New research led by Stanford Medicine has found that it can — if a therapy is matched with the right patients. In a study of adults with both depression and obesity — a difficult-to-treat combination — cognitive behavioral therapy that focused on problem solving reduced depression in a third of patients. These patients also showed adaptative changes in their brain circuitry.

Moreover, these neural adaptations were apparent after just two months of therapy and could predict which patients would benefit from long-term therapy.

The findings add to evidence that choosing treatments based on the neurological underpinnings of a patient’s depression — which vary among people — increases the odds of success.

The same concept is already standard practice in other medical specialties.

“If you had chest pain, your physician would suggest some tests — an electrocardiogram, a heart scan, maybe a blood test — to work out the cause and which treatments to consider,” said Leanne Williams, PhD, the Vincent V.C. Woo Professor, a professor of psychiatry and behavioral sciences, and the director of Stanford Medicine’s Center for Precision Mental Health and Wellness.

“Yet in depression, we have no tests being used. You have this broad sense of emotional pain, but it’s a trial-and-error process to choose a treatment, because we have no tests for what is going on in the brain.”

Williams and Jun Ma, MD, PhD, professor of academic medicine and geriatrics at the University of Illinois at Chicago, are co-senior authors of the study published Sept. 4 in Science Translational Medicine. The work is part of a larger clinical trial called RAINBOW (Research Aimed at Improving Both Mood and Weight).

Problem solving

The form of cognitive behavioral therapy used in the trial, known as problem-solving therapy, is designed to improve cognitive skills used in planning, troubleshooting and tuning out irrelevant information. A therapist guides patients in identifying real-life problems — a conflict with a roommate, say — brainstorming solutions and choosing the best one.

These cognitive skills depend on a particular set of neurons that function together, known as the cognitive control circuit.

Previous work from Williams’ lab, which identified six biotypes of depression based on patterns of brain activity, estimated that a quarter of people with depression have dysfunction with their cognitive control circuits — either too much or too little activity.

The participants in the new study were adults diagnosed with both major depression and obesity, a confluence of symptoms that often indicates problems with the cognitive control circuit. Patients with this profile generally do poorly on antidepressants: They have a dismal response rate of 17%.

Of the 108 participants, 59 underwent a year-long program of problem-solving therapy in addition to their usual care, such as medications and visits to a primary care physician. The other 49 received only usual care.

They were given fMRI brain scans at the beginning of the study, then after two months, six months, 12 months and 24 months. During the brain scans, the participants completed a test that involves pressing or not pressing a button according to text on a screen — a task known to engage the cognitive control circuit. The test allowed the researchers to gauge changes in the activity of that circuit throughout the study.

“We wanted to see whether this problem-solving therapy in particular could modulate the cognitive control circuit,” said Xue Zhang, PhD, a postdoctoral scholar in psychiatry who is the lead author of the study.

With each brain scan, participants also filled out standard questionnaires that assessed their problem-solving ability and depression symptoms.

Working smarter

As with any other depression treatment, problem-solving therapy didn’t work for everyone. But 32% of participants responded to the therapy, meaning their symptom severity decreased by half or more.

“That’s a huge improvement over the 17% response rate for antidepressants,” Zhang said.

When researchers examined the brain scans, they found that in the group receiving only usual care, a cognitive control circuit that became less active over the course of the study correlated with worsening problem-solving ability.

But in the group receiving therapy, the pattern was reversed: Decreased activity correlated with enhanced problem-solving ability. The researchers think this may be due to their brains learning, through the therapy, to process information more efficiently.

“We believe they have more efficient cognitive processing, meaning now they need fewer resources in the cognitive control circuit to do the same behavior,” Zhang said.

Before the therapy, their brains had been working harder; now, they were working smarter.

Both groups, on average, improved in their overall depression severity. But when Zhang dug deeper into the 20-item depression assessment, she found that the depression symptom most relevant to cognitive control — “feeling everything is an effort” — benefited from the more efficient cognitive processing gained from the therapy.

“We’re seeing that we can pinpoint the improvement specific to the cognitive aspect of depression, which is what drives disability because it has the biggest impact on real-world functioning,” Williams said.

