Abstract
Jamiolkowski RM, Nguyen QA, Farrell JS, McGinn RJ, Hartmann DA, Nirschl JJ, Sanchez MI, Buch VP, Soltesz I. Nat Med. 2024 May;30(5):1292–1299. doi: 10.1038/s41591-024-02924-9. Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of 6 patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.
Commentary
Santiago Ramόn y Cajal dedicates a single paragraph in his 2-volume collected works 1 to the fasciola cinereum (FC), a small midline structure wedged between CA1 and the third ventricle at the tail end of the hippocampal formation. The tube-like structure runs for about 1 mm in the sagittal plane in rats, but extends only 80 × 230 µm in the coronal plane. 2 Until recently, the FC has remained a forgotten backwater, averaging about 1 paper per decade. The recent development of new molecular tools to identify the structure, however, and recent studies establishing it is a distinct subfield of the hippocampus, have renewed interest.2,3 Cells forming the FC bear a mix of anatomical and physiological characteristics reminiscent of both hippocampal granule cells and pyramidal cells, with fan-like dendritic trees resembling granule cells and electrophysiological properties, which partially resemble distal CA1 pyramidal cells. 4 As with the rest of the hippocampus, functional studies support a role in memory. 2 In addition to unique functional roles, recent work by Jamiolkowski et al. 5 implicates the structure in epilepsy.
Jamiolkowski et al. 5 became interested in the FC following studies using single-chain fast light- and activity-regulated expression (scFLARE), a light- and calcium-gated molecular integrator that can reveal active neurons. In the intrahippocampal kainic acid (IHpKA) model of epilepsy, closed-loop activation of scFLARE after a spontaneous seizure consistently revealed activation of the FC in mice. The FC was also activated by acutely evoked (non-epileptic) seizures. To develop additional evidence for FC involvement in seizures, the investigators utilized Purkinje cell protein 4 (PCP4)-Cre recombinase expressing mice to label FC neurons with the calcium indicator jGCaMP8f. PCP4 provides for relatively specific targeting of FC neurons, while the calcium indicator allowed the investigators to measure neuronal activity patterns in IHpKA mice. In vivo calcium imaging revealed that FC neurons were active during interictal spikes and at seizure onset. To generate direct evidence for the role of the FC in seizures, the investigators used a closed-loop optogenetic silencing technique to inhibit FC neurons at the onset of detected seizures in the IHpKA model. Seizure-triggered optogenetic silencing of FC neurons significantly reduced seizure duration. Finally, the investigators present data on 6 patients with epilepsy who underwent stereoelectroencephalography (sEEG) studies to record from a variety of brain regions that included the FC. All 6 patients had seizures that involved the FC, with patterns ranging from independent activity to activity following spread from other regions. Perhaps most intriguing, 1 of the 6 patients underwent sEEG after laser ablation of the amygdala and anterior hippocampus, which failed to effectively control seizures. sEEG studies identified the FC as the seizure onset zone in this patient, which was subsequently ablated in a second surgery, producing an 83% reduction in seizures at follow-up. Collectively, findings support the conclusion that the FC is a previously unrecognized, and therapeutically targetable, seizure node in some animal models and patients with epilepsy.
The finding raises many questions. Firstly, additional studies are needed to establish whether FC involvement is a common feature of epilepsy, or whether involvement is restricted to specific models and patients. Conducting studies in additional animal models is straightforward, particularly given the development of new tools (e.g. PCP4-Cre mice) to identify and manipulate the structure. Human studies, however, will be more challenging. The FC was targeted for sEEG recording in the 6 patients examined based on clinical data suggesting seizure spread in the posterior hippocampus, where the FC is located in humans. This clinically justified approach likely concentrated on patients with FC involvement. Conducting invasive FC sEEG recordings in patients without other evidence of involvement would be hard to justify, which will make it difficult to establish the ubiquity of involvement. The use of non-invasive techniques, such as magnetoencephalography, could provide an opportunity to examine a more diverse pool of epilepsy types, although continued technological improvements are needed to reliably detect epileptiform activity in small and deep structures. 6 Longitudinal and pre-/post-op studies would also be particularly interesting. The small size, shape, and proximity to white matter tracts make the FC more challenging to remove or ablate, so it is conceivable that it may not be more inherently epileptogenic than other regions, just more often left behind—perhaps as in the patient that underwent the second, successful surgery to remove it.
A second question is whether the FC really exerts an outsized effect in seizures, that is, is it a critical epileptogenic node, or is it just one among many brain regions that can drive seizures? The small size of the structure has made it easy to ignore, but perhaps it is underestimated? Could the FC possess features that make it inherently epileptogenic? Resolving this issue will require a much more detailed characterization of its anatomy and physiology. There is agreement that the structure receives input from the lateral (but not medial) entorhinal cortex in rodents, but major outputs of the structure are not fully defined, with 1 paper reporting a projection to the crest of the dentate in rat, 2 while later papers, using mice, instead detected a projection to CA2 without a significant projection to the dentate.4,7 Whether the discrepancy reflects species differences, different projection patterns along the longitudinal axis of the structure, or other factors is not clear, but it highlights the need for additional basic neuroanatomy studies. Notably, either projection pattern could support seizure spread. The dentate has long been implicated in temporal lobe epilepsy, 8 and recent studies highlight important roles for CA2. 9 The internal circuitry of the FC is also not fully defined. Recent studies found evidence of recurrent circuitry within the structure in healthy mice, 4 which could promote hyperexcitability. The nature of inhibitory circuitry within the FC is also unclear. Like the dentate gyrus, the structure it most resembles, is it also regulated by robust feedforward and feedback inhibitory circuitry? Also like the dentate,10,11 does it form de novo recurrent circuits during the development of epilepsy? Interestingly, in rats, unilateral ablation of the entorhinal cortex leads to reinnervation from the contralateral hemisphere, following a path through the FC. 12 Whether such passing axons innervate FC neurons along the way has not been examined, but the findings suggest that the FC could play a role as a thoroughfare for epileptogenic rewiring. Further anatomical and physiological characterization of the structure in the normal and epileptic brain, and the development of a network model, would be extremely helpful for predicting whether the structure might be particularly epileptogenic.
The “tiny” (Cajal’s characterization) FC has been largely ignored for over a century. Jamiolkowski et al., 5 provide compelling evidence that the structure can serve as a critical node in the epileptic brain, changing the forecast for research on the FC going forward. Like the prehensile tail of the seahorse (and its mythological variant from whence the hippocampus derives its name), the FC may play an outsized role in controlling the hippocampus.
