Box 2.

Big Questions for Future Research

1. Does fornix degradation in hippocampal or diencephalic amnesia account for some of the deficits in episodic memory? One of the only studies to look at this found that an individual with developmental amnesia had a fornix that was partially missing (Rosenbaum et al., 2014). Given the principle of wallerian degeneration, it is nearly certain that the fornix is abnormal in any individual with hippocampal lesions.

2. Is myelin damage in the fornix the catalyst for amyloid and tau deposition, and for later hippocampal cell loss observed in Alzheimer's disease?

3. How does inflammation affect fornix myelination and what are the downstream effects on brain rhythms such as theta, acetylcholine transmission, and cognitive state?

4. Is the fornix damaged by chronic stress? There is evidence that the hippocampus is acutely sensitive to stress and that oligodendrocytes are also sensitive to stress (McEwen, 2017). Unfortunately, this literature has evolved along a separate axis from the literature on episodic memory. However, when taken together, these findings raise the possibility that socioeconomic deprivation, a potent stressor, may damage fornix myelin.

5. Do alterations in fornix microstructure account for pathological eating behavior? The fornix is the conduit by which memories are used to guide decisions; it is part of the interface between the limbic system and action. At least one study has reported that in humans, variation in fornix microstructure correlates with body mass index (Metzler-Baddeley et al., 2013). This relationship deserves further attention.

6. Does a diet high in omega-3 fatty acids, which helps form myelin, improve fornix microstructure and episodic memory? One study found this to be true (Zamroziewicz et al., 2017), but more evidence is needed.

7. How do changes in fornix microstructure relate to episodic memory and other cognitive faculties in young children? Fornix macrostructure is fully developed by age 2, but episodic memory continues to develop for several years beyond that (Ngo et al., 2019). Future investigators should examine whether variation in fornix microstructure relates to the maturity of memory ability in young children.

8. Is the fornix involved in cognitive domains beyond episodic memory? Most studies have focused on episodic memory (Table 2). However, the fornix likely plays an essential role in navigation and memory-guided decision making.