Due to past work, we’ve already identified the brain structure that controls the activity of the key vocal organ, the syrinx, located in the bird’s throat. The new study, done by Zetian Yang and Michael Long of New York University, managed to place fine electrodes into this area of the brain in both species and track the activity of neurons there while the birds were awake and going about normal activities. This allowed them to associate neural activity with any vocalizations made by the birds. For the budgerigars, they had an average of over 1,000 calls from each of the four birds carrying the implanted electrodes.
For the zebra finch, neural activity during song production showed a pattern that was based on timing; the same neurons tended to be most active at the same point in the song. You can think of this as a bit like a player piano central organizing principle, timing when different notes should be played. “Different configurations [of neurons] are active at different moments, representing an evolving population ‘barcode,’” as Yang and Long describe this pattern.
That is not at all what was seen with the budgerigars. Here, instead, they saw patterns where the same populations of neurons tended to be active when the bird was producing a similar sound. They broke the warbles down into parts that they characterized on a scale that ranged from harmonic to noisy. They found that the groups of neurons tended to be more active whenever the warble was harmonic, and different groups tended to spike when it got noisy. Those observations led them to identify a third population, which was active whenever the budgerigars produced a low-frequency sound.
In addition, Yang and Long analyzed the pitch of the vocalizations. Only about half of the neurons in the relevant region of the brain were linked to pitch. However, the half that was linked had small groups of neurons that fired during the production of a relatively narrow range of pitches. They could use the activity of as few as five individual neurons and accurately predict the pitch of the vocalizations at the time.
A specialized system sends pulses of pressure through the fluids in our brain.
Our bodies rely on their lymphatic system to drain excessive fluids and remove waste from tissues, feeding those back into the blood stream. It’s a complex yet efficient cleaning mechanism that works in every organ except the brain. “When cells are active, they produce waste metabolites, and this also happens in the brain. Since there are no lymphatic vessels in the brain, the question was what was it that cleaned the brain,” Natalie Hauglund, a neuroscientist at Oxford University who led a recent study on the brain-clearing mechanism, told Ars.
Earlier studies done mostly on mice discovered that the brain had a system that flushed its tissues with cerebrospinal fluid, which carried away waste products in a process called glymphatic clearance. “Scientists noticed that this only happened during sleep, but it was unknown what it was about sleep that initiated this cleaning process,” Hauglund explains.
Her study found the glymphatic clearance was mediated by a hormone called norepinephrine and happened almost exclusively during the NREM sleep phase. But it only worked when sleep was natural. Anesthesia and sleeping pills shut this process down nearly completely.
Taking it slowly
The glymphatic system in the brain was discovered back in 2013 by Dr. Maiken Nedergaard, a Danish neuroscientist and a coauthor of Hauglund’s paper. Since then, there have been numerous studies aimed at figuring out how it worked, but most of them had one problem: they were done on anesthetized mice.
“What makes anesthesia useful is that you can have a very controlled setting,” Hauglund says.
Most brain imaging techniques require a subject, an animal or a human, to be still. In mouse experiments, that meant immobilizing their heads so the research team could get clear scans. “But anesthesia also shuts down some of the mechanisms in the brain,” Hauglund argues.
So, her team designed a study to see how the brain-clearing mechanism works in mice that could move freely in their cages and sleep naturally whenever they felt like it. “It turned out that with the glymphatic system, we didn’t really see the full picture when we used anesthesia,” Hauglund says.
Looking into the brain of a mouse that runs around and wiggles during sleep, though, wasn’t easy. The team pulled it off by using a technique called flow fiber photometry which works by imaging fluids tagged with fluorescent markers using a probe implanted in the brain. So, the mice got the optical fibers implanted in their brains. Once that was done, the team put fluorescent tags in the mice’s blood, cerebrospinal fluid, and on the norepinephrine hormone. “Fluorescent molecules in the cerebrospinal fluid had one wavelength, blood had another wavelength, and norepinephrine had yet another wavelength,” Hauglund says.
This way, her team could get a fairly precise idea about the brain fluid dynamics when mice were awake and asleep. And it turned out that the glymphatic system basically turned brain tissues into a slowly moving pump.
Pumping up
“Norepinephrine is released from a small area of the brain in the brain stem,” Hauglund says. “It is mainly known as a response to stressful situations. For example, in fight or flight scenarios, you see norepinephrine levels increasing.” Its main effect is causing blood vessels to contract. Still, in more recent research, people found out that during sleep, norepinephrine is released in slow waves that roll over the brain roughly once a minute. This oscillatory norepinephrine release proved crucial to the operation of the glymphatic system.
