Publisher Health

The COVID-19 pandemic demonstrated the importance of being prepared with drug interventions to contain viral outbreaks that can otherwise have devastating consequences. In preparing for the next pandemic — or Disease X, there is an urgent need for versatile platform technologies that could be repurposed upon short notice, to combat infectious outbreaks.
A team of researchers, led by Assistant Professor Minh Le from the Institute for Digital Medicine (WisDM) and Department of Pharmacology at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), discovered that nano-sized particles released by cells, termed “extracellular vesicles” (EVs), can curb the viral infectivity of SARS-CoV-2 — its wild type and variant strains — and potentially other infectious diseases. Asst Prof Le said, “Our study showed that these cell-derived nanoparticles are effective carriers of drugs that target viral genes precisely. These EVs are therefore an efficient tool for therapeutic intervention in patients who are infected with COVID-19 or other infectious diseases.”
The study, conducted in collaboration with NUS Medicine’s Biosafety Level 3 (BSL3) Core Facility, the Cancer Science Institute of Singapore at National University of Singapore, and the School of Physical and Mathematical Sciences at Nanyang Technological University (NTU), demonstrated potent inhibition of COVID-19 infection in laboratory models using a combination of EV-based inhibition and anti-sense RNA therapy mediated by antisense oligonucleotides (ASOs). A versatile tool that can be applied to any gene of interest, ASOs can recognise and bind to complementary regions of target RNA molecules and induce their inhibition and degradation.
In the study, published in ACS Nano, the authors utilised human red blood cell-derived EVs to deliver ASOs to key sites infected with SARS-CoV-2, resulting in efficient suppression of SARS-CoV-2 infection and replication. The researchers also discovered that EVs exhibited distinct antiviral properties, capable of inhibiting phosphatidylserine (PS) receptor-mediated pathways of viral infection — a key pathway utilised by many viruses to facilitate viral infection. These viral inhibitory mechanisms were applicable to multiple variants of SARS-CoV-2, including the Delta and Omicron strains, ensuring their broad effectiveness against SARS-CoV-2 infection.
The results from the study point to anti-sense RNA therapy with ASOs as a potentially effective approach that could serve to combat future viral outbreaks. The platform that was developed to deliver ASOs through EVs to target the SARS-CoV-2 viral genes can be readily applied to treat other viral infections by replacing the ASO sequences with those complementary to the target viral genes. Asst Prof Le and her graduate students Migara Jay and Gao Chang, the first authors of the study, are currently developing more potent combinations of ASOs with the help of artificial intelligence prediction models to achieve enhanced viral inhibition. This collaborative effort includes partnership with the research teams of Associate Professor Edward Chow from WisDM, NUS Medicine, and NUS Medicine’s BSL3 Core Facility.
Associate Professor Justin Chu, Director of the BSL3 Core Facility at NUS Medicine, and co-author of the study, added, “This remarkable extracellular vesicle-based delivery platform technology coupled with anti-viral therapy is highly promising to combat a broad range of viruses and even Disease X.” The latter is a general description for emerging and unknown infectious threats, such as novel coronaviruses. The term was used to alert and encourage the development of platform technologies, including vaccines, drug therapies and diagnostic tests, which could be quickly customised and then deployed against future epidemic and pandemic outbreaks. Assoc Prof Chu is also from the Infectious Diseases Translational Research Programme at NUS Medicine.
Professor Dean Ho, Provost’s Chair Professor and Director of WisDM at NUS Medicine, said, “This work brings the scalable and well-tolerated extracellular vesicle-based drug delivery platform an important step closer towards clinical validation studies.”

