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First Human Tests of Memory Boosting Brain Implant a Big Leap Forward

Every year, hundreds of millions of people experience the pain of a failing memory.

“You have to begin to lose your memory, if only bits and pieces, to realize that memory is what makes our lives. Life without memory is no life at all.” — Luis Buñuel Portolés, Filmmaker

The reasons are many: traumatic brain injury, which haunts a disturbingly high number of veterans and football players; stroke or Alzheimer’s disease, which often plagues the elderly; or even normal brain aging, which inevitably touches us all.

Memory loss seems to be inescapable. But one maverick neuroscientist is working hard on an electronic cure.

Funded by DARPA, Dr. Theodore Berger, a biomedical engineer at the University of Southern California, is testing a memory-boosting implant that mimics the kind of signal processing that occurs when neurons are laying down new long-term memories.

The revolutionary implant, already shown to help memory encoding in rats and monkeys, is now being tested in human patients with epilepsy — an exciting first that may blow the field of memory prosthetics wide open.

To get here, however, the team first had to crack the memory code.

Deciphering Memory

From the very onset, Berger knew he was facing a behemoth of a problem.

We weren’t looking to match everything the brain does when it processes memory, but to at least come up with a decent mimic, said Berger.

“Of course people asked: can you model it and put it into a device? Can you get that device to work in any brain? It’s those things that lead people to think I’m crazy. They think it’s too hard,” he said.

But the team had a solid place to start.

The hippocampus, a region buried deep within the folds and grooves of the brain, is the critical gatekeeper that transforms memories from short-lived to long-term. In dogged pursuit, Berger spent most of the last 35 years trying to understand how neurons in the hippocampus accomplish this complicated feat.

At its heart, a memory is a series of electrical pulses that occur over time that are generated by a given number of neurons, said Berger. This is important — it suggests that we can reduce it to mathematical equations and put it into a computational framework, he said.

Berger hasn’t been alone in his quest.

By listening to the chatter of neurons as an animal learns, teams of neuroscientists have begun to decipher the flow of information within the hippocampus that supports memory encoding. Key to this process is a strong electrical signal that travels from CA3, the “input” part of the hippocampus, to CA1, the “output” node.

This signal is impaired in people with memory disabilities, said Berger, so of course we thought if we could recreate it using silicon, we might be able to restore — or even boost — memory.

Bridging the Gap

Yet this brain’s memory code proved to be extremely tough to crack.

The problem lies in the non-linear nature of neural networks: signals are often noisy and constantly overlap in time, which leads to some inputs being suppressed or accentuated. In a network of hundreds and thousands of neurons, any small change could be greatly amplified and lead to vastly different outputs.

It’s a chaotic black box, laughed Berger.

With the help of modern computing techniques, however, Berger believes he may have a crude solution in hand. His proof?

Use his mathematical theorems to program a chip, and then see if the brain accepts the chip as a replacement — or additional — memory module.

Berger and his team began with a simple task using rats.

They trained the animals to push one of two levers to get a tasty treat, and recorded the series of CA3 to CA1 electronic pulses in the hippocampus as the animals learned to pick the correct lever. The team carefully captured the way the signals were transformed as the session was laid down into long-term memory, and used that information — the electrical “essence” of the memory — to program an external memory chip.

They then injected the animals with a drug that temporarily disrupted their ability to form and access long-term memories, causing the animals to forget the reward-associated lever.

Next, implanting microelectrodes into the hippocampus, the team pulsed CA1, the output region, with their memory code.

The results were striking — powered by an external memory module, the animals regained their ability to pick the right lever.

Encouraged by the results, Berger next tried his memory implant in monkeys, this time focusing on a brain region called the prefrontal cortex, which receives and modulates memories encoded by the hippocampus.

Placing electrodes into the monkey’s brains, the team showed the animals a series of semi-repeated images, and captured the prefrontal cortex’s activity when the animals recognized an image they had seen earlier.

with a hefty dose of cocaine, the team inhibited that particular brain region, which disrupted the animal’s recall.

Next, using electrodes programmed with the “memory code,” the researchers guided the brain’s signal processing back on track — and the animal’s performance improved significantly.

A year later, the team further validated their memory implant by showing it could also rescue memory deficits due to hippocampal malfunction in the monkey brain.

A Human Memory Implant

Last year, the team cautiously began testing their memory implant prototype in human volunteers.

Because of the risks associated with brain surgery, the team recruited 12 patients with epilepsy, who already have electrodes implanted into their brain to track down the source of their seizures.

Repeated seizures steadily destroy critical parts of the hippocampus needed for long-term memory formation, explained Berger. So if the implant works, it could benefit these patients as well.

