Spreading the Word on a Possible Alzheimer’s Treatment

[Internetado]

Discoveries that transcend boundaries are among the greatest delights
of scientific research, but such leaps are often overlooked because
they outstrip conventional thinking. Take, for example, a new discovery
for treating dementia that defies received wisdom by combining two
formerly unrelated areas of research: brain waves and the brain’s
immune cells, called microglia. It’s an important finding, but it still
requires the buy-in and understanding of researchers to achieve its
true potential. The history of brain waves shows why.

In 1887, Richard Caton announced his discovery of brain waves at a
scientific meeting. “Read my paper on the electrical currents of the
brain,” he wrote in his personal diary. “It was well received but not
understood by most of the audience.” Even though Caton’s observations
of brain waves were correct, his thinking was too unorthodox for others
to take seriously. Faced with such a lack of interest, he abandoned his
research and the discovery was forgotten for decades.

Flash forward to October 2019. At a gathering of scientists that I
helped organize at the annual meeting of the Society for Neuroscience
in Chicago, I asked if anyone knew of recent research by
neuroscientists at the Massachusetts Institute of Technology who had
found a new way to treat Alzheimer’s disease by manipulating microglia
and brain waves. No one replied.

I understood: Scientists must specialize to succeed. Biologists
studying microglia don’t tend to read papers about brain waves, and
brain wave researchers are generally unaware of glial research. A study
that bridges these two traditionally separate disciplines may fail to
gain traction. But this study needed attention: Incredible as it may
sound, the researchers improved the brains of animals with Alzheimer’s
simply by using LED lights that flashed 40 times a second. Even sound
played at this charmed frequency, 40 hertz, had a similar effect.


Today, brain waves are a vital part of neuroscience research and
medical diagnosis, though doctors have never manipulated them to treat
degenerative disease before now. These oscillating electromagnetic
fields are produced by neurons in the cerebral cortex firing electrical
impulses as they process information. Much as people clapping their
hands in synchrony generate thunderous rhythmic applause, the combined
activity of thousands of neurons firing together produces brain waves.

These waves come in various forms and in many different frequencies.
Alpha waves, for example, oscillate at frequencies of 8 to 12 hertz.
They surge when we close our eyes and shut out external stimulation
that energizes higher-frequency brain wave activity. Rapidly
oscillating gamma waves, which reverberate at frequencies of 30 to 120
hertz, are of particular interest in Alzheimer’s research, because
their period of oscillation is well matched to the
hundredth-of-a-second time frame of synaptic signaling in neural
circuits. Brain waves are important in information processing because
they can influence neuronal firing. Neurons fire an electrical impulse
when the voltage difference between the inside and outside of the
neuron reaches a certain trigger point. The peaks and troughs of
voltage oscillations in brain waves nudge the neuron closer to the
trigger point or farther away from it, thereby boosting or inhibiting
its tendency to fire. The rhythmic voltage surging also groups neurons
together, making them fire in synchrony as they “ride” on different
frequencies of brain waves.

I already knew that much, so to better understand the new work and its
origins, I sought out Li-Huei Tsai, a neuroscientist at MIT. She said
the idea of using one of these frequencies to treat Alzheimer’s came
from a curious observation. “We had noticed in our own data, and in
that of other groups, that 40-hertz rhythm power and synchrony are
reduced in mouse models of Alzheimer’s disease,” she said, as well as
in patients with the disease. Apparently, if you have Alzheimer’s, your
brain doesn’t produce strong brain waves in that particular frequency.
In 2016, her graduate student Hannah Iaccarino reasoned that perhaps
boosting the power of these weakened gamma waves would be helpful in
treating this severe and irreversible dementia.

To increase gamma wave power, the team turned to optogenetic
stimulation, a novel technique that allows researchers to control how
and when individual neurons fire by shining lasers directly into them,
via fiber-optic cables implanted in the brain. Tsai’s team stimulated
neurons in the visual cortex of mice with Alzheimer’s, making them fire
impulses at 40 hertz. The results, published in 2016 in Nature, showed
a marked reduction in amyloid plaques, a hallmark of the disease.


It was a good indication that these brain waves might help, but Tsai’s
team knew that an optogenetic approach wasn’t an option for humans with
the disease, because of ethical concerns. They began to look for other
ways of increasing the brain’s gamma wave activity. Tsai’s MIT
colleague Emery Brown pointed her to an older paper showing that you
can boost the power of gamma waves in a cat’s brain simply by having it
stare at a screen illuminated by a strobe light flickering at certain
frequencies, which included 40 hertz. “Hannah and our collaborators
built a system to try that sensory stimulation in mice, and it worked,”
Tsai told me. The thinking is that the flashing lights whip up gamma
waves because the rhythmic sensory input sets neural circuits “rocking”
at this frequency, like when people rock a stuck car out of a rut by
pushing together in rhythm.

In fact, the strobe lights had an additional effect on mice: They also
cleared out amyloid plaques. But it wasn’t clear exactly how the
optogenetic stimulation or the flashing-light therapy could do that.