A research team led by Prof. Nancy IP, the President and The Morningside Professor of Life Science at The Hong Kong University of Science and Technology (HKUST), and the Director of the Hong Kong Center for Neurodegenerative Diseases (HKCeND), has identified VCAM1, a cell surface protein found on immune cells of the brain, as a therapeutic target for Alzheimer’s disease (AD), paving the way for developing novel therapeutics to combat this debilitating condition.
AD is a devastating neurodegenerative disorder that affects over 50 million people worldwide. A key pathological hallmark of the disease is the accumulation of amyloid-beta (Aβ) plaques in the brain, which leads to progressive decline in cognitive function. Microglia, resident immune cells of the brain, are thought to play a vital role in the clearance of Aβ plaques, a function that is impaired in AD.
The research team sought to investigate how microglia control Aβ clearance and how they become dysfunctional in AD. Through their elegant study, the team discovered that VCAM1, a cell surface protein on microglia, mediates microglial migration towards Aβ and promotes microglial clearance of Aβ. The team also discovered that another protein found in Aβ plaques, APOE, acts in conjunction with VCAM1 to mobilize microglia to Aβ plaques. The team further found that stimulating the “VCAM1-APOE” pathway reduced AD pathology in a mouse model of AD. These findings suggest that proper VCAM1 functioning is critical for microglial migration and clearance of Aβ.
The team also examined VCAM1-expressing microglia in the brain tissue of AD patients. Interestingly, AD patients exhibited elevated levels of soluble VCAM1 in the cerebrospinal fluid, which suggested dysregulated VCAM1-APOE signaling. This observation correlates with reduced clearance of Aβ by microglia.
Collectively, the findings of the study implicate VCAM1-APOE signaling in the pathogenesis of AD and identify VCAM1 as a promising target for AD therapy.
“These exciting findings have not only expanded our understanding of the disease pathology, but also unveiled a new target for developing disease interventions.” said Prof. Nancy Ip. “While there is an urgent need for effective disease-modifying treatments, we need to first identify the right drug targets. We will continue our efforts using innovative approaches towards this goal.”

Damage to the body’s peripheral nerves can cause pain and movement disorders. Researchers at the Leipzig University have recently investigated how damaged nerves can regenerate better. They found that fat tissue strongly supports the Schwann cells needed for repair during the healing process. The results were published in the journal Cell Metabolism.
Our bodies are transversed by millions of nerve fibres that transmit information. This allows us to do things like control muscles and perceive sensory impressions. Peripheral nerves, like those in our arms and legs, are often damaged by acute injuries, for example, in accidents. As a result, those affected suffer from loss of muscle strength and sensory problems such as numbness. Peripheral nerves do have a strong regenerative potential, but complete recovery of nerve function is still rare for reasons that are not yet fully understood.
When a nerve is crushed or severed, the individual nerve fibres affected by the damage initially die. In principle, they have the ability to grow back and regenerate completely. This depends on the Schwann cells that surround the nerve fibres. These cells do not die after nerve damage, but instead are responsible for coordinating the breakdown and regrowth of nerve fibres in their original areas. Schwann cells therefore play a key role in the repair process. It was previously unknown how these cells cope with the enormous metabolic load associated with the breakdown and rebuilding of nerve tissue. Researchers at the University of Leipzig Medical Center have now discovered that Schwann cells receive crucial support with nerve repair from the fat tissue that surrounds nerves in the body. Using genetically modified mice, they have shown that the chemical messenger leptin plays a key role in this process.
Leptin is mainly produced by cells in fat tissue and is known for its appetite-suppressing effects in the context of nutrition. Surprisingly, the current research project showed that leptin signalling is also an important factor in the repair of damaged nerves by Schwann cells. “Leptin derived from fat cells stimulates the energy balance of the Schwann cells by activating their mitochondria,” explains Dr Robert Fledrich from the Institute of Anatomy at Leipzig University and one of the two study leaders.
“At the same time, the mitochondria of the Schwann cells use parts of the damaged nerve tissue as an energy substrate so that successful regeneration can take place,” adds Professor Ruth Stassart from the Paul Flechsig Institute of Neuropathology at the University of Leipzig Medical Center and co-leader of the study. “The metabolism of the Schwann cells is therefore optimised for nerve regeneration and significantly promotes the restoration of the original nerve function,” the two researchers explain.
The communication between fat cells and Schwann cells could potentially open up new treatment options that positively influence the metabolism of repair cells in the event of nerve damage. The researchers hope that the new findings will help to improve the regeneration of damaged nerves in humans in the future.

