In a perspective published in Frontiers in Psychiatry, researchers from UCLA Health and Harvard Medical School coin the term “behavioral psychedelics” — “the study of psychedelics to foster intentional changes in habits and behaviors to improve health and resilience.”

“Changing human behavior may sound simple but is exceedingly difficult, especially for behaviors that arise from years of thinking and acting in relatively rigid, routinized ways,” write the authors, George Slavich, PhD, professor of psychiatry and behavioral sciences at UCLA and research scientist at the UCLA Semel Institute for Neuroscience and Human Behavior, and Edmund Neuhaus, PhD, assistant professor of psychology at Harvard. “One emerging strategy for accomplishing behavior change involves using psychedelic compounds to make the mind more malleable and open.”

According to the authors, “psychedelics-assisted psychotherapy” may provide many health benefits and even cost savings, but the current therapeutic approach is poorly targeted.

“Looking forward, we believe that further refinement is needed to operationalize and test [the] components to establish a best-practice standard of care for treating psychiatric, addiction, somatic, and behavioral health problems,” they said.

The authors say their behavioral psychedelics concept is intended to develop “targeted approaches for therapeutic change that help people achieve enduring functional improvements in self-care, social connection, and family, school, and community responsibilities to help them live the life they desire.”

“Psychedelic compounds have the potential to turbocharge the process of transforming the mind, and the race to realize their benefits is in full swing. To maximize these benefits, we believe this work should include behavior as a treatment target with measurable treatment metrics to establish best practices and guidelines,” Slavich and Neuhaus write.

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However, a team of Penn State researchers has come up with a theory to explain and then predict it: Zentropy.

Zentropy is a play on entropy, a concept central to the second law of thermodynamics that expresses the measure of the disorder of a system that occurs over a period of time when there is no energy applied to keep order in the system. Think of a playroom in a preschool; if no energy is put into keeping it tidy, it quickly becomes disordered with toys all over the floor, a state of high entropy. If energy is put in via cleaning up and organizing the room once the children leave, then the room returns to a state of order and low entropy.

Zentropy theory notes that the thermodynamic relationship of thermal expansion, when the volume increases due to higher temperature, is equal to the negative derivative of entropy with respect to pressure, i.e., the entropy of most material systems decreases with an increase in pressure. This enables Zentropy theory to be able to predict the change of volume as a function of temperature at a multiscale level, meaning the different scales within a system. Every state of matter has its own entropy, and different parts of a system have their own entropy.

“When we talk about the configuration entropy (different ways particles rearrange within a system) that entropy is only part of the entropy of the system,” said Zi-Kui Liu, Dorothy Pate Enright Professor of Materials Science and Engineering and primary investigator in the study. “So, you have to add the entropy of individual components of that system into the equation, and then you consider the different scales, the universe, the Earth, the people, the materials, these are different scales within different systems.”

The authors of the study, published in the Journal of Phase Equilibria and Diffusion, believe that Zentropy may be able to predict anomalies of other physical properties of phases beyond volume. This is because responses of a system to external stimuli are driven by entropy.

Macroscopic functionalities of materials stem from assemblies of microscopic states (microstates) at all scales at and below the scale of the macroscopic state of investigation. These functionalities are challenging to predict because only one or a few microstates can be considered in a typical computational approach such as the predictive “from the beginning” calculations, which help determine the fundamental properties of materials.

“This challenge becomes acute in materials with multiple phase transitions, which are processes that convert matter from one state to another, such as vaporization of a liquid,” Liu said. “This is often where the most transformative functionalities exist, such as superconductivity and giant electromechanical response.”

Zentropy theory “stacks” these different scales into an entropy theory that encompasses the different elements of an entire system, presenting a nested formula for the entropy of complex multiscale systems, according to Liu.

“You have these different scales and you can stack them up with Zentropy theory,” Liu said. “For example, atoms as a vibrational property, that’s low scale, then you have electronic interaction, that even lower scale. So now how do you stack them together to cover the entire system? So that is what the Zentropy equation is about, stacking them together. It creates a partition function that is the sum of all the entropy scales.”

This approach has been something Liu’s lab has worked on for more than 10 years and five different published studies.

“The idea actually became very simple after we studied it and understood it,” Liu said.