Indeed, some participants reported that problem-solving therapy helped them think more clearly, allowing them to return to work, resume hobbies and manage social interactions.

Fast track to recovery

Just two months into the study, brain scans showed changes in cognitive control circuit activity in the therapy group.

“That’s important, because it tells us that there is an actual brain change going on early, and it’s in the time frame that you’d expect brain plasticity,” Williams said. “Real-world problem solving is literally changing the brain in a couple of months.”

The idea that thoughts and behaviors can modify brain circuits is not so different from how exercise — a behavior — strengthens muscles, she added.

The researchers found that these early changes signaled which patients were responding to the therapy and would likely improve on problem-solving skills and depression symptoms at six months, 12 months and even one year after the therapy ended, at 24 months. That means a brain scan could be used to predict which patients are the best candidates for problem-solving therapy.

It’s a step toward Williams’ vision of precision psychiatry — using brain activity to match patients with the therapies most likely to help them, fast-tracking them to recovery.

“It’s definitely advancing the science,” Zhang said. “But it’s also going to transform a lot of people’s lives.”

Researchers from University of Washington, University of Pittsburgh School of Medicine and The Ohio State University also contributed to the work.

The study received funding from the National Institutes of Health (grants UH2 HL132368, UH3 HL132368 and R01 HL119453).

But in certain exotic materials, electrons can appear to flow with single-minded purpose. In these materials, electrons may become locked to the material’s edge and flow in one direction, like ants marching single-file along a blanket’s boundary. In this rare “edge state,” electrons can flow without friction, gliding effortlessly around obstacles as they stick to their perimeter-focused flow. Unlike in a superconductor, where all electrons in a material flow without resistance, the current carried by edge modes occurs only at a material’s boundary.

Now MIT physicists have directly observed edge states in a cloud of ultracold atoms. For the first time, the team has captured images of atoms flowing along a boundary without resistance, even as obstacles are placed in their path. The results, which appear in Nature Physics, could help physicists manipulate electrons to flow without friction in materials that could enable super-efficient, lossless transmission of energy and data.

“You could imagine making little pieces of a suitable material and putting it inside future devices, so electrons could shuttle along the edges and between different parts of your circuit without any loss,” says study co-author Richard Fletcher, assistant professor of physics at MIT. “I would stress though that, for us, the beauty is seeing with your own eyes physics which is absolutely incredible but usually hidden away in materials and unable to be viewed directly.”

The study’s co-authors at MIT include graduate students Ruixiao Yao and Sungjae Chi, former graduate students Biswaroop Mukherjee PhD ’20 and Airlia Shaffer PhD ’23, along with Martin Zwierlein, the Thomas A. Frank Professor of Physics. The co-authors are all members of MIT’s Research Laboratory of Electronics and the MIT-Harvard Center for Ultracold Atoms.

Forever on the edge

Physicists first invoked the idea of edge states to explain a curious phenomenon, known today as the Quantum Hall effect, which scientists first observed in 1980, in experiments with layered materials, where electrons were confined to two dimensions. These experiments were performed in ultracold conditions, and under a magnetic field. When scientists tried to send a current through these materials, they observed that electrons did not flow straight through the material, but instead accumulated on one side, in precise quantum portions.

To try and explain this strange phenomenon, physicists came up with the idea that these Hall currents are carried by edge states. They proposed that, under a magnetic field, electrons in an applied current could be deflected to the edges of a material, where they would flow and accumulate in a way that might explain the initial observations.

“The way charge flows under a magnetic field suggests there must be edge modes,” Fletcher says. “But to actually see them is quite a special thing because these states occur over femtoseconds, and across fractions of a nanometer, which is incredibly difficult to capture.”

Rather than try and catch electrons in an edge state, Fletcher and his colleagues realized they might be able to recreate the same physics in a larger and more observable system. The team has been studying the behavior of ultracold atoms in a carefully designed setup that mimics the physics of electrons under a magnetic field.

“In our setup, the same physics occurs in atoms, but over milliseconds and microns,” Zwierlein explains. “That means that we can take images and watch the atoms crawl essentially forever along the edge of the system.”