“When we used the flow fiber photometry method to look into the brains of mice, we saw these slow waves of norepinephrine, but we also saw how it works in synchrony with fluctuation in the blood volume,” Hauglund says.
Every time the norepinephrine level went up, it caused the contraction of the blood vessels in the brain, and the blood volume went down. At the same time, the contraction increased the volume of the perivascular spaces around the blood vessels, which were immediately filled with the cerebrospinal fluid.
When the norepinephrine level went down, the process worked in reverse: the blood vessels dilated, letting the blood in and pushing the cerebrospinal fluid out. “What we found was that norepinephrine worked a little bit like a conductor of an orchestra and makes the blood and cerebrospinal fluid move in synchrony in these slow waves,” Hauglund says.
And because the study was designed to monitor this process in freely moving, undisturbed mice, the team learned exactly when all this was going on. When mice were awake, the norepinephrine levels were much higher but relatively steady. The team observed the opposite during the REM sleep phase, where the norepinephrine levels were consistently low. The oscillatory behavior was present exclusively during the NREM sleep phase.
So, the team wanted to check how the glymphatic clearance would work when they gave the mice zolpidem, a sleeping drug that had been proven to increase NREM sleep time. In theory, zolpidem should have boosted brain-clearing. But it turned it off instead.
Non-sleeping pills
“When we looked at the mice after giving them zolpidem, we saw they all fell asleep very quickly. That was expected—we take zolpidem because it makes it easier for us to sleep,” Hauglund says. “But then we saw those slow fluctuations in norepinephrine, blood volume, and cerebrospinal fluid almost completely stopped.”
No fluctuations meant the glymphatic system didn’t remove any waste. This was a serious issue, because one of the cellular waste products it is supposed to remove is amyloid beta, found in the brains of patients suffering from Alzheimer’s disease.
Hauglund speculates it could be possible zolpidem induces a state very similar to sleep but at the same time it shuts down important processes that happen during sleep. While heavy zolpidem use has been associated with increased risk of the Alzheimer disease, it is not clear if this increased risk was there because the drug was inhibiting oscillatory norepinephrine release in the brain. To better understand this, Hauglund wants to get a closer look into how the glymphatic system works in humans.
“We know we have the same wave-like fluid dynamics in the brain, so this could also drive the brain clearance in humans,” Haugland told Ars. “Still, it’s very hard to look at norepinephrine in the human brain because we need an invasive technique to get to the tissue.”
But she said norepinephrine levels in people can be estimated based on indirect clues. One of them is pupil dilation and contraction, which work in in synchrony with the norepinephrine levels. Another other clue may lay in microarousals—very brief, imperceivable awakenings which, Hauglund thinks, can be correlated with the brain clearing mechanism. “I am currently interested in this phenomenon […]. Right now we have no idea why microarousals are there or what function they have” Hauglund says.
But the last step she has on her roadmap is making better sleeping pills. “We need sleeping drugs that don’t have this inhibitory effect on the norepinephrine waves. If we can have a sleeping pill that helps people sleep without disrupting their sleep at the same time it will be very important,” Hauglund concludes.
Jacek Krywko is a freelance science and technology writer who covers space exploration, artificial intelligence research, computer science, and all sorts of engineering wizardry.
That mind is partly revealed through Herzog’s running narration, such as when he muses about collective behavior and whether fish have souls—a digression sparked by his interview with Siri co-inventor Tom Gruber. “In the background, I saw his TV screen still on, we didn’t switch it off, and I saw some very, very strange school of fish,” said Herzog. “I asked him about the school of fish, which he had filmed himself. And all of a sudden, I’m only interested in the fish and common behavior. Why do they behave in big schools, in unison? Why do they do that? Do they dream? And if they think, what are they thinking about? I immerse the audience into a very strange form of underwater landscape and behavior of fish.”
Werner Herzog’s inspiration for Theater of Thought arose from conversations with Columbia University neuroscientist Rafael Yuste, who served as science advisor on the film. Argot Pictures
We glimpse the inner workings of Herzog’s mind in the kinds of questions he asks his subjects, such as when he queries IBM’s Dario Gil, who works on quantum computing, about his passion for fishing, eliciting an enthusiastic smile in response. He agrees to interview University of Washington neuroscientist Christof Koch after Koch’s early-morning row on the Puget Sound and includes music from New York University neuroscientist Joseph LeDoux‘s band, the Amygdaloids, in the film’s soundtrack. He asks married scientists Cori Bargmann and Richard Axel about music, their dinner conversations, and the linguistic capabilities of parrots. In so doing, he brings out their innate humanity, not just their scientific expertise.