Zentropy has potential to change the way materials are designed, especially those that are part of systems that are exposed to higher temperatures. These temperatures, given thermal expansion, could cause issues if the materials expand.

“This has the potential to enable the fundamental understanding and design of materials with emergent properties, such as new superconductors and new ferroelectric materials that could potentially lead to new classes of electronics,” Liu said. “Also, other applications such as designing better structural materials that withstand higher temperatures are also possible.”

While there are benefits for society in general, researchers could apply Zentropy to multiple fields. This is because of how entropy is present in all systems.

“The Zentropy theory has the potential to be applied to larger systems because entropy drives changes in all systems whether they are black holes, planets, societies or forests,” Liu said.

Along with Liu, other authors of the study include Yi Wang, research professor in materials science and engineering, and Shun-Li Zhang, research professor in materials science and engineering. The work was supported by the National Science Foundation, the Department of Energy and the Department of Defense.

“When we look at the totality of evidence for both the primary and secondary cardiovascular endpoints in COSMOS, we see promising signals that a cocoa flavanol supplement may reduce important cardiovascular events, including death from cardiovascular disease,” said Sesso. “These findings merit further investigation to better understand the effects of cocoa flavanols on cardiovascular health.”

“Previous studies have suggested health benefits of flavanols — compounds in several plant-based foods including cocoa, tea, grapes, and berries,” said Manson. “COSMOS was not a chocolate trial — rather, it’s a rigorous trial of a cocoa extract supplement that contains levels of cocoa flavanols that a person could never realistically consume from chocolate without adding excessive calories, fat, and sugar to their diet.”

Smaller, short-term trials have found cardiovascular benefits for cocoa flavanols on blood pressure and blood vessel dilation. COSMOS offered the first opportunity to study if a cocoa flavanol supplement might also lead to longer-term reductions in clinical cardiovascular events. Investigators also looked for reductions in risk of cancer. In addition, the trial was designed to test a common multivitamin in the prevention of cancer and cardiovascular disease.

The primary cardiovascular outcome for the cocoa flavanol intervention was a composite of total cardiovascular events, including heart attacks, stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina. More than 21,000 participants were randomized to take daily capsules that contained 500 mg cocoa flavanols (donated by Mars Edge), a multivitamin tablet (donated by GSK Consumer Healthcare), neither or both.

The study found that cocoa flavanols reduced total cardiovascular events by 10 percent, but this was not statistically significant. However, several secondary analyses provided broader support for a potential benefit of cocoa flavanols on cardiovascular events. First, those receiving the cocoa flavanol supplement had a significant 27 percent reduction in death from cardiovascular disease. Second, when the study team took adherence to study pills into account (by looking at those taking their study pills regularly), the team saw a stronger, 15 percent reduction in total cardiovascular events and a 39 percent reduction in death from cardiovascular disease. Third, a composite endpoint of major cardiovascular events (heart attacks, strokes, and cardiovascular deaths), although not a trial focus, was also significantly reduced. The authors note in their report that their promising results on cocoa flavanols and cardiovascular events warrant cautious interpretation and underscore the need for additional research.

A daily multivitamin had no significant effect on total or individual cardiovascular events. There were no safety concerns for either cocoa flavanols or a multivitamin.

COSMOS concluded after about 3.6 years, which was likely too short to detect whether the supplements could have affected cancer risk. Although a daily multivitamin improved levels of several nutritional biomarkers, it had no significant effect on total invasive cancer, the primary outcome for the multivitamin analyses. Cocoa flavanols also had no significant effect on total invasive cancer. The authors note that continuing to follow COSMOS participants may help to clarify any longer-term effects on cancer and death. The investigators and collaborators are also leveraging COSMOS to study cognitive decline, falls, eye disease, and other aging-related outcomes that may be influenced by the supplements.

“Although our study suggests intriguing signals for cardiovascular protection with cocoa flavanols, any health benefits due to taking these supplements will need confirmation in a future trial,” said Manson. Adds Sesso: “Our message for consumers is to eat a healthy, balanced diet, rich in natural food sources of flavanols, and to stay tuned as we further evaluate other important health outcomes in COSMOS.”