The team asked the volunteers to look through a series of pictures, and then recall which ones they had seen 90 seconds later. As the participants learned, the team recorded the firing patterns in both CA1 and CA3 — that is, the input and output nodes.

Using these data, the team extracted an algorithm — a specific human “memory code” — that could predict the pattern of activity in CA1 cells based on CA3 input.

Compared to the brain’s actual firing patterns, the algorithm generated correct predictions roughly 80% of the time.

It’s not perfect, said Berger, but it’s a good start.

Using this algorithm, the researchers have begun to stimulate the output cells with an approximation of the transformed input signal.

We have already used the pattern to zap the brain of one woman with epilepsy, said Dr. Dong Song, an associate professor working with Berger. But he remained coy about the result, only saying that although promising, it’s still too early to tell.

Song’s caution is warranted. Unlike the motor cortex, with its clear structured representation of different body parts, the hippocampus is not organized in any obvious way.

It’s hard to understand why stimulating input locations can lead to predictable results, said Dr. Thoman McHugh, a neuroscientist at the RIKEN Brain Science Institute. It’s also difficult to tell whether such an implant could save the memory of those who suffer from damage to the output node of the hippocampus.

“That said, the data is convincing,” McHugh acknowledged.

Berger, on the other hand, is ecstatic. “I never thought I’d see this go into humans,” he said.

But the work is far from done.

Within the next few years, Berger wants to see whether the chip can help build long-term memories in a variety of different situations. After all, the algorithm was based on the team’s recordings of one specific task — what if the so-called memory code is not generalizable, instead varying based on the type of input that it receives?

Berger acknowledges that it’s a possibility, but he remains hopeful.

I do think that we will find a model that’s a pretty good fit for most conditions, he said. After all, the brain is restricted by its own biophysics — there’s only so many ways that electrical signals in the hippocampus can be processed, he said.

“The goal is to improve the quality of life for somebody who has a severe memory deficit,” said Berger.

“If I can give them the ability to form new long-term memories for half the conditions that most people live in, I’ll be happy as hell, and so will be most patients.”


No More Pills? Tiny Nerve-Zapping Implants to Fight Disease

(When a pharmaceutical product to be manufactured in 2023, and is announced now, wouldn’t this piece be considered a propaganda item for the company and Not for the eventual product?)

Imagine a future where we can treat diabetes or autoimmune disorders with an electrical zap delivered by a device no larger than a speck of dust.

The device, implanted through microsurgery, sits silently on a single nerve bundle, monitoring electrical signals sent out by the brain to itself and various organs in the body.

When it detects a problem — a rogue misfire, or a shift in activity patterns — the device powers up, sending out counter-pulses to correct the signal.

In this way, it keeps your body running smoothly and disease at bay. No pills. No injections. No pain. (Assuming that we know better than our body what and when to adjust to disturbances)

According to Alphabet and pharmaceutical giant GlaxoSmithKline (GSK), that future is just 7 years away

Imagine a future where we can treat diabetes or autoimmune disorders with an electrical zap delivered by a device no larger than a speck

This week, Verily, Alphabet’s life science unit (formerly Google Life Sciences), teamed up with Britain’s biggest drug maker to announce their new $715 million venture Galvani Bioelectronics.

With research centers based in GSK’s biotech hub in the UK and around the Bay Area, the company hopes to develop miniaturized, implantable electronic systems — dubbed “electroceuticals” — to correct irregular nerve pulses that contribute to a multitude of chronic diseases.

Hopes are high. According to Reuters, Kristoffer Famm, head of bioelectronics research at GSK and president of Galvani, says that their first products might be submitted for marketing approval as early as 2023.

Electricity as drugs

Eletroceuticals may sound futuristic, but using electricity to treat disease is nothing new — think pacemakers for correcting wonky heartbeats, or deep brain stimulation for rewiring broken neural circuits in depression and Parkinson’s disease.

(When electricity was discovered in the 19th century, every ailment was considered to be cured using electric shocks)

It’s easy to see why electroceuticals are sparking interest. Unlike run-of-the-mill chemical drugs that act on a protein or other molecule, electrical pulses directly hack into the main language of our nervous system to change its operating instructions. (Changing operating instructions? I won’t trust this alternative for any long-term benefits)

That’s a big deal. “The nervous system is crisscrossing our viscera to control many aspects of our organ function,” explains Famm in an earlier interview with Nature.

Rather than using drugs, which are rarely specific for a single biological process, we could zap a major nerve and, with surgical precision, change the instructions that an organ receives and thereby alter its function.

Electricity can not only jump start a heart or jolt a brain into health, but under the right conditions, a well-placed zap may also coax resistant pancreatic cells to release insulin, persuade clenched arteries to relax, or berate hyperactive immune cells to stop attacking your own tissue.