A spinning world

In their new study, the team worked with a cloud of about 1 million sodium atoms, which they corralled in a laser-controlled trap, and cooled to nanokelvin temperatures. They then manipulated the trap to spin the atoms around, much like riders on an amusement park Gravitron.

“The trap is trying to pull the atoms inward, but there’s centrifugal force that tries to pull them outward,” Fletcher explains. “The two forces balance each other, so if you’re an atom, you think you’re living in a flat space, even though your world is spinning. There’s also a third force, the Coriolis effect, such that if they try to move in a line, they get deflected. So these massive atoms now behave as if they were electrons living in a magnetic field.”

Into this manufactured reality, the researchers then introduced an “edge,” in the form of a ring of laser light, which formed a circular wall around the spinning atoms. As the team took images of the system, they observed that when the atoms encountered the ring of light, they flowed along its edge, in just one direction.

“You can imagine these are like marbles that you’ve spun up really fast in a bowl, and they just keep going around and around the rim of the bowl,” Zwierlein offers. “There is no friction. There is no slowing down, and no atoms leaking or scattering into the rest of the system. There is just beautiful, coherent flow.”

“These atoms are flowing, free of friction, for hundreds of microns,” Fletcher adds. “To flow that long, without any scattering, is a type of physics you don’t normally see in ultracold atom systems.”

This effortless flow held up even when the researchers placed an obstacle in the atoms’ path, like a speed bump, in the form of a point of light, which they shone along the edge of the original laser ring. Even as they came upon this new obstacle, the atoms didn’t slow their flow or scatter away, but instead glided right past without feeling friction as they normally would.

“We intentionally send in this big, repulsive green blob, and the atoms should bounce off it,” Fletcher says. “But instead what you see is that they magically find their way around it, go back to the wall, and continue on their merry way.”

The team’s observations in atoms document the same behavior that has been predicted to occur in electrons. Their results show that the setup of atoms is a reliable stand-in for studying how electrons would behave in edge states.

“It’s a very clean realization of a very beautiful piece of physics, and we can directly demonstrate the importance and reality of this edge,” Fletcher says. “A natural direction is to now introduce more obstacles and interactions into the system, where things become more unclear as to what to expect.”

This research was supported, in part, by the National Science Foundation.

How does GPS work?

GPS satellites are equipped with an extremely accurate atomic clock and know their positions at all times. They continually transmit the time and their location using radio waves. A mobile phone or other navigation device receives these signals from all satellites within their line of sight. The difference between the arrival time at the local clock of the receiver and the transmission time recorded by the satellite clock corresponds to the time taken for the signal to travel from the satellite to the receiver (the “time of flight”). Since radio waves travel at the speed of light, the time of flight determines the distance covered by the signal. The satellite positions and the distances are used to calculate the position of the receiver using a system of equations.

This simplified description does not take into account the fact that the local clock in the receiver is not an atomic clock. If it is inaccurate by just one millionth of a second, the calculated position will be inaccurate by at least 300 meters. The GPS problem is the need for the phone or other navigation device to determine the precise time along with the location — known in the theory of relativity as space-time.

If too few satellites are in the line of sight, the system no longer functions reliably and delivers multiple solutions, in other words several different locations where the receiver could be. This can lead to the situation where a phone indicates an incorrect location or no location at all. Until now the number of satellites needed to obtain unique solutions to the GPS problem has only been conjectured.

Five satellites for a precise location

Mireille Boutin, a professor of discrete algebra and geometry at TU/e and Gregor Kemper, a professor of algorithmic algebra at TUM, have now produced a mathematical proof showing that with five or more satellites, the exact position of the receiver can be uniquely determined in almost all cases. “Although this was a long-standing conjecture, nobody had managed to find a proof. And it was far from simple: We worked on the problem for over a year before we got there,” says Gregor Kemper. At present every location on Earth has sight contact to at least four satellites at all times. “Roughly speaking, with only four satellites, the probability of having a unique solution to the GPS problem appears to be 50 percent. Proving that statement is one of our next projects,” says Kemper. With three or fewer satellites in the line of sight, GPS navigation definitely does not work.