Life expectancy and healthy ageing in mice can be determined by a protein present in some cells of the immune system, according to a study published in the journal Cell Reports. When this protein — known as the CD300f immune receptor — is absent, animal models have a shorter life expectancy and suffer from pathologies associated with cognitive decline and premature ageing, especially in females.
“Our study indicates that alterations in immune system cells, for instance, in macrophages and microglia, can determine the healthy ageing degree in mice,” notes Hugo Peluffo, leader of this study and member of the Faculty of Medicine and Health Sciences and the Institute of Neurosciences (UBneuro) of the University of Barcelona.
Understanding how the CD300f immune receptor — and the myeloid cells of the immune system — can determine by themselves the onset rate of ageing-associated pathologies, “will help to better understand this process, and it will contribute to the design of strategies to regulate its action. For instance, using the immune receptor CD300f as a target in biomedicine,” notes the expert. “Also, our team has previously shown that some variants of the CD300f immune receptor could be useful as biomarkers in patients.”
The paper, whose first author is the expert Frances Evans (Institute Pasteur and Udelar), includes the participation of teams from the Molecular Imaging Uruguayan Center (CUDIM), among other institutions.
What is the role of this receptor in ageing?
The CD300f receptor is a protein expressed by immune system cells that modulates cell metabolism and inflammation. This study reveals the first evidence of its role in the processes related to ageing and senescence.
“In particular, we discovered that mice that lacked the CD300f immune receptor developed prematurely some pathologies associated with ageing (cognitive deficits, motor incoordination, tumours, etc.) and even damage in several organs such as the brain, the liver or the lungs. Moreover, we observed an important effect on females, the most affected ones,” says Hugo Peluffo.

The study is based on a detailed monitoring of several cohorts of animals for thirty months, a methodological innovation that allowed the researchers to see the process of real ageing in these animals without using accelerated ageing models, which do not fully represent a process that necessarily involves the gradual accumulation of changes with age.
Immune receptors and Alzheimer’s disease
The researcher points out that “the aim is to keep studying the consequences of the dysfunction of the CD300f immune receptor on brain ageing, in particular on microglia.”
In these lines, a project led by Professor Hugo Peluffo to study the relationship between ageing and Alzheimer’s disease has just received one of the Alzheimer’s research grants from the Pasqual Maragall Foundation. It will explore how immune cells in the nervous system, known as microglia, influence the ageing process and the late onset of Alzheimer’s. “In this project, funded by the Pasqual Maragall Foundation, we will study the potential role of this immune receptor in Alzheimer’s disease,” says the researcher.

As Americans gear up for winter, many will face one of their toughest foes: ice. From delaying flights to making roads slippery, ice accumulation on surfaces wreaks havoc in many ways.
But not all ice is created equal. In new research from the University of Illinois Chicago, scientists studied the stickiness of ice containing everyday contaminants such as salt, soap and alcohol. Most laboratory studies typically test ice made from pure water, but in nature, ice is seldom pure.
“Be it dirty sidewalks or the hull of Arctic-going marine ships, there’s always impurities there,” said senior author Sushant Anand, associate professor of mechanical and industrial engineering at UIC. “So, the natural question that comes to mind is: What is the influence of these compounds on how strongly ice sticks to surfaces?”
Anand’s laboratory prepared ice with varying concentrations of contaminants and tested how strongly they clung to different industrial materials. Surprisingly, they found that impure ice was much less sticky than ice made from pure water under certain conditions.
The cause of this slipperiness was traced back to the way water freezes when it contains impurities and the unique structure where ice touches a solid material, called a quasi-liquid layer.
“The ice region near a solid has liquid-like properties, and its thickness could contribute to how tightly ice sticks,” Anand said. “But this region is really difficult to analyze through experiments.”
So, he teamed up with UIC colleague Subramanian Sankaranarayanan and his group at UIC/Argonne National Laboratory to study this layer and how it changes with different levels of impurities, using molecular dynamics simulations. They found that as impure water freezes, it expels contaminants that drain along channels and ice-grain boundaries toward the ice base, where it forms a liquid layer that gives ice extra slipperiness.