Rather than developing a library of chemical drugs that targets individual diseases, a single electroceutical prototype could, in theory, be programmed to treat multiple diseases.

According to a spokesperson from GSK, Galvani plans to tackle “a wide range of chronic diseases that are inflammatory, metabolic and endocrine disorders, which includes Type 2 diabetes,” but adding that the company hasn’t yet developed specific product plans.

Galvanizing the field

Last year already saw big wins for electroceuticals. In May, the US Food and Drug Administration approved a device that contracts airway muscles to help people with severe sleep apnea breathe properly without using an oxygen mask. A month later, the agency also gave its nod to an implantable weight-loss device that stimulates a nerve near the stomach to make a person feel full.

To really tap into the potential of electroceuticals, the devices will have to get much smaller. Nerves are incredibly compact, and unrelated circuits often run in close proximity. Because of this, electrical devices that zap a whole chunk of tissue run the risk of significant side effects — it’s like jump starting your car, but also blowing out the fuses in your entire house.

(And that’s what will occur eventually: If an accident can occur, it will occur. Blowing most of the fuses in your nervous system is Not a small accident)

This is where Galvani comes in. By combining engineering, bioinformatics and neuroscience, the company hopes to shrink implanted devices to the size of a grain of rice. Although specific plans are still under wraps, back in 2013 GSK published a roadmap that will likely guide the fledgling company.

“Many of the stepping stones are already in place,” wrote Famm and his colleagues.

First, the scientists will need to trace neural circuits that control disease to identify easy access points for intervention. (Excellent endeavour: a complete mapping or Taxonomy of the nervous centers)

They’ll also need to understand the signals running through those circuits in order to build a ‘dictionary’ of patterns that represent healthy and diseased states. By decoding the neural language, researchers can then program future electroceuticals to understand nerve impulses and, in turn, generate corrective pulses of their own.

Then there’s the engineering side of things. Bioengineers will need to design wireless, biocompatible microchips that can reliably perform real-time computation with low power.

When implanted through keyhole surgeries, the hope is that these electroceuticals will last at least decades.

According to Famm, the first generation of marketable implants will be roughly the size of an average pill. However, eventually they’ll be smaller than a grain of rice.

That goal may not be far off, and Galvani’s got serious competition.

Ryan Neely/University of California at Berkeley

An implantable, wireless sensor like this could allow real-time monitoring of nerve or muscle activity anywhere in the body, using external ultrasound to power and read out voltages.

In this photo, the sensor mote is attached to a peripheral nerve fiber of a rat. Credit:Ryan Neely/University of California at Berkeley

This week, a team at the University of California, Berkeley published a new wireless, implantable sensor that’s only three millimeters (about a tenth of an inch) in length. Aptly named “neural dust,” the device contains a piezoelectric crystal that converts ultrasonic vibrations from outside the body into electricity. This energy is then used to power a tiny transistor that contacts both the crystal and a nerve fiber.

When an impulse jolts through the nerve, it tweaks the circuits in the transistor, which in turn change the vibration of the crystal. These tiny flutters are then picked up by an ultrasound receiver and subsequently decoded. In this way, the device lets researchers closely monitor each spike of activity in a nerve.

Although the device is currently “read-only,” the team — not associated with Galvani — says that they are developing neural dust that can also stimulate nerves in a self-sustaining, closed-loop system.

Famm seems to welcome a healthy dose of competition in the nascent but burgeoning field.

“Clearly, open innovation … will be important,” he wrote back in 2013 (who wrote it?).

Quoting the poet Cesare Pavese, Famm continued, “’If you wish to travel far and fast, travel light. Take off all your envies, jealousies, unforgiveness, selfishness and fears.’ Together we can bring about the era of electroceuticals.”

Shelly Fan is a neuroscientist at the University of California, San Francisco, where she studies ways to make old brains young again.

In addition to research, she’s also an avid science writer with an insatiable obsession with biotech, AI and all things neuro.

She spends her spare time kayaking, bike camping and getting lost in the woods.

Think Your Conscious Brain Directs Your Actions? Think Again

Think your deliberate, guiding, conscious thoughts are in charge of your actions?

Think again.

In a provocative new paper in Behavioral and Brain Sciences, a team led by Dr. Ezequiel Morsella at San Francisco State University came to a startling conclusion: Consciousness is no more than a passive machine running one simple algorithm — to serve up what’s already been decided, and take credit for the decision.

conscious-decision-making-dethroned-2Rather than a stage conductor, it’s just a tiny part of what happens in the brain that makes us “aware.”

All the real work goes on under the hood — in our unconscious minds.

