Glymphatic and neurofluidic dysfunction in classical trigeminal neuralgia: a multimodal MRI study of brain-CSF functional and structural dynamics

Abstract

Objective: To investigate whether dysfunction of the glymphatic system and altered neurofluidic dynamics contribute to the pathophysiology of classical trigeminal neuralgia (CTN), and to explore the potential interplay between brain-CSF coupling and structural brain changes.

Methods: A total of 131 patients with CTN and 106 age- and sex-matched healthy controls were recruited. All participants underwent multimodal MRI, including high-resolution structural imaging, resting-state functional MRI, and diffusion tensor imaging. Key indices included choroid plexus (CP) volume as a proxy for CSF production, global BOLD-CSF coupling as a measure of functional neurofluidic interaction, and the DTI-based ALPS index reflecting glymphatic clearance. Additional markers included peak width of skeletonized mean diffusivity (PSMD) and global gray/white matter and CSF volume. Partial correlation analyses were performed between imaging metrics and clinical assessments.

Results: CTN patients showed significantly increased CP volume (P = 0.022) and gBOLD-CSF coupling (P < 0.001), along with reduced bilateral ALPS indices (P = 0.002, P = 0.004). PSMD and CSF volume were elevated (P < 0.001, P < 0.001), while gray and white matter volumes were reduced (P = 0.028, P = 0.009). gBOLD-CSF coupling correlated positively with depression, anxiety, and pain-related disability scores (P < 0.001), and negatively with MMSE (P = 0.022).

Conclusion: This study provides multimodal MRI evidence of glymphatic dysfunction and neurofluidic alterations in CTN, supporting a conceptual framework in which disrupted brain-CSF interaction may influence peripheral sensory modulation through a putative brain-CSF-ganglion pathway. These results may inform mechanistic hypotheses and guide future research on the neurofluidic underpinnings of neuropathic pain, potentially providing new insights into the pathogenesis of CTN.

Keywords: Brain-CSF coupling; Choroid plexus volume; Classical trigeminal neuralgia; Glymphatic system; Neurofluidic dynamics.

Fig. 1

(A) Extraction of gBOLD signal: The gBOLD signal is extracted from the gray matter regions, while the CSF signal is extracted from the CSF region in the bottom slices of the fMRI acquisition. (B) Representative participant’s gBOLD and CSF signals: The corresponding changes in both signals are shown, demonstrating a marked amplitude correlation. (C) Average gBOLD-CSF cross-correlation functions for the TN, HC, and all participants: The average gBOLD-CSF coupling index shows a positive peak at a lag of -3 s (R = 0.19, P < 0.001, permutation test, n = 10,000), and a significant negative peak at a lag of + 3 s (R = -0.21, P < 0.001, permutation test, n = 10,000). The gray shaded area represents the 95% confidence interval. The negative derivatives of the gBOLD-CSF cross-correlation function show a pattern consistent with systemic coupling between the whole-brain signal and CSF flow. gBOLD, global blood oxygen level-dependent; CSF, cerebrospinal fluid; fMRI, functional magnetic resonance imaging

Fig. 2

A.DTI Image Preprocessing and DTI-ALPS Index Calculation: The raw diffusion tensor images underwent brain extraction, eddy current correction, and motion correction to compute the diffusion tensor parameters. These parameters were then registered to standard space using T1-weighted images. B. Extraction of Diffusion Rates Along x, y, and z Axes: Diffusion rates along the x, y, and z axes were extracted from the diffusion tensor images in standard space, projecting fibers and associated tracts. The ALPS index was then calculated as the ratio of these diffusion rates. C. PSMD Calculation Process: The MD map was projected onto the FA skeleton, and a custom-designed mask was applied to obtain the MD skeleton for each subject. PSMD was determined by calculating the difference between the 95th and 5th percentiles of the voxel-based MD skeleton, based on histogram analysis. PSMD: Peak width of the skeletonized mean diffusivity; DTI-ALP: Diffusion tensor imaging along perivascular spaces

Fig. 3

Boxplot of ALPS Index for Healthy Controls and CTN Patients. ALPS, analysis along the perivascular space; HC, healthy controls; CTN, Classical Trigeminal Neuralgia

Fig. 4

(A), Regression analysis results showing the relationship between age and choroid plexus volume, ALPS index, and gBOLD-CSF coupling index. (B), Violin plot of gBOLD-CSF coupling in HC and CTN patients

Fig. 5

Partial Correlation Heatmap Between Glymphatic Function Indices, Brain Structural Indices, and Clinical Scales. ALPS, Analysis Along the Perivascular Space; gBOLD, Global Blood Oxygen Level Dependent; GMV, Gray Matter Volume; WMV, White Matter Volume; CSF, Cerebrospinal Fluid; TIV, Total Intracranial Volume; PSMD, Peak Width of Skeletonized Mean Diffusivity; chp_vol, Choroid Plexus Volume; MMSE, Mini-Mental State Examination; TNQOLS, Trigeminal Neuralgia Quality of Life Scale; SDS, Self-Rating Depression Scale; SDA, Self-Reported Anxiety Scale. No correction for multiple comparisons was applied