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Description
Alzheimer’s disease (AD) is a neurodegenerative disease for which there is no cure. Decades of research have revealed the unique genetic, molecular and cellular pathology of AD. However, largely due to a lack of techniques enabling the precise measurement of neural circuit activity in vivo, we know little about how it affects the high-level processing that underlies cognitive functions such as memory and spatial navigation. To address this gap in knowledge, our first aim is to capitalize on recent technical developments in our labs to measure activity of thousands of neurons simultaneously in AD mice that are trained to perform a cognitive task. We will focus on a cortical area called the retrosplenial cortex (RSC), a key brain structure for memory and navigation and an early target of AD. A second aim is to test and further develop a novel and highly-promising therapy that significantly improves memory in mouse models of the disease. By presenting multisensory stimuli (visual and auditory) at 40 Hz to restore gamma oscillations in the cortex, this therapy (acronym: GENUS) reduces extracellular peptide aggregates and significantly improves cognition. We will use this therapy to test whether the improvements in cognition are mirrored by a restoration of relevant microcircuit function in RSC. A third major aim is to develop a new device, called GAMMAHEAL, to dynamically optimise the multisensory stimuli by using real-time feedback information from cortical rhythms. We will apply this closed-loop stimulation platform in mice and humans, and develop it such that, at project completion, it is ready to be applied in human AD patients.
Summary of project results
A New Frontier in Alzheimer’s Treatment
Alzheimer’s disease is a devastating neurodegenerative disorder that affects approximately 50 million people worldwide, with projections estimating that this number could rise to 153 million by 2050. Despite extensive research, the exact causes of Alzheimer’s remain unclear. One leading hypothesis suggests that toxic protein buildup in the brain disrupts neural circuits, causing neuronal cell death and progressive cognitive decline. While advances in diagnostics allow for earlier detection, effective treatments remain elusive. Current therapies primarily focus on managing symptoms and slowing disease progression, but they do not stop or reverse the underlying damage. Immunotherapy has shown some promise in clearing protein deposits, yet it comes with serious risks, including brain hemorrhage and edema, limiting its widespread use.
In response to this urgent medical need, researchers have developed GENUS (Gamma ENtrainment Using Sensory stimulation)—a promising, non-invasive therapy that uses pulses of light and sound at 40 Hz (40 pulses per second) to stimulate brain activity. By reinforcing the brain’s natural rhythms, GENUS has been shown to help clear toxic protein deposits and improve cognitive function. Currently undergoing clinical trials, this approach holds great potential as an early intervention for Alzheimer’s patients, offering a safer and likely more effective alternative to existing treatments.
Our project, CIRCUITGENUS, took this therapy one step further by making it personalized and adaptive. While GENUS traditionally relies on a fixed 40 Hz frequency, not all patients may respond optimally to the same stimulation pattern. Additionally, constant exposure to the same rhythm could lead to diminished effectiveness over time due to brain adaptation. CIRCUITGENUS addressed these limitations by developing a dynamic, closed-loop system that adjusts the stimulation frequency in real time, ensuring that patients receive the most effective and sustained therapeutic benefits.
Our innovative approach could make GENUS therapy significantly more effective, expanding its potential beyond Alzheimer’s disease to other neurological disorders, where brain rhythm disturbances play a role. As CIRCUITGENUS advances toward clinical application, it represents a significant step forward in the fight against Alzheimer’s, offering millions of patients and their families renewed hope for a future with better treatments and improved quality of life.
GAMMAHEAL: A Breakthrough in Non-Invasive Brain Stimulation
To advance Alzheimer’s treatment, a research team from the Transylvanian Institute of Neuroscience in Romania (TINS), led by Dr. Raul C. Mureșan, joined efforts with a top research group from University of Oslo (UiO), led by Dr. Koen Vervaeke. Together, we developed GAMMAHEAL, an innovative brain stimulation system that combines advanced hardware and an adaptive control algorithm. Unlike conventional fixed-frequency approaches, GAMMAHEAL dynamically adjusts stimulation based on real-time brain activity, ensuring maximum therapeutic impact. The system uses LED panels and sound pulses to deliver closed-loop stimulation, meaning it continuously fine-tunes its signals to match the brain’s needs.