“These insights could lead to the design of next-generation winterization techniques that slowly release contaminants to promote facile ice shedding,” said graduated PhD student Rukmava Chatterjee, first author of the paper.
The surprising test results raised another question: If small salt concentrations make ice less likely to stick to surfaces, why do ships in arctic climates that sail through salt water still struggle with ice formation?
Experiments revealed that the water freezing rate can influence how impurities migrate to regions where ice touches a solid. A slow freezing process causes the isolation of contaminants into concentrated pockets or even complete expulsion, producing purer and stronger ice. Faster freezing preserves the contaminants within the ice and their accumulation at the ice-solid interface, leading to weaker adhesion.
“Our study represents just the tip of the iceberg, opening new lines of investigation of how impure ice adheres with widespread implications across multiple disciplines,” Anand said.
In addition to Anand, Chatterjee and Sankaranarayanan, UIC co-authors include Rajith Unnikrishnan Thanjukutty, Christopher Carducci, Arnab Neogi, Suman Chakraborty, Vijay Prithiv Bathey Ramesh Bapu and Suvo Banik.
The research was supported by the National Science Foundation CBET-1805753 and CBET-1847627. Simulation studies were performed at the Center for Nanoscale Materials, a U.S. Department of Energy Office of Science User Facility, and supported by the U.S. DOE, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.

An international study group led by researchers of Children’s Hospital of Philadelphia (CHOP) have identified how three novel genes cause neurodevelopmental disorders. Researchers now have a better sense of the genes’ roles in human brain development and function and their ability to serve as potential therapeutic targets in the future. The findings were recently published online by the Journal of Clinical Investigation.
Over the last couple of decades, researchers have identified more than 1500 genes in different signaling pathways associated with neurodevelopmental disorders. On average, about one third of patients with neurodevelopmental disorders receive a genetic diagnosis. However, little is known about how these genes are networked and how their malfunction leads to these disorders.
Prior research in other disorders has shown that issues related to gene splicing may be to blame. Before being turned into proteins, genes are transcribed into introns, or strands of RNA that do not code for proteins, and exons that code for proteins. Introns are removed in a process called splicing, which is carried out by a protein complex called the spliceosome. Variants impacting the spliceosome have rarely been implicated with neurodevelopmental disorders. However, through a series of complex testing, researchers in this study showed that malfunctions in the spliceosome are responsible for some neurodevelopmental disorders.
“Using multiple techniques, including phenotyping, genomic sequencing and modeling in fly and stem cells, we were able to map the genetic architecture of three genes associated with neurodevelopmental disorders, particularly developmental delay, intellectual disability and autism,” said Dong Li, Ph.D., a research faculty member in the Center for Applied Genomics and the Division of Human Genetics at CHOP and lead author on the study. “Combining fly and human genetics helped us understand the mechanisms of how variants of these genes affect the machinery of the spliceosome and cause these disorders.”
In this study, researchers utilized genomic and clinical data from unrelated patients with neurodevelopmental disorders. Among the cohort, 46 patients had missense variants of the gene U2AF2 and six patients had variants of the gene PRPF19. In human stem cell and fly models, the researchers noticed issues with the formation of neurites, or protrusions on neurons that give them their shape, as well as issues with splicing and social deficits in the fly models. Deeper profiling revealed that at third gene, RBFOX1, had missense variants that affected splicing and loss of proper neuron function. These findings were later compared with those of patients in the study, which confirmed that variants in the three genes can lead to neurodevelopmental disorders.
“We used fruit flies to study the effects of losing the function of these three genes one at a time and found that two genes independently led to brain structural and functional abnormalities, highlighting the essentiality of these genes in development,” said study co-author Yuanquan Song, Ph.D., an associate professor from the Department of Pathology & Laboratory Medicine at CHOP. “Apart from identifying patients with such variants in these genes for the first time, our extended translational modeling study efforts aimed to determine the underlying functions for these variants further elucidated their clinical relevance.”
“Not only does this study identify three causative genes associated with neurodevelopmental disorders, but it helps us understand how critical pre-mRNA splicing is to the development of the central nervous system,” said senior study author Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at CHOP.

