Abnormal iron accumulation within the deep gray matter (DGM) is a well-established feature of multiple sclerosis (MS), which has been associated with neurodegeneration and progressive clinical disability 1-3. Susceptibility-based MRI techniques, including susceptibility-weighted imaging (SWI), R2*, and quantitative susceptibility mapping (QSM), have provided sensitive, non-invasive tools to characterize iron-related tissue changes in the brain 4. Traditionally, these measures have been interpreted as reflecting cumulative pathological iron deposition, which is thought to occur slowly and largely irreversibly over the course of the disease. However, more recent longitudinal work has started to challenge this view of simple progressive iron accumulation. In this issue of JMRI, the article “Association between intermittent fasting and susceptibility-weighted MRI phase values in deep gray matter of patients with multiple sclerosis: an observational cohort study” quantifies longitudinal DGM iron changes using SWI-phase values under Ramadan-style intermittent fasting 5. It introduces an important and conceptually novel dimension to the interpretation of susceptibility imaging in MS, suggesting that intermittent fasting may produce dynamic, widespread, and potentially reversible reductions in SWI-derived paramagnetic phase values in the DGM. Intermittent fasting has been gaining attention as a promising intervention for MS, with evidence from both preclinical and clinical investigations supporting its immunomodulatory and neuroprotective potential. Notable work by Cignarella et al. demonstrated that intermittent fasting induces shifts in gut microbiota composition, increasing microbial diversity and enhancing immunity through microbiota-dependent metabolic pathways 6. Subsequent studies have further shown that intermittent calorie restriction can influence T-cell populations 7, suggesting a potential role in regulating immune and inflammatory processes that may influence the disease course in patients with MS. Ramadan fasting represents a form of intermittent fasting, widely practiced among Muslims, which involves fasting from dawn to sunset. In the context of MS, observational studies suggest that Ramadan fasting is generally well tolerated in patients with baseline mild disability and infrequent relapses 8. In the current study, 36 MS patients were divided into a Ramadan fasting group (n = 20) and a non-fasting control group (n = 14), and two patients were included as longitudinal case studies. Mean phase values were manually quantified across nine DGM structures (dentate nucleus, red nucleus, substantia nigra, pulvinar, thalamus, globus pallidus, putamen, lentiform nucleus, and caudate nucleus). The fasting group demonstrated a consistent reduction in phase values across all DGM structures, contrasted with stable or rising values in non-fasting controls in all structures except the thalamus. Case studies also revealed phase value reductions during successive fasting, which reversed during non-fasting periods. The findings highlight the dynamic nature of susceptibility-based phase values over relatively short time periods, which may reflect metabolic influences on brain iron homeostasis and iron accumulation in MS. A key feature of phase contrast measurements is that they can remain relatively stable provided that the product of the field strength and echo time is kept constant, assuming consistent head geometry relative to the main magnetic field. In this study, only one scanner was used for all acquisitions, and the authors mitigated orientation-dependence by aligning slices to the AC–PC line; therefore, inter-system variability was minimized. The inclusion of a non-fasting control group and longitudinal data further reduces the possibility that observed changes are due to measurement instability. However, while the authors utilized scanner-generated phase images, the specific filtering parameters used to remove background field inhomogeneities were not detailed, a methodological factor that can influence the absolute quantification of phase values. It is also important to note that phase images, unlike QSM, suffer from non-local field effects. A phase shift in a specific voxel can be influenced by magnetic sources outside that voxel (the dipole effect), meaning phase values are not a direct, local quantification of tissue magnetic susceptibility. Furthermore, whether these changes reflect true parenchymal net iron depletion versus systemic iron redistribution remains unresolved. The interpretive challenge is further complicated by the multifactorial nature of susceptibility-weighted phase contrast. While SWI-filtered phase imaging is often interpreted as a semi-quantitative measure of tissue iron, it integrates non-iron phase effects from multiple sources, including myelin content, local susceptibility anisotropy, deoxyhemoglobin concentration and hydration status 9. Ramadan fasting induces well-documented physiological changes, including hemoconcentration and mild dehydration, with increases in hematocrit, hemoglobin and plasma osmolality 10, potentially confounding iron-specific interpretation of phase values. Nevertheless, this study presents a timely illustration of the sensitivity of DGM phase measurements to short-term metabolic states. By demonstrating directionally consistent changes across multiple DGM structures, this work presents an important foundation for future integrated studies aimed at evaluating iron-related imaging biomarkers. To maximize the potential of susceptibility imaging, future investigations should consider multimodal protocols incorporating QSM, which eliminates non-local dipole effects and provides a more accurate quantification of tissue susceptibility, alongside myelin-sensitive imaging, and diffusion and perfusion metrics. Together with concurrent assessment of serum/CSF iron indices and hematological parameters, this would enable the systematic characterization of short-term dynamic changes in DGM iron and associated demyelination-related, hemodynamic, or metabolic susceptibility effects.
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