“That’s what I do. If you don’t have it in you, you shouldn’t be a filmmaker,” said Herzog. “But you see, also, the joy of getting into all of this and the joy of meeting these scientists. We are talking about speaking parrots. What if two parrots learned a language that is already extinct and they would speak to each other? What would we make of it? So I’m asking, spontaneously, because I saw it, I sensed it, there was something I should depart completely from scientific quests. And yet there’s a deep scientific background to it.”
As if we didn’t have enough reasons to get at least eight hours of sleep, there is now one more. Neurons are still active during sleep. We may not realize it, but the brain takes advantage of this recharging period to get rid of junk that was accumulating during waking hours.
Sleep is something like a soft reboot. We knew that slow brainwaves had something to do with restful sleep; researchers at the Washington University School of Medicine in St. Louis have now found out why. When we are awake, our neurons require energy to fuel complex tasks such as problem-solving and committing things to memory. The problem is that debris gets left behind after they consume these nutrients. As we sleep, neurons use these rhythmic waves to help move cerebrospinal fluid through brain tissue, carrying out metabolic waste in the process.
In other words, neurons need to take out the trash so it doesn’t accumulate and potentially contribute to neurodegenerative diseases. “Neurons serve as master organizers for brain clearance,” the WUSTL research team said in a study recently published in Nature.
Built-in garbage disposal
Human brains (and those of other higher organisms) evolved to have billions of neurons in the functional tissue, or parenchyma, of the brain, which is protected by the blood-brain barrier.
Everything these neurons do creates metabolic waste, often in the form of protein fragments. Other studies have found that these fragments may contribute to neurodegenerative diseases such as Alzheimer’s.
The brain has to dispose of its garbage somehow, and it does this through what’s called the glymphatic system (no, that’s not a typo), which carries cerebrospinal fluid that moves debris out of the parenchyma through channels located near blood vessels. However, that still left the questions: What actually powers the glymphatic system to do this—and how? The WUSTL team wanted to find out.
To see what told the glymphatic system to dump the trash, scientists performed experiments on mice, inserting probes into their brains and planting electrodes in the spaces between neurons. They then anesthetized the mice with ketamine to induce sleep.
Neurons fired strong, charged currents after the animals fell asleep. While brain waves under anesthesia were mostly long and slow, they induced corresponding waves of current in the cerebrospinal fluid. The fluid would then flow through the dura mater, the outer layer of tissue between the brain and the skull, taking the junk with it.
Just flush it
The scientists wanted to be sure that neurons really were the force that pushed the glymphatic system into action. To do that, they needed to genetically engineer the brains of some mice to nearly eliminate neuronal activity while they were asleep (though not to the point of brain death) while leaving the rest of the mice untouched for comparison.
In these engineered mice, the long, slow brain waves seen before were undetectable. As a result, the fluid was no longer pushed to carry metabolic waste out of the brain. This could only mean that neurons had to be active in order for the brain’s self-cleaning cycle to work.
Furthermore, the research team found that there were fluctuations in the brain waves of the un-engineered mice, with slightly faster waves thought to be targeted at the debris that was harder to remove (at least, this is what the researchers hypothesized). It is not unlike washing a plate and then needing to scrub slightly harder in places where there is especially stubborn residue.
The researchers also found out why previous experiments produced different results. Because the flushing out of cerebrospinal fluid that carries waste relies so heavily on neural activity, the type of anesthetic used mattered—anesthetics that inhibit neural activity can interfere with the results. Other earlier experiments worked poorly because of injuries caused by older and more invasive methods of implanting the monitoring hardware into brain tissues. This also disrupted neurons.
“The experimental methodologies we used here largely avoid acute damage to the brain parenchyma, thereby providing valuable strategies for further investigations into neural dynamics and brain clearance,” the team said in the same study.
Now that neurons are known to set the glymphatic system into motion, more attention can be directed towards the intricacies of that process. Finding out more about the buildup and cleaning of metabolic waste may contribute to our understanding of neurodegenerative diseases. It’s definitely something to think about before falling asleep.
Indian elephants have larger brains than we do (obviously). Mice have a higher brain-to-body mass ratio, and long-finned pilot whales have more neurons. So what makes humans—and more specifically, human brains—special?
