealed larger volume for patients compared to controls for the whole hypothalamus (Cohen's d = 0.71, p = 0.0028) and for the left (d = 0.70, p = 0.0037) and right part of the hypothalamus (d = 0.65, p = 0.0075) and left (d = 0.72, p = 0.0036) and right tubular-inferior (d = 0.71, p = 0.0037) hypothalamic subregions. CONCLUSIONS: In conclusion, patients with post-H1N1 NT1 showed significantly larger hypothalamic volume than controls, in particular in the tubular-inferior subregions which could reflect several processes as previous studies have indicated neuroinflammation, gliosis, and changes in the numbers of different cell types.

Genetic control of variability in subcortical and intracranial volumes.

Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

Widespread white matter changes in post-H1N1 patients with narcolepsy type 1 and first-degree relatives.

Study Objectives: To assess white matter involvement in H1N1-vaccinated hypocretin deficient patients with narcolepsy type 1 (NT1) compared with first-degree relatives (a potential risk group) and healthy controls. Methods: We compared four diffusion tensor imaging-based microstructural indices (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) in 57 patients with NT1 (39 females, mean age 21.8 years, 51/57 H1N1-vaccinated, 57/57 HLA-DQB1*06:02-positive, 54/54 hypocretin-deficient), 54 first-degree relatives (29 females, mean age 19.1 years, 37/54 H1N1-vaccinated, 32/54 HLA-DQB1*06:02-positive), and 55 healthy controls (38 females, mean age 22.3 years). We tested for differences between these groups, for parametric effects (controls > first-degree relatives > patients) and associations in patients (cerebrospinal fluid [CSF] hypocretin-1 and disease duration) and first-degree relatives (HLA-DQB1*06:02 and H1N1-vaccination). We employed tract-based spatial statistics and used permutation testing and threshold-free cluster enhancement for inference. Results: Patients with NT1 had a widespread, bilateral pattern of significantly lower FA compared with first-degree relatives and healthy controls. Additionally, patients with NT1 also exhibited significantly higher RD and lower AD in several focal white matter clusters. The parametric model showed that first-degree relatives had intermediate values. Full sample of patients with NT1 showed no significant associations with disease duration or CSF hypocretin-1. Conclusions: Our study suggests widespread abnormal white matter involvement far beyond the already known focal hypothalamic pathology in NT1, possibly reflecting the combined effects of the loss of the widely projecting hypothalamic hypocretin neurons, and/or secondary effects of wake/sleep dysregulation. These findings demonstrate the importance of white matter pathology in NT1.