The Passive Frame Theory, as Morsella calls it, is based on decades of experimental data observing how people perceive and generate motor responses to odors.

It’s not about perception (“I smell a skunk”), but about response (running from a skunk).

The key to cracking what consciousness does in the brain is to work backwards from an observable physical action, explains Morsella in his paper.

If this isn’t your idea of “consciousness,” you’re not alone.

Traditionally, theorists tried to tackle the enigmatic beast by looking at higher levels of human consciousness, for example, self-consciousness — the knowledge that you exist — or theory of mind — that you and others have differing beliefs, intents, desires and perspectives.

While fascinating on a philosophical level, this approach is far too complex to explain on a fundamental level what consciousness is for.

Instead, Morsella believes that studying basic consciousness ­— the awareness of a color, an urge, a sharp pain — is what will lead to a breakthrough.

If a creature has an experience of any kind — something it is like to be that creature ­ — then it has this form of consciousness,” Morsella said in an email to Singularity Hub. It doesn’t have to be high-level, and “ it’s unlikely to be unique to humans.”

The Passive Frame Theory goes like this:

 Nearly all the decisions and thoughts that need to be made throughout the day are performed by many parts of the unconscious brain, well below our level of awareness. (The associative autonomous sub-branches of the hierarchy in our nervous system?)

conscious-decision-making-dethroned-8When the time comes to physically act on a decision, various unconscious processes deliver their opinions to a central “hub,” like voters congregating at town hall.

The hub listens in on the conversation, but doesn’t participate; all it does is provide a venue for differing opinions to integrate and decide on a final outcome. (Integrative behaviour seek the higher levels in the hierarchy for holistic resolutions)

Once the unconscious makes a final decision on how to physically act (or react), the hub — consciousness — executes that work and then congratulates itself for figuring out a tough problem.

In a way, the unconscious mind is like a group of talented ghostwriters working on a movie script for a celebrated screenwriter.

If all goes smoothly, they bypass the screenwriter and deliver the final product straight to the next level.

If, on the other hand, conflict arises — say the ghostwriters differ in their ideas on how the story should unfold — their argument may reach the ears of that famous screenwriter, who becomes aware of the problem, but nevertheless sits and waits for the writers to figure it all out. Once that happens, the screenwriter hands off the script, and gets all the credit.

Similar to the screenwriter, consciousness doesn’t debate or solve conflict in our heads; consciousness needs to be “on” in order to relay the final outcome — so it is essential — but it doesn’t participate in the nitty-gritty of decision-making.

Why did consciousness emerge in this way? Morsella thinks the answer is evolution.

Like all animals, humans try to conserve mental energy and automate our biological processes.

Most of the time we run on instincts, reflexes and minute-to-minute immediate thoughts. Take breathing as an example — it’s completely automated, to the point that consciously trying to maintain a steady rhythm is surprisingly hard. In this case, conscious thought just bogs the process down.

Unlike most animals, however, humans gradually evolved into complex social beings capable of cultivating our intelligence for language and other higher faculties.

Faced with increasingly difficult decisions on how to act, we suddenly needed a middleman to slow our unconscious mind down. (The nurturing process that got ingrained into our genes?)

conscious-decision-making-dethroned-4 Say you find yourself underwater; your instinct is to breathe, but better judgment — delivered by an unconscious cry of alarm (“don’t breathe!”) — tells you that you would drown. Your unconscious mind orders your consciousness to activate the muscles that will allow you to hold your breath and keep you alive. Consciousness triggers an adaptive motion.

The power of our unconscious mind doesn’t stop at basic bodily functions.

In the paper, Morsella cites language — a high-level, complex and perhaps distinctively human faculty — as another product of the unconscious mind.

When you speak, you’re only consciously aware of a few words at a time, and that is only so you can direct the muscles around your mouth and tongue to form those words. What you’re saying is prescribed under the hood; your conscious mind is simply following a script.

Morsella acknowledges that his theory is unconventional and difficult to accept.

“The number one reason it’s taken so long to reach this conclusion is because people confuse what consciousness is for with what they think they use it for,” Morsella said in a press release accompanying his paper.

But none of this theory takes away our treasured qualities as sentient human beings — our imagination, our language, our sense of self and others — it just points to the unconscious mind as the main player on our brainy fields.

In fact, Morsella hopes his theory could lead to new ideas about intrusive thoughts or obsessions that often occur in mental disorders.

“The passivity of consciousness explains why we are aware of urges and thoughts that are maladaptive,” Morsella said to Singularity Hub, because it doesn’t know that it shouldn’t be thinking about these thoughts.

“The system is less all-knowing and purposeful than we thought.”

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July 2022

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