Graphene, a material which consists of a single layer of carbon atoms, has been celebrated by many as the “next big thing” in material science. But according to Purdue University researchers, its thermal properties may not be as revolutionary as previously thought.
“Graphene is the first two-dimensional material that human beings ever created,” said Xiulin Ruan, professor of mechanical engineering. “It’s basically a layer of carbon, one atom thick. It was first discovered in 2004, and won the Nobel Prize for Physics in 2010. Ever since then, it’s been studied by many researchers because of its unique properties.”
For example, graphene is said to conduct electricity better than any other material known to science, and is known for its material strength. Thermal transport researchers were also quick to give it the title of best heat conductor.
“Previously, the material thought to have the highest thermal conductivity was diamond,” said Zherui Han, a Ph.D. student in Ruan’s lab. “That’s the material that can transfer the most heat the quickest. But when graphene came out, mainstream studies showed it to be much better than diamond.”
Thermal conductivity is measured in watts per meter per Kelvin. On this scale, diamond’s thermal conductivity is generally understood to be about 2,000. But when scientists started measuring graphene’s thermal conductivity, early estimates reached above 5,000. Obviously this caught the interest of scientists like Ruan, whose research focuses on heat transfer.
“However, subsequent experimental measurements and modeling have refined graphene’s thermal conductivity,” Ruan said. “More recent papers brought the number to around 3,000, which is still quite better than diamond. But we found something altogether different.”
Ruan’s team has predicted the thermal conductivity of graphene at room temperature to be 1,300 W/(m K) — not only less than diamond, but also less than the raw graphite material that graphene is made from.

Their research has been published in Physical Review B as a letter, due to the significance and timeliness of the work.
The disparity between their work and previous work comes down to a phenomenon called four-phonon scattering. Phonons are how heat transfer scientists describe the movement of heat in solids on a quantum-mechanical level. Until recently, researchers could only understand three-phonon scattering to predict the transfer of heat through solids. But in 2016, Ruan’s team developed a general theory of four-phonon scattering, and a year later they successfully quantified four-phonon scattering. This led to Ruan receiving the highest honor from the International Phononics Society in 2023.
So how does this relate to graphene? “Graphene is a two-dimensional material of only one atom thick,” Han said. “Previous studies suggest that three-phonon scattering would be restricted by this two-dimensionality, which in theory makes graphene much more thermally conductive than bulk materials. But four-phonon scattering is not restricted by the 2D nature of graphene; in fact, the effect is quite strong. Our work has shown that four-phonon scattering becomes the leading scattering channel in graphene over three-phonon scattering. This is a striking result.”
One barrier to this discovery had been the availability of raw computing power. Calculating this four-phonon scattering required a parallel computing strategy, essentially utilizing a computing cluster with one terabyte of memory. This was accomplished at the Rosen Center for Advanced Computing at Purdue University.
At the moment, these calculations are all theoretical. The team is currently working with Prof. Li Shi at the University of Texas at Austin, supported by their collaborative National Science Foundation grants, to verify the findings experimentally. Previous measurements on graphene have had large error bars, which need to be reduced to verify their theory. They also plan to predict the thermal conductivity of graphene of multiple layers of atoms, rather than just one.
“Without experimental validations as yet, we know the community will be skeptical about this very non-mainstream prediction,” Ruan said. “We faced the same skepticism in 2017, when we predicted similar aspects of boron arsenide. Fortunately, that prediction was confirmed by three important experiments a year later. Since then, our four-phonon scattering theory has been supported by more and more experimental evidences, and we hope it will hold for graphene as well this time. We make our software open source, so other scientists can test the four-phonon theory.”
Zherui Han has posted his four-phonon thermal conductivity solver on GitHub, and published a paper describing the software’s usage. Any heat transfer scientist is welcome to use the software to conduct similar research.

“Graphene being the first two-dimensional material, many people thought it was like magic,” Han said. “It was believed to have all these superior properties: thermal, mechanical, optical, electrical. As thermal researchers, it’s our job to establish whether that part is true. Graphene is still a good heat conductor, but our work predicts it’s not better than diamond.”
“I always say, exceptions are how science moves forward,” Ruan said. “We are cautiously optimistic about our findings. With four-phonon scattering, it’s our hope to deliver much more accurate theoretical assessments of these materials in the future.”
This research was supported in part by the National Science Foundation (Grants No. 2015946 and No. 2321301).

