The hydrocephalic mouse belonged to a cohort of transgenic mice used in a resting-state study on early stages of cerebral amyloidosis. No evident behavioral differences could be observed with respect to gait, feeding, grooming, or mood. Stable physiological parameters were observed for all the animals without a noticeable difference, ensuring optimal recording conditions (Fig. S1): heart rate 336.5±42.3 (Fig. S1A) and blood oxygenation mean 95±4.4 (Fig. S1B). Anatomical images acquired for the hydrocephalic brain showed a broad expansion of the CSF volume, extending to 44% of the total brain volume (Fig. 1A). Cortical thickness was reduced to a range of 0.5 - 0.8 mm, compared to 0.9 - 1.5 mm in the control animals. The GE-EPI images acquired at high-field presented minimal geometric distortion, ensuring precise mapping of the functional networks (Fig. 1B).
We referred to rules defined in to identify relevant mouse RSNs in the ICA. Four plausible anatomically-relevant components for RSNs were found in the hydrocephalic mouse (Fig. 1C, D, E, F, bottom panels). In the control cohort, 4.14±1.01 plausible components could be identified. The representative components in one control animal are shown as reference (Fig. 1C, D, E, F, top panels). The incidence map for the four RSNs shows a 70–100% co-occurrence of the major anatomical regions within each RSN investigated, across all control subjects (Fig. S2). This indicates that individual-level RSNs were stable and spatially converged within the control cohort. One network was found to overlap with the cingulate and retrosplenial cortex, together with patterns of anti-correlations with the anterior parietal cortex (Fig. 1C, S2A), therefore, showing a spatial distribution corresponding to the rodent DMN. The second network identified presented FC extent attributable to the Salience network (SN), specifically, overlapping with the insular and secondary somatosensory cortex (Fig. 1D, S2B). The full extent of the DMN (Fig. 1C, S2A) and SN (Fig. 1D, S2B) are shown together with the 3-dimensional extension of the CSF in both controls (top panels) and hydrocephalic (bottom panels) mice (Fig. S3A, B). The third and fourth networks corresponded, respectively, to the anterior and posterior sensorimotor networks (Fig. 1E, F; S2C, D), including overlaps with the anterior motor and somatosensory (barrel field) cortex (Fig. 1E, S2C), and the posterior somatosensory (front and hindlimb, auditory, and visual) cortex (Fig. 1F, S2D). Only marginal clusters were observed within sub-cortical networks in the hydrocephalic mouse, while a fifth component, presenting a strong sub-cortical basis, could be observed in 8 of the 17 mice comprising the control cohort. We concluded that the RSN found in the hydrocephalic mouse corresponded to the counterparts found in the control cohort.
To validate these qualitative findings, reference components shown in figure 1 were regressed within the hydrocephalus scan or across all scans in the control animals. Z-statistics, denoting FC strength within a RSN, were extracted using two ROIs located within the DMN and two within the SN (Fig. 1G, H, I, J). Specifically, FC within the cingulate cortex and retrosplenial cortex, two key elements of the DMN (red and yellow arrow in Fig. 1C, respectively), ranged 6.16±2.39 and 5.41±2.28 in the control cohort, while it reached 10.71 and 6.85 in the hydrocephalic mouse (Fig. 1G, H). With respect to the SN, the magnitude of FC within the insula and somatosensory cortex (green and cyan arrow in Fig. 1D, respectively) ranged 8.99±3.10 and 8.36±2.13 in the control group and 12.65 and 7.53 in the hydrocephalic mouse (Fig. 1I, J). In summary, network strength in the hydrocephalic mouse was found to be within ±1 standard deviation of the estimate in the control group in three of the four ROIs, and ±2 standard deviations in the fourth. We conclude that RSN within the hydrocephalic mouse presented FC strength on par with those found in animals from the control cohort.
This case report showed that, despite a major excess of CSF, the hydrocephalic mouse brain presented a surprising functional resilience. The intrinsic FC organization resembled the characteristics of four RSNs commonly present in the rodent brain, including DMN, SN, and sensorimotor networks. The spatial distribution and the magnitude of the RSNs have been found to be comparable to the littermate controls. Both the DMN and SN have been identified as major hubs underlying neuropathologies and neurodevelopment in human. The strong functional resilience to structural insults exhibited, in this case, departs from observations in human reports, where both these networks have been shown to be affected.
This first observation, made in a spontaneous hydrocephalus case, offers a rare glimpse into the functional organization of the mouse brain following a severe insult. This was made possible with ultra-high field magnets and advanced cryoprobe receiver coils allowing for high sensitivity of the resting fMRI signal. Moreover, previously optimized anesthesia and preprocessing protocols provide additional sensitivity for the robust and reliable detection of RSNs at the individual level in rodents. This is exemplified by the high reproducibility of the RSNs detected at the individual level in the control cohort.