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Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). 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. 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. We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS. • Single dose of 40 Gy radiation did not cause apparent necrosis in minipig's brain. • Single dose of 40 Gy radiation increased spontaneous firing rate in visual cortex. • Single dose of 40 Gy radiation shortened the peak time of visual evoked potential. • Inhibitory neurons were more sensitive to irradiation than excitatory neurons. • A circuit-wide, long-lasting modulation effect of low sub-ablative doses of SRS. [ABSTRACT FROM AUTHOR]

Background Therapeutic repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a standard of care for individuals with major depressive disorder (MDD) who do not benefit from, or are unable to tolerate, antidepressant pharmacotherapy. Depth of stimulation is limited with currently approved figure-eight coils and larger coils capable of deeper penetration may be associated with loss of stimulation focality and undesired recruitment of motor cortex. A second generation 2-coil array rTMS system was designed to target converging brain pathways for potentially deeper prefrontal cortex stimulation. Methods A randomized, double-blind, sham-controlled trial examined the safety and efficacy of an investigational 2-coil rTMS device. Antidepressant treatment-resistant or treatment-intolerant MDD patients (n = 92) received 20 daily rTMS treatments with coil centers positioned over left dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC). 10 Hz stimulation (maximum summated power for both coils ≤ 120% motor threshold) was delivered. Primary efficacy endpoint was change in HAMD-24 score from baseline to the conclusion of treatments. Results Data from n = 75 (per-protocol sample) showed significantly greater improvement (mean HAMD-24 change) over time for the active (n = 38) versus sham (n = 37) group after 20 sessions (F = 7.174; p = 0.008) and also at the one-month follow-up (F = 6.748; p = 0.010). Response rates were 55.3% (active) versus 32.4% (sham) (p = 0.063); remission rates were 26.3% versus 18.9% (p > 0.05). Other secondary outcomes were generally supportive. Conclusions The results confirmed safety and acute efficacy of the 2-coil rTMS device. Despite modest sample size, primary outcome was clinically and statistically significant, and the effect size was comparable with those reported for regulatory trials with FDA-cleared devices. [ABSTRACT FROM AUTHOR]