Friberg, A. | Search bioRxiv

bioRxiv2026

Fractionated proton and photon FLASH irradiation mitigates radiation-induced lymphopenia through kinetic sparing of circulating lymphocytes

Background and purpose: Radiation-induced lymphopenia is associated with adverse outcomes in thoracic malignancies. FLASH radiotherapy delivers radiation over a timescale of hundreds of milliseconds, potentially reducing the fraction of irradiated circulating lymphocytes. In this study, we investigated whether FLASH mitigates lymphopenia after thoracic irradiation delivered with protons or photons. Materials and methods: C57BL/6 mice received three 13.5-Gy whole-heart fractions at 48-hour intervals using FLASH or standard dose-rate proton irradiation at the University of Pennsylvania (n=15), with photon validation at Queen's University Belfast (n=72). Leukocytes and CD4 T cells, CD8 T cells, B cells, and NK cells were quantified by hemocytometer and flow cytometry. A continuous-time Markov model simulated lymphocyte trafficking, dose accumulation, and post-irradiation recovery. Results: FLASH attenuated leukocyte depletion across both proton and photon irradiation modalities. In the proton cohort, white blood cell counts were significantly higher after FLASH at D1, D3, D7, and D14; CD4 T cells and NK cells were preserved through D14, while CD8 T cell sparing persisted through D21. Photon FLASH preserved CD45 leukocytes at D1, D3, D7, and D21, with sustained CD8 sparing at D21. Modeling showed that FLASH shifted the lymphocyte dose distribution toward lower exposures, increasing the proportion of lymphocytes receiving <1 Gy from 2.4% to 16.4%, and reduced the proportion of lymphocytes repeatedly irradiated across all three fractions from 36.3% at standard dose rate to 9.18%, despite similar median cumulative doses. The spleen contributed substantially to cumulative lymphocyte dose, and marrow-entering lymphocytes displayed a more high-dose-enriched distribution after FLASH irradiation. Conclusion: FLASH consistently mitigated radiation-induced lymphopenia for proton and photon modalities, with durable CD8 T cell preservation. These findings support a kinetic mechanism and provide a rationale for combining FLASH radiotherapy with immune-sparing planning and immunotherapy.

cell biology↗

bioRxiv2019

Enhanced insular connectivity with speech sensorimotor regions in trained singers: a resting-state fMRI study

The insula contributes to the detection of salient events during goal-directed behavior and participates in the coordination of motor, multisensory, and cognitive systems. Recent task-fMRI studies with trained singers suggest that singing experience can enhance the access to these resources. However, the long-term effects of vocal training on insula based networks are still unknown. In this study, we employed resting-state fMRI to assess experience-dependent differences in insula co-activation patterns between conservatory-trained singers and non-singers. Results indicate enhanced bilateral insula connectivity in singers relative to non-singers with constituents of the speech sensorimotor network in both hemispheres. Specifically, with the cerebellum (lobule VI, crus 2), primary somatosensory cortex, the parietal lobes, and the thalamus. Furthermore, singing training predicted enhanced bilateral co-activation of primary sensorimotor areas representing the larynx (with left dorsal anterior insula, dAI) and the diaphragm (with bilateral dAI)--crucial regions for cortico-motor control of complex vocalizations, as well as the thalamus (with bilateral posterior insula/left dAI) and the left putamen (with left dAI). Together, these data support a crucial role of the insula in respiratory and laryngeal control and suggest that singing experience enhances the integration of somatosensory information within the speech motor system, perhaps by strengthening salient associations of bodily signals associated with conscious and non-conscious aspects of expressive language production within a musical framework.

neuroscience↗