Myelin is an insulating sheath around axons — the processes connecting nerve cells — that is mostly composed of lipids and proteins. It enables rapid conduction of electrical signals and supports neuronal integrity and function. In the central nervous system, myelin is formed by specialized glial cells called oligodendrocytes. Myelinated fiber tracts are particularly vulnerable to various pathogenic processes and myelin diseases are often associated with chronic inflammation of the nervous system. A prime example is multiple sclerosis, a serious and frequent neurological disease in which immune cells drive demyelination, i.e., the loss of myelin. However, maladaptive immune reactions also contribute to other disorders associated with myelin defects, including hereditary and aging-related diseases.
Importantly, the degeneration of axons and neurons is a major determinant of clinical disease severity in such disorders. It is generally assumed that loss of myelin leads to increased vulnerability of denuded axons to a toxic inflammatory milieu and ultimately results in their demise. This purely detrimental view of demyelination is challenged by a recent study conducted at the Department of Neurology under corresponding author and lecturer Dr. Janos Groh from the Section of Developmental Neurobiology (Prof. Dr. Rudolf Martini, University Hospital Würzburg) and in collaboration with the Institute of Molecular Neurobiology (Prof. Dr. Mikael Simons, Technical University of Munich). Supported by Prof. Dr. Antoine-Emmanuel Saliba from the Helmholtz Institute for RNA-based Infection Research (Würzburg) and teams of researchers from Hannover, and Cambridge, they now published the results of their study in the scientific journal Nature Communications.
Myelin Gene Defects Instigate Distinct Immune Reactions
To investigate the relationship between loss of myelin and axon degeneration, the researchers studied mouse models of rare diseases carrying defects in the major myelin protein of the central nervous system. “These models of rare monogenetic diseases offer unique opportunities to reveal mechanisms that have broad relevance for much more frequent disorders” says Rudolf Martini. The scientists had previously discovered that the formation of abnormal or “bad” myelin in these mice leads to an inflammatory reaction comprising an accumulation of cytotoxic CD8+ T cells. In the analyzed disease models, these adaptive immune cells target and damage fiber segments with abnormal myelin, reminiscent of multiple sclerosis.
Surprisingly and in contrast to the prevailing view, they found an inverse relationship of axon loss and demyelination when comparing the disease models. Fibers that remained myelinated despite the chronic attack of T cells had a higher risk to degenerate, while those that lost their myelin survived. Moreover, behavioral deficits of the mice correlated more clearly with neurodegeneration than demyelination.
Persistence of Abnormal Myelin as a Risk Factor for Axon Degeneration
“This inverse relationship was unexpected and prompted us to study the interactions of abnormal oligodendrocytes and another immune cell type called microglia in more detail” explains Janos Groh. Microglia are cells of the innate immune system that populate the central nervous system and can orchestrate detrimental as well as beneficial immune reactions. In their study, the authors used different pharmacological approaches to modulate the removal of abnormal myelin by microglia. We show that efficient microglia-mediated removal of perturbed myelin under adaptive immune attack allows the survival of axons at reversible stages of damage.” Groh adds. Thus, persistent ensheathment with “bad” myelin seems to be worse for neurons than the loss of myelin, at least when myelin is targeted by adaptive immunity.
Oligodendrocytes under Immune Attack Actively Harm Axons
The scientists could also identify a mechanism how oligodendrocytes attacked by T cells harm their axonal partners. They found an aberrant constriction response at the myelinating processes wrapped around the axons. “When we inhibited this aberrant constriction by paralyzing cytoskeletal filaments, we could reduce axon degeneration” Groh summarizes. “The T cell attack seemed to incite oligodendrocytes to strangulate axons like a constrictor snake” Martini adds.
“What is the biological sense of these highly organized, but self-mutilating processes?,” Martini asks. The researchers speculate that these reactions of oligodendrocytes can be beneficial in other conditions, like injuries to the nervous system. However, aberrant induction of these immune-driven mechanisms might be a harmful response in many diseases. According to Groh and Martini, their study identified putative targets for therapy in diseases associated with myelin defects and inflammation in the nervous system. Moreover, they emphasize that novel therapeutic approaches for myelin diseases ideally should block detrimental but still allow beneficial immune responses, like the removal of “bad” myelin. This might help to foster neural resilience mechanisms as a prerequisite for recovery from damage to the nervous system.

