McNab, J. A. | bioRxiv Science

bioRxiv2026

Diffusion MRI Tractography Predicts Electrophysiological Connectivity and Explains Spectral Signatures of Evoked Potentials in the Human Brain

White matter fiber bundles are the structural conduits of information flow in the human brain and thereby mediate the spatial trajectories and timings of the electrophysiological signaling. Here, we combined diffusion magnetic resonance imaging (dMRI) and stereoelectroencephalography (SEEG) recordings in neurosurgical patients to develop an integrated framework for predicting and interpreting causal electrophysiological connectivity patterns between pairs of brain regions. We used repeated single-pulse electrical stimulation in 40 participants implanted with a total of 5794 intracranial electrodes throughout the human brain, encompassing both cortical and multiple thalamic nuclei. A nonlinear, time-frequency manifold learning approach was used to define electrophysiological connectivity, which was then compared with subject-specific and atlas-based structural connectivity. Across 150,000 electrode pairs, we found that the presence of a structural connection predicted causal electrophysiological connectivity with a probability of ~0.95; and its absence predicted the lack of the direct electrophysiological connectivity with a probability of ~0.8. We also show evidence of indirect/polysynaptic pathways supported by both modalities and reported neural features from time-frequency decomposition that distinguished between direct and indirect signaling. We demonstrated that an early phase-locked broadband component (10-70 ms) marked direct structural pathways, whereas delayed and slower components reflected indirect propagation. Notably, we reported that thalamic involvement within an indirect pathway results in increased latency (> 200 ms) and enhanced late oscillatory behavior, despite increased conduction velocity measures along thalamo-cortical pathways. Therefore, our multimodal framework maps human brain connectivity, bridging structural architecture, causal electrophysiological dynamics, and network-level communication.

neuroscience↗

bioRxiv2024

Impact of Pathogenic Variants of the Ras-MAPK Pathway on Major White Matter Tracts in the Human Brain

Noonan syndrome (NS) and Neurofibromatosis type-1 (NF1) are genetic conditions linked to pathogenic variants in genes of the Ras-MAPK signaling pathway. Both conditions hyperactivate signaling of the Ras pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of NS and NF1 and human imaging studies show white-matter abnormalities in both conditions. While these findings suggest Ras pathway hyper-activation effects on white-matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of NS and NF1 on human white-matter microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with NS (n=24), NF1 (n=28), and age and sex-matched controls (n=31). We contrasted the clinical groups (NS or NF1) and controls using voxel-wise, tract-based, and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD). NS and NF1 showed similar patterns of reduced FA and increased AD, RD, and MD on white-matter relative to controls and different spatial patterns. NS presented a more extensive spatial effect than NF1 on white-matter integrity as measured by FA. Tract-based analysis also demonstrated differences in effect magnitude with overall lower FA in NS compared to NF1 (d=0.4). At the tract-level, NS specific-effects on FA were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; ps <0.012) and NF1 specific-effects were detected in the corpus callosum (ps<0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-MAPK pathway are associated with white-matter abnormalities as measured by diffusion in the developing brain. Overall NS and NF1 show common effects on FA and diffusion scalars, as well as specific unique effects, namely on temporoparietal-frontal tracts (intra-hemispheric) in NS and on the corpus callosum (inter-hemispheric) in NF1. The observed specific effects not only confirm prior observations from independent cohorts of NS and NF1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras pathway.

neuroscience↗