Hamed Zaer1, Wei Fan2, Dariusz Orlowski1, Andreas N Glud1, Morten B Jensen3, Esben S Worm3, Slávka Lukacova3, Trine W Mikkelsen1, Lise M Fitting1, Liisa M Jacobsen1, Thomas Portmann4, Jui-Yi Hsieh4, Christopher Noel4, Georg Weidlich5, Woody Chung5, Patrick Riley5, Cesare Jenkins5, John R Adler6, M Bret Schneider7, Jens Christian H Sørensen1, Albrecht Stroh8. 1. Centre for Experimental Neuroscience (Cense), Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. 2. Leibniz Institute for Resilience Research, Mainz, Germany. 3. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Oncology & Radiation Therapy, Aarhus University Hospital, Aarhus, Denmark. 4. NeuCyte, Inc, San Carlos, CA, USA. 5. Zap Surgical Systems, Inc, San Carlos, CA, USA. 6. Zap Surgical Systems, Inc, San Carlos, CA, USA; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. 7. Zap Surgical Systems, Inc, San Carlos, CA, USA; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. 8. Leibniz Institute for Resilience Research, Mainz, Germany; Institute for Pathophysiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. Electronic address: albrecht.stroh@unimedizin-mainz.de.
Abstract
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.
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.