TITAN TEMPORAL INTERFERENCE AND TWIN-AUGMENTED NEUROMODULATION FOR ENHANCING MEMORY FORMATION
This project brings together expertise in systems and computational neuroscience to develop innovative, knowledge-based neuromodulation strategies aimed at improving cognitive abilities, specifically memory formation. Building on our previous AEI-funded project, we propose the use of Temporal
Interference (TI), a novel technique that enables selective stimulation of deep brain regions while minimizing activation of superficial areas. The research
will be conducted in animal models (rodents), leveraging our combined expertise in experimental and computational neuroscience to design and refine
these interventions. Additionally, we will apply the concept of Digital Twins to personalize neuromodulation approaches and address interindividual
variability, laying the groundwork for future translational applications.
Our research has significant implications for neurology and psychiatry, addressing conditions such as Parkinsons disease, depression, substance
addiction, and OCD. TI represents a transformative advance in non-invasive neuromodulation due to its ability to stimulate almost any brain region,
including deep structures. Unlike invasive techniques such as DBS or non-invasive methods like tACS, DCS, and TMS, which face limitations in depth
and specificity, TI offers a more efficient and accessible alternative. The project integrates experimental findings and computational models to iteratively
refine stimulation protocols, addressing off-target effects and improving efficacy.
A central aspect of the proposal is the modulation of the excitation/inhibition (E/I) balance and the regulation of connectivity between key brain regions
involved in memory, such as the dentate gyrus (DG), hippocampus, nucleus accumbens (NAc), and prefrontal cortex (PFC). Experimental studies in
rodents have shown that modifying the E/I balance in the DG promotes functional connectivity among memory-related structures, enhancing memory
formation. It was also demonstrated that deep brain stimulation of the NAc reorganizes mesocorticolimbic circuits, facilitating long-term memory
encoding. These findings underpin the design of TI protocols, such as TI-E/I to target the DG, TI-NAc to modulate the NAc, and TI-CTC to enhance
hippocampus-PFC communication. These strategies will enable simultaneous stimulation of multiple brain areas, overcoming the limitations of unifocal
neuromodulation.
The project also aims to conceptualize and validate brain Digital Twins as a tool to address interindividual variability. Using advanced brain imaging
techniques, we will develop Digital Twins in rodents as a proof of concept to refine and test neuromodulation procedures *in silico*. This innovation has
the potential to revolutionize neuromodulation by enabling personalized interventions and advancing toward human Digital Twins for clinical applications.
TI, as a non-invasive, precise, and scalable technique, could democratize access to advanced neuromodulation therapies. The knowledge-based
approaches proposed here represent a paradigm shift, moving beyond trial-and-error methods toward scientifically grounded strategies with significant
translational potential.
Investigadores
Raul de Palma
Catharina E. Graafland