One of this blog’s more frequent and thoughtful readers/commenters, “Mauraelisabeth3,” has asked a good question about the possibility auditory and visual sensory gamma-frequency stimulation as a treatment for PSP.  I responded by promising a blog post on the subject, and here it is:

As always, some scientific background first:  An electroencephalogram (EEG) is a recording of electrical waves emanating from the surface of the brain, as measured by wires pasted to the scalp.  The various brain waves are classified by their frequencies.  The ones relevant to ordinary patient care range from the slowest (i.e., lowest frequency), called “delta,” at 1-4 cycles per second (or “Hertz” or “Hz), to “theta” (4-8 Hz), “alpha” (8-13 Hz) and “beta” (13-30 Hz).  Most of the EEG activity in a healthy, relaxed but awake adult with eyes closed is alpha, and with increasing alertness or with eye opening, there’s more beta.  Theta and delta are important in normal sleep and in many kinds of brain diseases. 

But there’s a higher frequency called “gamma,” which can be found mainly in deeper areas of the brain not usually detected by routine EEG, or if it is detected, it’s hard to distinguish from artifact caused by scalp muscle activity.  It turns out that in people with Alzheimer’s disease, there’s a reduction in gamma activity in the areas deep in the brain that are the headquarters of the memory problem. 

Now to the matter at hand:  There’s a way to “entrain” the EEG activity of those memory-related areas to increase their gamma activity.  An AD mouse model called 5XFAD (with 5 mutations in 2 genes relevant to AD: amyloid precursor protein and presenilin 1) improves in multiple ways after such stimulation, including reducing its load of beta-amyloid, the main component of the amyloid plaques of AD.  A mouse with a mutated form of the tau protein shows improvement in some measures as well, and tau, of course, is the protein central to PSP. Here’s a technical review article on the topic, but it’s from 2018.

A company called Cognito Therapeutics, based in Cambridge, MA, was started by scientists at MIT who have performed much of the early lab work.  So far, the company has sponsored one small, controlled trial showing some improvement in people with AD, but it’s not published other than in very cursory form on the company’s website.  A year ago, in December 2022, Cognito started a Phase 3 trial in AD, meaning a large trial of the sort that, if successful, could win FDA approval for the device for AD.  It’s scheduled to conclude in 2025.  For one hour a day, participants wear glasses flashing a light at 40 Hz (the most relevant point in the gamma range) and headphones playing a tone at the same frequency.  A 40 Hz flash is just barely perceptible as flashing (50 Hz is the standard “fusion frequency”) and a 40 Hz tone is a low rumble.

Some caveats about the treatment: 

• The most recent literature I found is far from unanimous on whether AD consistently has reduced gamma activity in relevant brain regions, and I found no evidence at all that PSP does. 
• Although the small clinical trial to date found no adverse effects, there is evidence from the mouse experiments that the gamma stimulation increases the activity of the microglia, the brain’s main inflammatory cells.  That could be a good thing if it enhances the scavenging of unwanted, aggregation-prone protein. But it could be a bad thing if it aggravates the inflammation thought to comprise an important part of the pathogenetic process in many neurodegenerative diseases, including AD and PSP.
• In the few clinical trials to date, an hour’s stimulation provides only about one day of measurable benefit.  Such a regimen might prove impractical in the real world.

Bottom line:  Would I recommend volunteering for a trial of 40-Hz sensory stimulation in PSP . . .

• . . . if some more lab data in mice, or very early phase human data supported the benefit and safety of such a treatment in PSP, and
• . . . if such a trial fully communicated the scientific uncertainties and safety concerns? 

Yes, I probably would.

Keep in mind that devices producing 40-Hz light and/or sound are already commercially available as meditation aids.  No clue here if they help, harm or neither, but until I know more, I’ll categorize them along with all the other placebos out there.