As far as organs go, human brains certainly consume a ton of energy—almost 50 grams of sugar, or 12 lumps, every day. This is one of the highest energy demands relative to body metabolism known among species. But what uses up all of this energy? If the human brain is the predicted size and has the predicted number of neurons for a primate of its size, and each individual neuron uses comparable amounts of energy to those in other mammals, then its energy use shouldn’t be exceptional.
The cost of signaling
A group of neuroscientists speculated that maybe the amount of signaling that takes place within the human brain accounts for its heightened energy needs. A consequence of this would be that brain regions that are more highly connected and do more signaling will use more energy.
To test their hypothesis, the scientists started by imaging the brains of 30 healthy, right-handed volunteers between 20 and 50 years old. The imaging took place at two separate institutions, and it allowed the researchers to correlate a given brain region’s energy use (as measured by glucose metabolism) with its level of signaling and connectivity. They found that energy use and signaling scaled in tandem in all 30 brains. But certain regions stuck out. Signaling pathways in certain areas of the cortex—the front of the brain—require almost 70 percent more energy than those in sensory-motor regions.
The frontal cortex is one of the regions that expanded the most during human evolution. According to Robert Sapolsky, “What the prefrontal cortex is most about is making tough decisions in the face of temptation—gratification postponement, long-term planning, impulse control, emotional regulation. The PFC is essential for getting you to do the right thing when it is the harder thing to do.” This is the stuff that humans must constantly contend with. And energetically, it is extraordinarily costly.
Increased modulation is also key for cognition
It is not only signaling that takes energy; it is modulating that signaling, ensuring that it occurs at the appropriate levels and only at the appropriate times.
Using the Allen Human Brain Atlas, these researchers looked at gene activity in the frontal cortex. They found elevated activity of neuromodulators and their receptors. The authors note that “the human brain spends excessive energy on the long-lasting regulation of (fast) neurotransmission with (slow) neuromodulators such as serotonin, dopamine, or noradrenaline.” And also endogenous opiates. “This effect is more about setting the tone of general excitability than transferring individual bits of information,” they write.
Once they correlated energy use to signaling and slow-acting neuromodulation in the cortex, the last thing the scientists did was look at the Neurosynth project, which maps cognitive functions to brain regions. Lo and behold, the energy-hogging, highly connected, strongly modulated, and evolutionarily expanded parts of the cortex are the same ones involved in complex functions like memory processing, reading, and cognitive inhibition. This supports their idea of “an expensive signaling architecture being dedicated to human cognition.”
Neuralink, Elon Musk’s brain-machine interface (BMI) company, has announced that it has received approval from the US Food and Drug Administration (FDA) to conduct its first tests on humans. The company is developing minimally invasive brain chips which it hopes to use to restore vision and mobility for people with disabilities.
Neuralink says it doesn’t have immediate plans to recruit participants, however the FDA approval marks a significant step forward after a previous bid was rejected on safety grounds.
In March, Reutersreported the FDA’s major safety concerns involved the device’s lithium battery, the potential for the implant’s tiny wires to migrate to other areas of the brain, and questions over whether and how the device can be removed without damaging brain tissue.
Musk’s BMI startup first revealed a wireless version of its ‘N1 Link’ implant working in pigs in 2020, which streamed neural data in order to track limb movement. It has since showcased its neural implants working in primates, notably allowing a macaque test subject to play Pong using only its thoughts.
N1 Link (left), Removable charger/transmitter (right) | Image courtesy Neuralink
Neuralink’s N1 Implant is hermetically sealed in a biocompatible enclosure which the company says is capable of withstanding harsh physiological conditions. The N1 Implant is implanted by a custom a surgical robot; Neuralink says this ensures accurate and efficient placement of its 64 flexible threads which are distrusted to 1,024 electrodes.
Powered by a small lithium battery that can be wirelessly charged using a compact, inductive charger, the implant is said to incorporate custom low-power chips and electronics that process neural signals and transmit them wirelessly to the Neuralink Application.
Neuralink is currently focused on giving people with quadriplegia the ability to control computers and mobile devices with their thoughts. In the future, the company hopes to restore capabilities such as vision, motor function, and speech, and eventually expand “how we experience the world,” the company says on its website.
That last bit is undoubtedly the company’s most ambitious goal, which the company has said will not only include reading electrical brain signals from paralyzed and neurotypical users alike, but also eventually the ability to “write” signals back to the brain.