Sesso and Manson reported receiving investigator-initiated grants from Mars Edge, a segment of Mars Incorporated dedicated to nutrition research and products, for infrastructure support and donation of COSMOS study pills and packaging, and Pfizer Consumer Healthcare (now part of GSK Consumer Healthcare) for donation of COSMOS study pills and packaging during the conduct of the study. Dr. Sesso additionally reported receiving investigator-initiated grants from Pure Encapsulations and Pfizer Inc., and honoraria and/or travel for lectures from the Council for Responsible Nutrition, BASF, NIH, and American Society of Nutrition during the conduct of the study.

Funding: The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) is supported by an investigator-initiated grant from Mars Edge, a segment of Mars dedicated to nutrition research and products, which included infrastructure support and the donation of cocoa extract-containing study pills and packaging. Pfizer Consumer Healthcare (now part of GSK Consumer Healthcare) provided support through the partial provision of study pills (Centrum Silver) and packaging. COSMOS is also supported in part by grants AG050657, AG071611, EY025623, and HL157665 from the National Institutes of Health, Bethesda, MD. The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005. Neither company had a role in the trial design or conduct, data collection (other than blinded assays supported by Mars Edge and completed independently), data analysis, or manuscript preparation or review.

This novel brain-computer interface has thus far been tested in rodents. The details were published online on February 25 in the journal Advanced Functional Materials. This work is led by a team in the lab of electrical engineering professor Shadi Dayeh at the University of California San Diego, together with researchers at Boston University led by biomedical engineering professor Anna Devor.

This new brain-computer interface is on par with and outperforms the “Utah Array,” which is the existing gold standard for brain-computer interfaces with penetrating microneedles. The Utah Array has been demonstrated to help stroke victims and people with spinal cord injury. People with implanted Utah Arrays are able to use their thoughts to control robotic limbs and other devices in order to restore some everyday activities such as moving objects.

The backing of the new brain-computer interface is flexible, conformable, and reconfigurable, while the Utah Array has a hard and inflexible backing. The flexibility and conformability of the backing of the novel microneedle-array favors closer contact between the brain and the electrodes, which allows for better and more uniform recording of the brain-activity signals. Working with rodents as model species, the researchers have demonstrated stable broadband recordings producing robust signals for the duration of the implant which lasted 196 days.

In addition, the way the soft-backed brain-computer interfaces are manufactured allows for larger sensing surfaces, which means that a significantly larger area of the brain surface can be monitored simultaneously. In the Advanced Functional Materials paper, the researchers demonstrate that a penetrating microneedle array with 1,024 microneedles successfully recorded signals triggered by precise stimuli from the brains of rats. This represents ten times more microneedles and ten times the area of brain coverage, compared to current technologies.

Thinner and transparent backings

These soft-backed brain-computer interfaces are thinner and lighter than the traditional, glass backings of these kinds of brain-computer interfaces. The researchers note in their Advanced Functional Materials paper that light, flexible backings may reduce irritation of the brain tissue that contacts the arrays of sensors.

The flexible backings are also transparent. In the new paper, the researchers demonstrate that this transparency can be leveraged to perform fundamental neuroscience research involving animal models that would not be possible otherwise. The team, for example, demonstrated simultaneous electrical recording from arrays of penetrating micro-needles as well as optogenetic photostimulation.

Two-sided lithographic manufacturing

The flexibility, larger microneedle array footprints, reconfigurability and transparency of the backings of the new brain sensors are all thanks to the double-sided lithography approach the researchers used.

Conceptually, starting from a rigid silicon wafer, the team’s manufacturing process allows them to build microscopic circuits and devices on both sides of the rigid silicon wafer. On one side, a flexible, transparent film is added on top of the silicon wafer. Within this film, a bilayer of titanium and gold traces is embedded so that the traces line up with where the needles will be manufactured on the other side of the silicon wafer.

Working from the other side, after the flexible film has been added, all the silicon is etched away, except for free-standing, thin, pointed columns of silicon. These pointed columns of silicon are, in fact, the microneedles, and their bases align with the titanium-gold traces within the flexible layer that remains after the silicon has been etched away. These titanium-gold traces are patterned via standard and scalable microfabrication techniques, allowing scalable production with minimal manual labor. The manufacturing process offers the possibility of flexible array design and scalability to tens of thousands of microneedles.

