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Numerous studies have highlighted the potential neurological advantages of exposing volunteers and animal models to light, sound, and tactile stimuli at the brain’s gamma frequency rhythm of 40Hz. Recent research from The Picower Institute for Learning and Memory and the Alana Down Syndrome Center at MIT revealed that sensory stimulation at this frequency can enhance cognition, improve neural connectivity, and promote neurogenesis in mice with a genetic model of Down syndrome.
Li-Huei Tsai, a Picower Professor at MIT and senior author of the study published in PLOS ONE, expressed optimism about the findings while emphasizing the need for further research to determine the applicability of the approach, known as GENUS (Gamma Entrainment Using Sensory Stimulation), for clinical use in individuals with Down syndrome. Tsai’s lab is initiating a pilot study involving human participants at MIT.
“This research marks the first demonstration of GENUS’s positive impact on Down syndrome, yet we must remain cautious since there is no current evidence to confirm its efficacy in humans,” noted Tsai, who leads The Picower Institute and The Alana Center and is a member of MIT’s Brain and Cognitive Sciences faculty.
Nonetheless, she asserted that the findings bolster the idea that GENUS may elicit a broad, restorative neurological response to various health challenges. While most prior GENUS studies focused on Alzheimer’s disease, others have indicated potential benefits for conditions like “chemo brain” and stroke.
Potential Benefits for Down Syndrome
The research team, led by postdoc Md Rezaul Islam and former graduate student Brennan Jackson, utilized the Ts65Dn mouse model, which mimics crucial aspects of Down syndrome but does not completely replicate the human experience, which stems from an additional copy of chromosome 21.
In initial experiments, the team found that an hour of daily exposure to 40Hz light and sound over three weeks led to notable improvements in performance on three standard short-term memory assessments, including tasks that required recognizing familiar versus novel stimuli and spatial navigation. As these memory tasks engage the hippocampus, the researchers observed a marked increase in activity indicators in mice receiving GENUS stimulation compared to those that did not.
To unravel the mechanisms behind the cognitive enhancements, the researchers examined how the gene expression profiles of hippocampal cells were altered. Using single-cell RNA sequencing, they analyzed the transcription activity of nearly 16,000 individual neurons and other cell types. They found significant variations in gene expression linked to the formation and organization of synapses between stimulated and unstimulated mice.
Further investigation into the hippocampus revealed that GENUS-stimulated mice had a significantly higher number of synapses in a crucial subregion known as the dentate gyrus.
In-Depth Analysis
The team assessed not only individual gene expression but also the coordinated patterns across multiple genes. They identified several “modules” of co-expression, reinforcing the idea that stimulation at 40Hz correlated with improvements in synaptic connectivity. Additionally, they noted the importance of TCF4, a key transcription regulator crucial for neurogenesis.
The analysis indicated that TCF4 levels were lower in Down syndrome-afflicted mice, whereas GENUS stimulation increased TCF4 expression. Subsequent experiments confirmed that stimulated mice exhibited heightened neurogenesis compared to their unstimulated counterparts in the dentate gyrus. While these findings indicate only a correlation, the researchers surmise that enhanced neurogenesis may account for some cognitive improvements observed.
“The increase in functionally connected synapses in the dentate gyrus is likely linked to the rise in adult neurogenesis following GENUS treatment in Down syndrome mice,” stated Islam.
This study represents the first documentation of GENUS’s association with increased neurogenesis.
Analysis of the gene expression modules revealed that a cluster of genes usually decreasing in expression due to aging or Alzheimer’s disease maintained higher levels in mice subjected to 40Hz stimulation. Moreover, these mice retained more Reelin-expressing cells in the hippocampus, a type of neuron particularly vulnerable in Alzheimer’s yet associated with cognitive resilience. Notably, around 90% of individuals with Down syndrome develop Alzheimer’s, typically after turning 40.
“Our study indicates that GENUS increases the proportion of Reelin-expressing neurons in the hippocampus of a Down syndrome mouse model, suggesting it may foster cognitive resilience,” elaborated Islam.
Collectively, these findings strengthen the emerging view that GENUS can stimulate cellular and molecular processes in the brain, promoting a homeostatic response to various pathogenic challenges such as neurodegeneration in Alzheimer’s, demyelination in chemo brain, or impaired neurogenesis in Down syndrome.
However, the authors acknowledged limitations within the study. The Ts65Dn model does not fully encapsulate human Down syndrome, and the research was conducted solely with male mice. Additionally, the cognitive evaluations were limited to short-term memory assessments, and the study did not explore alterations in other essential brain regions like the prefrontal cortex.
Alongside Jackson, Islam, and Tsai, the research team included Maeesha Tasnim Naomi, Brooke Schatz, Noah Tan, Mitchell Murdock, Dong Shin Park, Daniela Rodrigues Amorim, Fred Jiang, S. Sebastian Pineda, Chinnakkaruppan Adaikkan, Vanesa Fernandez, Ute Geigenmuller, Rosalind Mott Firenze, Manolis Kellis, and Ed Boyden.
The research was funded by the Alana Down Syndrome Center at MIT and the Alana USA Foundation, along with contributions from the National Science Foundation, the “la Caixa” Banking Foundation, an EMBO long-term postdoctoral fellowship, and individual donors.
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