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BACKGROUND This study examines the efficacy of biologically guided dose painting in Gamma Knife stereotactic radiosurgery (GKSRS) to improve radiographic response in patients with recurrent high-grade gliomas by increasing radiation dosage in functionally active tumor subregions identified through magnetic resonance spectroscopy (MRS) and T1-weighted perfusion magnetic resonance imaging (T1-PMRI). MATERIAL AND METHODS In this single-arm cohort of patients (n=23) with recurrent high-grade glioma, all patients previously treated with surgery, chemotherapy, and fractionated radiotherapy underwent GKSRS. Functional imaging (MRS and T1-weighted PMRI) delineated metabolically active ("aggressive") and less active ("passive") tumor regions. A modified radiosurgery plan prescribed 18 Gy to aggressive and 15 Gy to passive zones. For intra-patient comparison, a uniform-dose plan (plan 1, 16 Gy) was generated but not delivered. All statistical analyses were performed in Python 3.11 (SciPy-v1.11, statsmodels-v0.14, lifelines-v0.28) executed in Visual Studio Code 1.88 (Microsoft). RESULTS Across 23 patients, plan 2 vs plan 1 showed no significant change in whole-brain mean dose (P=0.716), integral dose (P=0.792), or V12 (P=0.583). Among 11 patients with follow-up imaging, K-trans decreased significantly (median, -18%; P=0.028; Wilcoxon) with a trend for initial area under the gadolinium concentration-time curve (IAUC; median, -22%; P=0.031 for table; overall P=0.08 for initial under curve analysis). Higher baseline K-trans correlated with greater K-trans reduction (r=-0.84, P=0.0012). CONCLUSIONS Using advanced MRI techniques (accounting for K-trans and IAUC on T1-PMRI, and MRS) to determine aggressive zones in salvage treatment for recurrent high-grade gliomas, and then focusing radiotherapy on these zones, can increase Gamma Knife efficiency without increasing the morbidity rate.