Diffusion tensor imaging-functional MRI fusion reveals disrupted white matter structure-function coupling in HIV-associated asymptomatic neurocognitive impairment.

Objective: Conventionally, blood oxygen level-dependent (BOLD) signals derived from resting-state functional magnetic resonance imaging (rs-fMRI) are attributed to gray matter, but recent evidence confirms stable low-frequency oscillations within white matter. While structure-function coupling is pivotal in neuropsychiatry, it remains underexplored in HIV-associated neurocognitive disorders (HAND). Focusing on Asymptomatic Neurocognitive Impairment (ANI), the earliest stage of HAND, this study establishes a white matter skeleton-based fusion framework integrating diffusion tensor imaging (DTI) and rs-fMRI to investigate underlying mechanisms. Methods: We enrolled 47 patients with ANI and 48 matched healthy controls. Fractional anisotropy (FA) images from DTI and BOLD signals derived from rs-fMRI were projected onto a unified white matter skeleton to achieve structure-function spatial alignment. FA, skeleton-based white matter amplitude of low-frequency fluctuations (SWALFF), and its dynamic variability (dSWALFF) were calculated. Group differences in white matter structure and function were assessed, with structure-function coupling examined in regions showing overlapping FA-SWALFF and FA-dSWALFF alterations. Additionally, a novel White Matter Dys-coupling Index (WDI) was proposed to quantify the deviation between structural integrity and functional activity and evaluate its clinical relevance. Results: Compared to controls, ANI patients exhibited widespread FA reductions and increased mean diffusivity (MD) and radial diffusivity (RD), indicating diffuse demyelination. Functionally, a spatial dissociation emerged: SWALFF was reduced in posterior occipital pathways (left vertical occipital fasciculus, forceps major), whereas SWALFF and dSWALFF were elevated in prefrontal pathways (forceps minor). Overlapping regions revealed complex coupling patterns, ranging from concordant decline to compensatory upregulation and decoupling. The interaction between FA and dSWALFF further highlighted instability in dynamic regulation. The WDI was significantly correlated with infection duration, immune status, and cognitive domain scores. Conclusion: This study identifies a characteristic "coupling imbalance" in the white matter of ANI patients, defined by the coexistence of structural degeneration and functional reorganization. We propose the WDI as a quantitative metric for this deviation. Its significant associations with clinical and cognitive metrics suggest its potential as a neuroimaging biomarker for the early identification and mechanistic understanding of HAND.