Diencephalic integrity explains aspects of hippocampal amnesia

Research on amnesia has been fundamental in establishing the role of the human hippocampus in memory. Even though other structures within the hippocampal-diencephalic-cingulate network also play a role in episodic memory, studies of hippocampal amnesia often ignore the importance of changes in this broader network. In a large cohort of patients (n = 38) with hippocampal damage due to autoimmune limbic encephalitis, we previously found that amnesia was predominantly explained by resting-state functional abnormalities across this network. Here, we examined the integrity of individual diencephalic nuclei and white matter pathways, and its relationship with memory function. We found atrophy in the mammillary bodies, and the anterior, laterodorsal, pulvinar, and dorsomedial thalamic nuclei. Atrophy was often as pronounced as that in the hippocampal formation. Diencephalic volumes predicted memory over and above any hippocampal/subicular subfield volume estimate. White matter was compromised within and beyond this network. Fornix integrity was linked to diencephalic and hippocampal volumes, but not to recollection/recall. We strongly advise caution in employing the term "focal hippocampal damage" in cognitive neuroscience, and highlight the need to study the significance of plausibly knock-on effects in specific diencephalic nuclei and white matter tracts within broader circuits.