Non-ablative doses of focal ionizing radiation alters function of central neural circuits

• Main Authors: Adler, J.R., Jr (Author), Chung, W. (Author), Fan, W. (Author), Fitting, L.M (Author), Glud, A.N (Author), Hsieh, J.-Y (Author), Jacobsen, L.M (Author), Jenkins, C. (Author), Jensen, M.B (Author), Lukacova, S. (Author), Mikkelsen, T.W (Author), Noel, C. (Author), Orlowski, D. (Author), Portmann, T. (Author), Riley, P. (Author), Schneider, M.B (Author), Sørensen, J.C.H (Author), Stroh, A. (Author), Weidlich, G. (Author), Worm, E.S (Author), Zaer, H. (Author)
• Format: Article
• Language: English
• Published: Elsevier Inc. 2022
• Subjects: Minipig; Neuromodulation; Spontaneous firing rate; Stereotactic radiosurgery; Visual cortex; Visual evoked potential
• Online Access: View Fulltext in Publisher
• Physical Description: 12
• ISBN: 1935861X (ISSN)
• DOI: 10.1016/j.brs.2022.04.001

Background: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. Objective: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). Methods: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. Results: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. Conclusion: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS. © 2022 The Authors