Geometry and uniqueness

The researchers arrived at the proof by characterizing the GPS problem in geometric terms. They found out that the position of the receiver cannot be uniquely determined if the satellites are located on a hyperboloid of revolution of two sheets. This is a curved surface that is open in all directions. Although this result is theoretical, it has the practical benefit of offering a better understanding of inaccuracies in determining positions.

Dr. Zihao Ou, assistant professor of physics at The University of Texas at Dallas, is lead author of the study, published in the Sept. 6 print issue of the journal Science.

Living skin is a scattering medium. Like fog, it scatters light, which is why it cannot be seen through.

“We combined the yellow dye, which is a molecule that absorbs most light, especially blue and ultraviolet light, with skin, which is a scattering medium. Individually, these two things block most light from getting through them. But when we put them together, we were able to achieve transparency of the mouse skin,” said Ou, who, with colleagues, conducted the study while he was a postdoctoral researcher at Stanford University before joining the UT Dallas faculty in the School of Natural Sciences and Mathematics in August.

“For those who understand the fundamental physics behind this, it makes sense; but if you aren’t familiar with it, it looks like a magic trick,” Ou said.

The “magic” happens because dissolving the light-absorbing molecules in water changes the solution’s refractive index — a measure of the way a substance bends light — in a way that matches the refractive index of tissue components like lipids. In essence, the dye molecules reduce the degree to which light scatters in the skin tissue, like dissipating a fog bank.

In their experiments with mice, the researchers rubbed the water and dye solution onto the skin of the animals’ skulls and abdomens. Once the dye had completely diffused into the skin, the skin became transparent. The process is reversible by washing off any remaining dye. The dye that has diffused into the skin is metabolized and excreted through urine.

“It takes a few minutes for the transparency to appear,” Ou said. “It’s similar to the way a facial cream or mask works: The time needed depends on how fast the molecules diffuse into the skin.”

Through the transparent skin of the skull, researchers directly observed blood vessels on the surface of the brain. In the abdomen, they observed internal organs and peristalsis, the muscle contractions that move contents through the digestive tract.

The transparent areas take on an orangish color, Ou said. The dye used in the solution is commonly known as FD&C Yellow #5 and is frequently used in orange- or yellow-colored snack chips, candy coating and other foods. The Food and Drug Administration certifies nine color additives — tartrazine is one — for use in foods.

“It’s important that the dye is biocompatible — it’s safe for living organisms,” Ou said. “In addition, it’s very inexpensive and efficient; we don’t need very much of it to work.”

The researchers have not yet tested the process on humans, whose skin is about 10 times thicker than a mouse’s. At this time it is not clear what dosage of the dye or delivery method would be necessary to penetrate the entire thickness, Ou said.

“In human medicine, we currently have ultrasound to look deeper inside the living body,” Ou said. “Many medical diagnosis platforms are very expensive and inaccessible to a broad audience, but platforms based on our tech should not be.”

Ou said one of the first applications of the technique will likely be to improve existing research methods in optical imaging.

“Our research group is mostly academics, so one of the first things we thought of when we saw the results of our experiments was how this might improve biomedical research,” he said. “Optical equipment, like the microscope, is not directly used to study live humans or animals because light can’t go through living tissue. But now that we can make tissue transparent, it will allow us to look at more detailed dynamics. It will completely revolutionize existing optical research in biology.”

In his new Dynamic Bio-imaging Lab at UTD, Ou will continue the research he started with Dr. Guosong Hong, assistant professor of materials science and engineering at Stanford and a corresponding author of the study. Ou said the next steps in the research will include understanding what dosage of the dye molecule might work best in human tissue. In addition, the researchers are experimenting with other molecules, including engineered materials, that could perform more efficiently than tartrazine.

Study authors from Stanford, including co-corresponding author Dr. Mark Brongersma, the Stephen Harris Professor in the Department of Materials Science and Engineering, were funded by grants from federal agencies including the National Institutes of Health, the National Science Foundation and the Air Force Office of Scientific Research. As an interdisciplinary postdoctoral scholar, Ou was supported by the Wu Tsai Neuroscience Institute at Stanford. The researchers have applied for a patent on the technology.