Following a clue from Alois Alzheimer himself, the researchers quickly
shifted their attention from neurons to microglia. In Alzheimer’s first
description of brain tissue taken from patients with “presenile
dementia,” which he examined under a microscope near the turn of the
20th century, he noted that the deposits of amyloid plaques were
surrounded by these immune cells. Subsequent research confirmed that
microglia engulf the plaques pockmarking these patients’ brains.

Tsai and colleagues decided to check out these immune cells in the
animals whose brain waves they’d boosted. They observed that microglia
in all the treated animals had bulked up in size, and more of them were
digesting amyloid plaques.

How did these cells know to do this? Unlike immune cells in the
bloodstream, which are unaware of neuronal transmissions, the brain’s
microglia are tuned in to the rhythms of electrical activity in the
brain. While immune cells in the bloodstream and microglia in the brain
both have cellular sensors to detect disease and injury, microglia can
also detect neurons firing electrical impulses. That’s because they
have the same neurotransmitter receptors that neurons use to transmit
signals through synapses. This gives microglia the ability to “listen
in” on information flowing through neural networks and, when those
transmissions are disturbed, to take action to repair the circuitry.
Thus, the right brain waves can drive microglia to consume the toxic
protein deposits.

“I find this intersection to be one of the most exciting and intriguing
results of our work,” Tsai told me. Her team reported last year in
Neuron that prolonging the LED strobe-light flashing for three to six
weeks not only cleared out the toxic plaques in mice brains but also
prevented neurons from dying and even preserved synapses, which
dementia can destroy.

The team wanted to know if other types of rhythmic sensory input could
also rock the neural circuits like a stuck car, producing gamma waves
that resulted in fewer amyloid plaques. In an expanded study in Cell,
they reported that just as seeing flashes at 40 hertz resulted in fewer
plaques in the visual cortex, sound stimulation at 40 hertz reduced
amyloid protein in the auditory cortex. Other regions were similarly
affected, including the hippocampus — crucial for learning and memory —
and the treated mice performed better on memory tests. Exposing the
mice to both stimuli, a light show synchronized with pulsating sound,
had an even more powerful effect, reducing amyloid plaques in regions
throughout the cerebral cortex, including the prefrontal region, which
carries out higher-level executive functions that are impaired in
Alzheimer’s.


I was amazed, so just to make sure I wasn’t getting unduly excited
about the possibility of using flashing lights and sounds to treat
humans, I talked to Hiroaki Wake, a neuroscientist at Kobe University
in Japan who was not involved with the work. “It would be fantastic!”
he said. “The treatment may also be effective for a number of
neurodegenerative disorders like Parkinson’s disease and ALS,” where
microglia also play a role. He notes, however, that while the link
between microglia and brain oscillations is well founded, the
biological mechanism by which 40-hertz stimulation prods microglia into
removing the plaques and rescuing neurons from destruction remains
unknown.

Tsai said the mystery may be solved soon. A team of researchers at the
Georgia Institute of Technology, including Tsai lab veteran Annabelle
Singer, laid out a possibility in a February paper. They reported that
in normal mice, gamma stimulation with LED lights rapidly induced
microglia to generate cytokines, proteins that neurons (and immune
cells generally) use to signal one another. They’re one of the main
regulators of neuroinflammation in response to brain injury and
disease, and the microglia released them surprisingly quickly, within
just 15 to 60 minutes of the stimulation. “These effects are faster
than you see with many drugs that target immune signaling or
inflammation,” Singer said.

Cytokines come in many forms, and the study found that getting the
microglia to produce different kinds required specific frequencies.
“Neural stimulation doesn’t just turn immune signaling on,” Singer
said. It took a particular rhythm to produce these particular proteins.
“Different types of stimulation could be used to tune immune signaling
as desired.”

That means doctors could potentially treat different diseases just by
varying the light and sound rhythms they use. The different stimuli
would rock the neurons into producing appropriate brain wave
frequencies, causing nearby microglia to release specific types of
cytokines, which tell microglia in general how to go to work repairing
the brain.


Of course, it may still be a while before such treatments are available
for patients. And even then, there may be side effects. “Rhythmic
sensory stimulation likely affects many types of cells in brain
tissue,” Tsai said. “How each of them senses and responds to gamma
oscillations is unknown.” Wake also pointed out that rhythmic
stimulation could do more harm than good, because such stimuli could
induce seizures, common in many psychiatric and neurodegenerative
disorders.

Still, the potential benefits are great. Tsai’s team has just begun
assessing their strobe-light method on patients, and they’re sure to be
joined by others as more researchers learn of this promising work.
(Most experts I talked to were not aware of this research until I
asked.)

Just as new species spring up at the boundaries between ecosystems, new
science can flourish at the interface between disciplines. It takes a
sharp eye to spot it, but as Richard Caton found, it can also require a
bit of persuasion to convince others.

https://www.quantamagazine.org/stimulated-brain-waves-offer-a-possible-treatment-for-alzheimers-20200527/

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Eduardo