Complementary Sensitivity of Fixed-Time and Fixed-Oscillation Regimes to Exchange and Structural Disorder in the...

Oscillating-gradient spin-echo (OGSE) diffusion MRI probes cell geometry and membrane integrity through the frequency-dependence of kurtosis, but prior studies have reported inconsistent findings depending on how frequency is varied. We compared frequency-dependent kurtosis in the human brain under two regimes: varying frequency with fixed total waveform duration (fixed- $T$ ) or number of oscillations (fixed- $N$ ).

Eleven healthy volunteers were scanned on the 3 T Connectome 2.0 system with OGSE using 500 mT/m gradients. Mean kurtosis (MK) was measured using three fixed- $T$ waveforms ( $T$  ≈ 80 ms) and four fixed- $N$ waveforms ( $N$  = 1). The adiabatic Kärger exchange model was fit to MK in 48 white matter (WM) and 70 gray matter (GM) regions, yielding estimates of water exchange time ( $t_{\mathrm{ex}}$ ), intracellular fraction ( $f_{\mathrm{ic}}$ ), extracellular tortuosity ( ${\alpha }_D$ ), and asymptotic kurtosis ( $K_{\infty }$ ).

Distinct frequency-dependence was observed between regimes. In fixed- $T$ , MK decreased with frequency in both WM and GM, reflecting diffusion coarse-graining from structural disorder. In fixed- $N$ , MK increased with frequency in GM but was relatively flat in WM, indicating greater sensitivity to exchange. Parameter estimates showed biologically meaningful contrasts: WM exhibited longer $t_{\mathrm{ex}}$ , higher $f_{\mathrm{ic}}$ , and greater ${\alpha }_D$ , consistent with tightly packed, myelinated axons and anisotropic extracellular space. GM showed shorter $t_{\mathrm{ex}}$ and higher $K_{\infty }$ , reflecting greater heterogeneity and CSF partial volume.

Fixed- $T$ and fixed- $N$ OGSE provide complementary sensitivity to microstructural features. Fixed- $T$ emphasizes structural disorder, while fixed- $N$ highlights membrane permeability and exchange. The extended frequency regimes enabled by ultra-strong gradients advance OGSE as a powerful tool for probing human brain tissue microstructure.