Taking into account whether people believe they are receiving a real treatment or a fake one (placebo) could provide better insights that could help improve interventions for conditions such as depression and ADHD.
A team of psychologists, led by Professor Roi Cohen Kadosh from the University of Surrey, analysed five independent studies that covered different types of neurostimulation treatments to understand the role of patients’ subjective beliefs. These patients included both clinical patients being treated for ADHD and depression, as well as healthy adults.
The study found that patients’ beliefs about whether they were receiving real or placebo treatments explained the treatment outcomes in four of the five studies. On some occasions, the subjects’ beliefs explained the treatment’s results better than the actual treatment itself. Assumptions about the treatment intensity also played a significant role in the treatment.
Professor Roi Cohen Kadosh from the University of Surrey said that the results have provided a twist that scientists must consider in future research:
“The common wisdom is that the same medical treatment would produce similar results across patients, but our latest study suggests a fascinating twist. While you’d expect uniform improvements in a group of people with depression undergoing the same neurostimulation treatment, outcomes can vary widely.
“What’s truly eye-opening is that this variability could be largely influenced by the participants’ own beliefs about the treatment they’re receiving. In essence, if an individual believes they’re receiving an effective treatment — even when given a placebo — that belief alone might contribute to significant improvements in their condition.”
In the first study analysed, 121 participants were treated with different forms of Transcranial Magnetic Stimulation (rTMS) for depression. The results showed that participants’ perceptions about receiving real or placebo treatment mattered more than the actual type of rTMS in reducing depression.

The second study involved 52 older people with late-life depression who received either a real or placebo of deep rTMS. Surrey researchers found that the effect of treatment on reducing depression scores depended on the combination of the participants’ perceptions about receiving real or placebo treatment and the actual treatment they received.
In the third dataset, researchers investigated the effects of home-based Transcranial Direct Current Stimulation (tDCS) treatment on 64 adults diagnosed with ADHD. At the end of the study, participants’ beliefs about the treatment they thought they had received were also collected. This study differed from the first two as both the subjects’ beliefs and the actual treatment had a dual effect on reducing inattention scores.
In the fourth study, 150 healthy participants got varying doses of tDCS for mind wandering. Those who believed they got a more potent dose reported more mind wandering, even if the actual treatment wasn’t a factor.
The fifth study analysed the impact of transcranial random noise stimulation on working memory. Unlike previous studies, participants’ beliefs didn’t affect the results, highlighting the varying influence of beliefs in brain stimulation research. Thus, Roi Cohen Kadosh and his team show how subjective beliefs can vary in their effect on research — from fully explaining results beyond the actual treatment, to interacting with the treatment, to having no influence at all.
Dr Shachar Hochman, a co-author on this work from the University of Surrey, said:
“The concept that a placebo or sham treatment can mimic genuine treatment effects is well-established in science. While researchers have closely monitored this phenomenon, it has been typically catalogued separately from the in-depth analyses of the actual treatment outcomes. What sets our study apart is that we have brought together these two datasets — subjective beliefs and objective treatment measures. This has the potential to reveal new insights into treatment efficacy.”
Professor Roi Cohen Kadosh added:
“Our findings show that there could be real value in recording participants’ subjective beliefs at multiple points in the experiment to better understand their impact and put forward the importance of sharing this data and incorporating it within the research process. Recording beliefs might be useful beyond the realms of neurostimulation — we may find similar results in pharmacological studies and more state-of-the-art interventions such as virtual reality, and I would encourage other scientists to use our analytical approach to re-examine results in past interventions and to incorporate it in future ones.”