Initially tested in rodents, GAMMAHEAL allowed us to study how the brain responds to both fixed-frequency and adaptive stimulation. Using invasive recordings, we gathered crucial data on brain dynamics, revealing that adaptive stimulation significantly enhances gamma oscillations—the brain waves associated with cognitive processing. When applied to humans, GAMMAHEAL successfully induced strong and sustained gamma oscillations without causing adaptation or fatigue, making it a highly promising non-invasive therapy for Alzheimer’s patients. With these promising results, our optimized therapy is now ready for clinical trials.
Beyond its immediate therapeutic potential, CIRCUITGENUS has led to unexpected scientific discoveries. We developed superlets analysis, a powerful technique now widely used in various scientific disciplines from Quantum Mechanics, to Material Science, Meteorology, Engineering, and even to track whales in the ocean.
Our research also revealed that rodents’ visual systems are particularly efficient at processing blue light, an insight that may inform future studies on sensory-driven brain stimulation. Additionally, we identified the retrosplenial cortex as a crucial hub that dynamically interacts with other brain circuits to compute spatial information and contribute to planning.
Perhaps one of our most exciting findings is the realization that fast brain oscillations play a key role in regulating cerebral blood flow. We named this mechanism GAMER (GAmma MEdiated ciRcuit maintenance) and published it in a prestigious international scientific journal. GAMER suggests that rhythm-based stimulation could have even broader implications, potentially benefiting not just Alzheimer’s patients but also individuals with stroke, vascular dementia, and other neurological conditions where blood flow regulation is critical.
Revolutionizing Alzheimer’s Treatment with CIRCUITGENUS
The CIRCUITGENUS project has achieved groundbreaking discoveries that bring us closer to effective, non-invasive treatments for Alzheimer’s disease. A major focus of our research was uncovering the role of the retrosplenial cortex (RSC)—a brain region that plays a critical role in memory, navigation, and planning. The RSC is a key component of the default-mode network, linking the hippocampus (which is central to memory) with the neocortex (involved in higher cognitive functions). While the RSC is essential for processing contextual memory, we discovered that it does not work alone in computing spatial information but rather collaborates with other brain areas, providing a more dynamic and integrated view of how memory and planning are implemented in the brain.
Building on these insights, we developed GAMMAHEAL, an innovative stimulation device that uses pulses of light and sound to enhance brain function. Unlike traditional stimulation devices, GAMMAHEAL allows for both fixed-frequency stimulation and adaptive closed-loop stimulation, meaning it can dynamically adjust to real-time brain activity to maximize effectiveness. This advanced approach has proven to be more efficient at generating gamma oscillations—specific brain waves associated with improved memory, cognition, and neural health.
The impact of CIRCUITGENUS extends far beyond treating Alzheimer’s. Individuals in the early stages of the disease could greatly benefit from this approach, as enhanced brain activity may help slow cognitive decline and improve quality of life. Elderly individuals at risk of memory loss may also find this therapy useful as a preventative measure to maintain cognitive health. The potential applications are not limited to Alzheimer’s alone; patients suffering from neurodegenerative diseases such as Parkinson’s disease, vascular dementia, and multiple sclerosis may also experience benefits from brain stimulation targeting gamma oscillations. Another promising avenue is stroke rehabilitation, as our discovery of the connection between gamma oscillations and cerebral blood flow suggests new ways to support brain recovery after an ischemic event.
Beyond direct patient benefits, CIRCUITGENUS has provided valuable tools for researchers and clinicians. The superlets technique, developed as part of this project, has already found applications across various scientific fields, offering a more precise method for analyzing brain activity but also proving to be a cutting-edge tool for investigation of physical and natural phenomena. Understanding how rhythmic brain activity influences cognition and neural function not only enhances current therapeutic approaches but also lays the foundation for the next generation of treatments for neurological and psychiatric disorders.
Summary of bilateral results
Our team has filed an international joint patent for GAMMAHEAL with the World International Property Organization (WIPO) in Geneva. We plan to further develop this technology, aiming for clinical validation and commercialization through a Romanian startup. This startup will collaborate with clinical partners to provide non-invasive, low-cost AD treatment, potentially reducing Romania’s innovation gap with the EU.CIRCUITGENUS has strengthened bilateral relations, continuing a tradition of collaboration between the Mureșan lab and Norwegian partners. The project has enhanced the partnership between the Mureșan and Vervaeke labs, combining engineering and data analysis expertise with experimental design and behavioural testing. This collaboration successfully developed a robust GAMMAHEAL stimulation methodology, and facilitated new partnerships, such as those with the Glia Lab in Oslo, but also labs in Hungary and Belgium in a consortium with the University of Oslo.