Biotechnology is driving the next generation in neuromodulation therapies for Parkinson's disease (PD), which is a progressive neurodegenerative disorder characterized by motor dysfunction due to the loss of dopaminergic neurons in the substantia nigra. While pharmacological therapies and Deep Brain Stimulation (DBS) are standard treatments, they often fail to fully address the non-motor impairments that significantly affect patients' quality of life. A novel therapeutic strategy integrating Focused Ultrasound Stimulation (FUS) with DBS, known as hybrid stimulation, has emerged as a promising approach. This combined modality leverages the continuous neuromodulation of DBS with the non-invasive, precise targeting of FUS, enhancing therapeutic efficacy through complementary mechanisms. DBS modulates neural firing patterns and promotes neuroplasticity, while FUS allows for precise, transient disruption of the brain barrier (BBB), enhances drug delivery, and induces localized neuro-thermal effects, potentially aiding neuroprotection and neurotransmitter regulation. This review critically evaluates the role of DBS and FUS in PD treatment, focusing on the need for a hybrid DBS-FUS approach. We highlight emerging preclinical and clinical evidence of their synergistic effects in modulating dopamine synthesis, neurotransmitter dynamics, and synaptic remodeling. Furthermore, we present a computational bibliographic analysis to assess research trends, knowledge gaps, and the evolving impact of hybrid neuromodulation strategies, offering a comprehensive perspective on their potential to address both motor and non-motor symptoms of PD.

Division of Experimental Neurobiology Preclinical Research Program National Institute of Mental Health Topolová 748 250 67 Klecany Czech Republic

Faculty of Bioscience Department of Physiology and Biochemistry Shaheed Benazir Bhutto University of Veterinary and Animal Sciences Sakrand 67210 Pakistan

Faculty of Science Department of Animal Physiology Charles University Albertov 6 Prague 128 00 Czech Republic

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Noninvasive Focused Ultrasound as a Safe Modulator of Calcium-Dependent Neurochemical Signalling in Primary Cortical Cultures