Toward closed-loop systems

Looking to the future, penetrating microneedle arrays with large spatial coverage will be needed to improve brain-machine interfaces to the point that they can be used in “closed-loop systems” that can help individuals with severely limited mobility. For example, this kind of closed-loop system might offer a person using a robotic hand real-time tactical feedback on the objects the robotic hand is grasping.

Tactile sensors on the robotic hand would sense the hardness, texture, and weight of an object. This information recorded by the sensors would be translated into electrical stimulation patterns which travel through wires outside the body to the brain-computer interface with penetrating microneedles. These electrical signals would provide information directly to the person’s brain about the hardness, texture, and weight of the object. In turn, the person would adjust their grasp strength based on sensed information directly from the robotic arm.

This is just one example of the kind of closed-loop system that could be possible once penetrating microneedle arrays can be made larger to conform to the brain and coordinate activity across the “command” and “feedback” centers of the brain.

Previously, the Dayeh laboratory invented and demonstrated the kinds of tactile sensors that would be needed for this kind of application, as highlighted in this video.

Pathway to commercialization

The advanced dual-side lithographic microfabrication processes described in this paper are patented (US 10856764). Dayeh co-founded Precision Neurotek Inc. to translate technologies innovated in his laboratory to advance state of the art in clinical practice and to advance the fields of neuroscience and neurophysiology.

Binge eating disorder, which affects about 3-5% of the U.S. population, is characterized by frequent episodes of eating large amounts of food and a sense of having no control over the behavior. The study’s findings suggest that abnormal development in the brain’s centers for reward and inhibition may play a role.

The recently published study is available online in the journal Psychiatry Research.

“In children with binge eating disorder, we see abnormality in brain development in brain regions specifically linked to reward and impulsivity, or the ability to inhibit reward,” said lead author Stuart Murray, Della Martin Associate Professor of Psychiatry and the Behavioral Sciences at the Keck School of Medicine of USC, where he serves as director of the Eating Disorders Program.

“These kids have a very, very heightened reward sensitivity, especially toward calorically dense, high-sugar foods. The findings underscore the fact that this is not a lack of discipline for these kids.”

Pandemic saw increase in eating disorders among young people

Experts say eating disorders in young people soared during the pandemic, along with steep increases in hospitalizations. Social isolation, stress, disruption of routine and a social media-fueled quest for perfection all exacerbated disorders such as anorexia, muscle dysmorphia and binge eating.

Binge eating disorder puts people at risk for obesity, metabolic syndrome, abnormal cardiac function and suicidal thoughts. Treatment goals include reducing the frequency of binge eating episodes by removing “trigger” foods, as well as addressing underlying anxiety or depression. Treatment with medication and talk therapy is effective about only half the time, Murray said.

For this study, Murray and his colleagues analyzed brain scans and other data from 71 children with diagnosed binge eating disorder and 74 children without binge eating disorder, who are part of a large longitudinal study called the Adolescent Brain and Cognitive Development Study. That study includes data of 11,875 children ages 9-10 who were enrolled in 2016-2018 and recruited from 21 sites around the U.S.

In the children with binge eating disorder, they saw elevations in gray matter density in areas that are typically “pruned” during healthy brain development. Synaptic pruning, a development phase that occurs between ages 2 and 10, eliminates synapses that are no longer used, making the brain more efficient. Disturbed synaptic pruning is linked to a number of psychiatric disorders.

“This study suggests to me that binge eating disorder is wired in the brain, even from a very, very early age,” Murray said. “The question that we don’t know, which is something that we will address in time, is whether successful treatment of binge eating disorder in kids helps correct brain development. The prognosis of almost all psychiatric diseases is better if you can treat them in childhood.”

About the study

In addition to Murray, other authors were Christina Duval, Ane Balkchyan and Steven Siegel of the Department of Psychiatry and the Behavioral Sciences at the Keck School of Medicine; Ryan Cabeen, Arthur Toga and Kay Jann of the USC Mary and Mark Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine; and Jason Nagata of University of California, San Francisco.

USC’s Department of Psychiatry and the Behavioral Sciences includes about 200 faculty members who provide services to patients at Children’s Hospital Los Angeles, Los Angeles County+USC Medical Center, Keck Hospital of USC, USC Norris Comprehensive Cancer Center and USC Student Health.

The study was supported by grants from the National Institutes of Health, including the National Institute of Mental Health (K23MH115184)