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The human brain is the most sophisticated and the finest processing unit ever designed, but mental and neurological disorders are an imminent threat to its functioning.Indeed, brain disorders comprise one of the most challenging health issues of modern society due to their tremendous health, social, and economic impact.However, pharmacological therapies face a physical obstacle e the blood-brain barrier (BBB) -that impedes most biopharmaceuticals from reaching brain tissues and thus blocks their efficiency.For this reason, researchers have been recently focusing on alternative, non-invasive, and drug-free therapeutic strategies to restore the healthy functionality and mechanobiology of the brain.Among these, non-invasive and natural-based therapeutic strategies such as transcranial photobiomodulation (tPBM, i.e., the application of modulated red/NIR light for therapeutic purposes) and ultrasound stimulation (tUS) are at the forefront of clinical interventions with the potential to improve different neuropathologies and the behavioral decline that typically accompanies neurodegeneration.These therapeutic stimuli have been proven to improve the metabolic activity of brain cells (including neurons and glia), block neuropathological mechanisms, alter the permeability of the BBB, among many others neuroprotective effects.However, these therapeutic solutions face four common barriers that hinder their wide clinical use: (1) limited knowledge of the optimal stimulation pattern; (2) insufficiently personalized stimulation; (3) limited access to deep brain structures; (4) poor stimulation selectively and spatial coverage.These barriers are a consequence of the insufficient understanding on how optical and ultrasonic waves interact with the brain and surrounding tissues and the bioavailability of the stimulus in targeted deep brain regions.For this reason, we believe that the development and optimization of optomechanical tools to mitigate neurodegeneration and stimulate brain activity require a holistic and integrated approach involving experimental, in silico, and in vitro models, from which efficient, customized, and innovative transcranial stimulation therapies may arise.