Diencephalic and white matter knock-on effects in hippocampal amnesia - why they matter

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 ignore the importance of damage in this broader network. In a large cohort of patients (n=38) with hippocampal damage due to autoimmune limbic encephalitis, we had found the amnesia was predominantly explained by abnormalities in this network. Here, we examined the integrity of specific diencephalic nuclei and of white matter pathways, and whether it explains patients amnesia. We found atrophy in the anterior thalamic nuclei and the mammillary bodies, but also in the laterodorsal, pulvinar, and dorsomedial nuclei. Atrophy was often as pronounced as that in the hippocampal formation, even though these patients are often studied as "human models" of hippocampal damage. 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", and highlight the need to study the significance of plausibly knock-on effects in diencephalic nuclei within broader circuits.