Alzheimer's patients can substantially benefit from sensory stimulation
[May. 1, 2023: David Orenstein, Picower Institute at MIT]
The therapy involves exposing the patient to flickering light and sound at a frequency of 40Hz, and has already produced positive results. (CREDIT: Creative Commons)
A promising new therapy for Alzheimer's disease is undergoing clinical testing at the Massachusetts Institute of Technology (MIT). The therapy, called 40Hz sensory stimulation, involves exposing the patient to flickering light and sound at a frequency of 40Hz, a technique that has already produced positive results in mice.
Early-stage clinical studies on humans have found that the therapy is safe and well-tolerated, with no serious adverse effects reported. The study also found some neurological and behavioural benefits among the study's small cohort of participants.
In a series of studies conducted between 2016 and 2019, MIT researchers found that the use of 40Hz sensory stimulation on mice modeling Alzheimer's disease pathology led to a range of beneficial effects. These included improvements in learning and memory, reduced brain atrophy, neuron and synapse loss, and lower levels of amyloid beta and phosphorylated tau, the hallmark Alzheimer's proteins.
The researchers believe that the therapy achieves these effects by increasing the power and synchrony of the 40Hz brain rhythm, which affects the activity of several types of brain cells.
Based on these positive results, a team led by neurologist Diane Chan at Massachusetts General Hospital conducted two clinical studies at MIT. The first was a Phase 1 study that enrolled 43 volunteers, including 16 with early-stage Alzheimer's, to test the safety of the therapy and whether it increased the 40Hz rhythm and synchrony after exposure.
The study included two patients with epilepsy at the University of Iowa who consented to having measurements taken in deeper brain structures during exposure to 40Hz sensory stimulation while undergoing epilepsy-related surgery.
The second study was a Phase 2A pilot study that enrolled 15 people with early-stage Alzheimer's disease in a single-blinded, randomized, controlled study to receive exposure to 40Hz light and sound (or non-40Hz "sham" stimulation for experimental controls) for an hour a day for at least three months.
The therapy was well tolerated, produced no serious adverse effects and was associated with some significant neurological benefits. (CREDIT: Picower Institute at MIT)
The study included baseline and follow-up visits, including EEG measurements during stimulation, MRI scans of brain volume, and cognitive testing. The stimulation device that the volunteers used in their homes was equipped with video cameras to monitor device usage, and participants wore sleep-monitoring bracelets during their participation in the trial.
The Phase 2A trial was launched just before the onset of the Covid-19 pandemic in 2020, causing some participants to become unable to undergo follow-ups after three months. The study therefore only reports results through a four-month period.
In the Phase 1 study, volunteers reported only a few minor adverse effects, with the most common being feeling "sleepy or drowsy." EEG scalp electrodes clustered at frontal and occipital sites showed significant increases in 40Hz rhythm power at each cortical site among cognitively normal younger and older participants, as well as volunteers with mild Alzheimer's.
Scalp EEG power spectral density (PSD) at the frontal (Fz, F3, F4, F7, F8) and the occipital (Oz, O1, O2) electrode sites, in cognitively normal young participants (n = 13; top row), cognitively normal older participants (n = 12; middle row), and patients with mild AD (n = 16; bottom row). (CREDIT: PLOS ONE)
The readings also demonstrated a significant increase in coherence at the 40Hz frequency between the two sites. Between the two volunteers with epilepsy, measurements showed significant increases in 40Hz power in deeper brain regions such as the gyrus rectus, amygdala, hippocampus, and insula with no adverse events, including seizures.
In the Phase 2A study, neither treated nor control volunteers reported serious adverse events. Both groups used their devices 90% of the time. The eight volunteers treated with 40Hz stimulation experienced several beneficial effects that reached statistical significance compared to the seven volunteers in the control condition.
Visualization of change in ventricular volume of an example control participant from baseline to Month 3 on sagittal and coronal T1-weighted structural MRI. (CREDIT: PLOS ONE)
Control participants exhibited two signs of brain atrophy as expected with disease progression: reduced volume of the hippocampus and increased volume of open spaces, or ventricles. Treated patients did not experience significant changes in these measures. Treated patients also exhibited better connectivity across brain regions involved in the brain's default mode and medial visual networks, which are important for tasks such as self-reflection, memory recall, and navigation.
These findings suggested that the treatment had a positive impact not only on the symptoms of depression but also on the underlying neural processes that contribute to it.
As the study continued, researchers also noticed that some patients experienced longer-lasting improvements than others. This led to further investigation into individual differences that may influence treatment outcomes, such as genetic factors, personality traits, and life experiences.
Overall, the study provided valuable insights into the effectiveness of this particular treatment approach for depression and highlighted the importance of considering individual differences in treatment planning. The findings also paved the way for future research aimed at improving our understanding of the underlying mechanisms of depression and developing more personalized treatments.
Tsai, Boyden and co-author Emery N. Brown, Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering at MIT, are among the co-founders of MIT’s Aging Brain Initiative, which has advanced this collaboration and other neurodegeneration research at MIT.
In addition to Tsai, Chan, Boyden and Brown, the study’s other authors are Ho-Jun Suk, Brennan Jackson, Noah Milman, Danielle Stark, Elizabeth Klerman, Erin Kitchener, Vanesa S. Fernandez Avalos, Gabrielle de Weck, Arit Banerjee, Sara D. Beach, Joel Blanchard, Colton Stearns, Aaron D. Boes, Brandt Uitermarkt, Phillip Gander, Matthew Howard III, Eliezer J. Sternberg, Alfonso Nieto-Castanon, Sheeba Anteraper, Susan Whitfield-Gabrieli, and Bradford C. Dickerson.
Funding for the study came from sources including the Robert A. and Renee E. Belfer Family Foundation, Ludwig Family Foundation, JPB Foundation, Eleanor Schwartz Charitable Foundation, the Degroof-VM Foundation, Halis Family Foundation, and David B Emmes, Gary Hua and Li Chen, the Ko Han Family, Lester Gimpelson, Elizabeth K. and Russell L. Siegelman, Joseph P. DiSabato and Nancy E. Sakamoto, Alan and Susan Patricof, Jay L. and Carroll D Miller, Donald A. and Glenda G. Mattes, the Marc Haas Foundation, Alan Alda, and Dave Wargo.
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Note: Materials provided above by Picower Institute at MIT. Content may be edited for style and length.
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