Each year in the United States there are more than 3 million cases of peripheral neuropathy, wherein nerves outside of the brain and spinal cord are damaged and cause pain and loss of feeling in the affected areas. Peripheral neuropathy can occur from diabetes, injury, genetically inherited disease, infection, and more. Salk scientists have now uncovered in mice a mechanism for repairing damaged nerves during peripheral neuropathy. They discovered that the protein Mitf helps turn on the repair function of specialized nervous system Schwann cells.
The findings, published in Cell Reports on November 28, 2023, have the potential to inspire novel therapeutics that bolster repair function and heal peripheral neuropathy.
“We wanted to know what mechanisms control damage response in peripheral nerves under varying conditions — like acute trauma, genetic disorders, or degenerative diseases,” says senior author Professor Samuel Pfaff. “We found that Schwann cells, which are special cells in nerves that protect and support neurons’ axons, enter their repair state because of a pathway mediated by the protein Mitf.”
The peripheral nervous system is made up of all the nerves that branch out from the brain and spinal cord to give us sensation throughout our bodies. There are many cell types in peripheral nerves, but Pfaff and his team focus on understanding neurons, which transmit information throughout the nervous system, and Schwann cells, which protect healthy neurons and repair damaged ones.
The peripheral nervous system’s ability to repair damage is remarkable considering that the central nervous system — made up of the brain and spinal cord — is not able to repair damage. Yet, the mechanisms that orchestrate this feat have remained poorly understood.
To unravel how Schwann cells differentiate to begin repairing peripheral nerve damage, the researchers looked at mouse models of Charcot Marie Tooth disease (CMT), a type of hereditary neuropathy.
“Going into this project, I thought that when you have a genetic nerve degeneration disorder, cells are dying and recovery isn’t possible,” says first author Lydia Daboussi, a former postdoctoral researcher in Pfaff’s lab and current assistant professor at UC Los Angeles. “But our findings show that there are gene programs turned on by Mitf that repair some of the damage done in those chronic disease scenarios, and when you turn those programs off, disease symptoms get worse.”
In mice with CMT, the researchers noticed that the Schwann cells completing the repairs had high levels of Mitf in their nuclei — where the genetic instructions for how to be a Schwann cell and how to conduct repairs are stored.

Upon investigation of this relationship between Mitf and Schwann cells, they found that Mitf was in the cytoplasm of Schwann cells until sensing neuronal damage. Damage then prompted Mitf to relocate from the cytoplasm of the cell to the nucleus, where it would direct the Schwann cell to make repairs.
To validate the importance of Mitf in creating repair Schwann cells, the researchers removed Mitf altogether. In cases of both trauma and CMT, nerve repair was arrested in the absence of Mitf — demonstrating that Mitf is required for peripheral nerve repair and regeneration.
According to Daboussi, Mitf acts like a fire extinguisher. Always there, sitting in the Schwann cell, unnoticed until damage occurs. And when that damage occurs, Mitf is ready to go and immediately turns on the cell’s repair functions.
Most surprising, noted Pfaff, was that Mitf was orchestrating these repairs during a chronic disease like CMT.
“Harnessing Schwann cell repair programs has great potential in treating chronic diseases,” says Pfaff, also the Benjamin H. Lewis Chair at Salk. “It’s possible that with targeted therapeutics, we can prompt more Schwann cells to repair peripheral nerve damage and push those repairs to completion in chronic cases. Furthermore, now that we have a better grasp on the repair mechanisms, we can see if it’s possible to initiate repairs in the brain stem and spinal cord, too.”
In the future, the researchers want to look more specifically at diabetes neuropathy — the most common peripheral neuropathy condition. They also hope to explore therapeutics that bolster this repair pathway to create more Schwann cells programmed to repair damage, regardless of if the source is trauma, genetics, or development over time.
Other authors include Giancarlo Costaguta, Miriam Gullo, Nicole Jasinski, Veronica Pessino, Brendan O’Leary, Karen Lettieri, and Shawn Driscoll of Salk.
The work was supported by the Sol Goldman Charitable Trust, Howard Hughes Medical Institute, National Institutes of Health (grants NCI CCSG: P30 014195, NCI CCSG: P30 014195, S10 OD023427, S10 OD026929, 1 RO1 NS123160-01), a George E. Hewitt Fellowship, a Salk Women & Science Fellowship, and a Jonas Salk Fellowship.