LESIONS ASSOCIATED WITH HYPERSOMNIA MAP TO A COMMON BRAIN NETWORK

Abstract

Abstract. Background: Hypersomnia is characterized by excessive daytime sleepiness, severely impairing daily functioning and often a significant source of distress for affected individuals. Brain lesions associated with new-onset hypersomnia may provide causal insights about neuroanatomy critical for sleep regulation. Moreover, mapping the whole-brain functional connectivity of these lesions may identify the brain networks that regulate sleep and wakefulness. The hypothesis that lesions causing hypersomnia map to a common brain network has not been formally tested. Methods: We conducted a systematic review of the literature and identified 63 hypersomnia-related lesions. Each lesion was mapped onto a common brain template, and functional networks were computed using resting-state functional connectivity data from 1,000 healthy individuals. Sensitivity analyses were performed at two thresholds (T > 4.7 and T > 7). A one-sample Welch’s t-test was performed to account for multiple comparisons. Two independent specificity analyses were conducted by comparing the hypersomnia network with lesion connectivity associated with other neuropsychiatric conditions (n = 997) and a cohort of stroke lesions (n = 135). We created a conjunction map and used it as a region of interest (ROI) to derive a hypersomnia brain network. We formally tested the hypothesis that the hypersomnia network exhibits preferential functional connectivity with the posterior hypothalamus, rather than the anterior hypothalamus, using two different ROIs from two separate atlases. The functional connectivity of the entire hypersomnia cohort to these ROIs was averaged, and a paired t-test was performed. Given the phenotypic similarities of hypersomnolence and coma, a one-sample t-test (FWE-corrected) was conducted to test the similarity of hypersomnia and coma-associated brain networks. An exploratory voxel-wise-two-sample t-test (FWE-corrected) was conducted to identify brain network patterns differentially associated with hypersomnia and coma, respectively. Lastly, we conducted an exploratory assay to compare the spatial topography of our hypersomnia network to brain networks associated with other neurological and psychiatric conditions. Results: Hypersomnia-causing lesions are part of a common brain network (in >95% of cases) connected to relevant arousal centers, which is both specific and consistent. The posterior hypothalamus shows preferential functional connectivity to hypersomnia-associated lesions, in contrast to the anterior hypothalamus. There is a significant similarity in functional connectivity networks between hypersomnia and coma. However, exploratory analysis reveals distinguishing properties between them. Our hypersomnia network demonstrates strong, significant spatial similarity with lesion networks associated with coma. Conclusion: Hypersomnia-associated lesions map to a common brain network, encompassing critical arousal centers and regions outside the classical ascending reticular activating system (ARAS). The functional connectivity networks are significantly similar between hypersomnia and coma. However, our exploratory analysis reveals that the functional connectivity networks of coma originate from the lower brainstem, whereas the functional connectivity networks of hypersomnia originate in the upper brainstem. These findings offer new insights into the functional networks of hypersomnia specifically and conscious arousal generally, and lays the groundwork for proposing new stimulation targets that could alleviate hypersomnia symptoms.