NS/ Bridging brain circuits with lab-grown neural networks
Neuroscience biweekly vol. 108, 10th April — 24th April
TL;DR
- Researchers have developed a technique to connect lab-grown neural ‘organoids’ (three-dimensional developmental brain-like structures grown from human stem cells) using axonal bundles, similar to the connections between regions in the human brain. This technique allows brain networks to be better represented experimentally in the lab and will improve understanding and studies of network-related brain disorders.
- Rice University engineers have developed the smallest implantable brain stimulator demonstrated in a human patient. Thanks to pioneering magnetoelectric power transfer technology, the pea-sized device developed in the Rice lab of Jacob Robinson in collaboration with Motif Neurotech can be powered wirelessly via an external transmitter and used to stimulate the brain through the dura ⎯ the protective membrane attached to the bottom of the skull.
- A new study has used virtual reality (VR) to help reduce cancer pain for hospitalized patients, potentially providing a non-invasive and non-pharmacologic approach to improve the quality of life for people with cancer.
- Northwestern Medicine investigators have developed a method to measure protein expression in an individual neuron, a discovery that will enable scientists to study how this process goes awry in disease, according to a study published in Molecular Psychiatry.
- Through a large-scale analysis, researchers at the Netherlands Institute for Neuroscience have uncovered the ways in which consensual touch can benefit a person’s physical and mental well-being.
- A University of Michigan study has shown that traumatic experiences during childhood may get “under the skin” later in life, impairing the muscle function of people as they age. The study examined the function of skeletal muscle of older adults paired with surveys of adverse events they had experienced in childhood. It found that people who experienced greater childhood adversity, reporting one or more adverse events, had poorer muscle metabolism later in life.
- A single low dose of esketamine — the active form of the anesthetic drug, ketamine — can reduce depressive episodes when given immediately after childbirth, a new study has found. The research, published in The British Medical Journal, suggests esketamine treatment could be considered after birth for those with depressive symptoms in pregnancy.
- When the brain has trouble filtering incoming information and predicting what’s likely to happen, psychosis can result, Stanford research shows.
- More synchrony between parents and children may not always be better, new research has revealed. For the first time a new study looked at behavioral and brain-to-brain synchrony in 140 families with a special focus on attachment. It looked at how they feel and think about emotional bonds whilst measuring brain activity as mums and dads solved puzzles with their kids.
- University of California, Irvine biomedical engineering researchers have uncovered a previously unknown source of two key brain waves crucial for deep sleep: slow waves and sleep spindles. Traditionally believed to originate from one brain circuit linking the thalamus and cortex, the team’s findings, published today in Scientific Reports, suggest that the axons in memory centers of the hippocampus play a role.
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The latest news and research
Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons
by Tatsuya Osaki, Tomoya Duenki, Siu Yu A. инChow, Yasuhiro Ikegami, Romain Beaubois, Timothée Levi, Nao Nakagawa-Tamagawa, Yoji Hirano, Yoshiho Ikeuchi in Nature Communications
The idea of growing functioning human brain-like tissues in a dish has always sounded pretty far-fetched, even to researchers in the field. Towards the future goal, a Japanese and French research team has developed a technique for connecting lab-grown brain-mimicking tissue in a way that resembles circuits in our brains.
It is challenging to study the exact mechanisms of brain development and functions. Animal studies are limited by differences between species in brain structure and function, and brain cells grown in the lab tend to lack the characteristic connections of cells in the human brain. What’s more, researchers are increasingly realizing that these interregional connections, and the circuits that they create, are important for many of the brain functions that define us as humans.
Previous studies have tried to create brain circuits under laboratory conditions, which have been advancing the field. Researchers from The University of Tokyo have recently found a way to create more physiological connections between lab-grown “neural organoids,” an experimental model tissue in which human stem cells are grown into three-dimensional developmental brain-mimicking structures. The team did this by linking the organoids via axonal bundles, which is similar to how regions are connected in the living human brain.
“In single-neural organoids grown under laboratory conditions, the cells start to display relatively simple electrical activity,” says co-lead author of the study Tomoya Duenki. “when we connected two neural organoids with axonal bundles, we were able to see how these bidirectional connections contributed to generating and synchronizing activity patterns between the organoids, showing some similarity to connections between two regions within the brain.”
The cerebral organoids that were connected with axonal bundles showed more complex activity than single organoids or those connected using previous techniques. In addition, when the research team stimulated the axonal bundles using a technique known as optogenetics, the organoid activity was altered accordingly and the organoids were affected by these changes for some time, in a process known as plasticity.
“These findings suggest that axonal bundle connections are important for developing complex networks,” explains Yoshiho Ikeuchi, senior author of the study. “Notably, complex brain networks are responsible for many profound functions, such as language, attention, and emotion.”
Given that alterations in brain networks have been associated with various neurological and psychiatric conditions, a better understanding of brain networks is important. The ability to study lab-grown human neural circuits will improve our knowledge of how these networks form and change over time in different situations, and may lead to improved treatments for these conditions.
Miniature battery-free epidural cortical stimulators
by Woods JE, Singer AL, Alrashdan F, et al. in Science Advances
Rice University engineers have developed the smallest implantable brain stimulator demonstrated in a human patient. Thanks to pioneering magnetoelectric power transfer technology, the pea-sized device developed in the Rice lab of Jacob Robinson in collaboration with Motif Neurotech and clinicians Dr. Sameer Sheth and Dr. Sunil Sheth can be powered wirelessly via an external transmitter and used to stimulate the brain through the dura ⎯ the protective membrane attached to the bottom of the skull.
The device, known as the Digitally programmable Over-brain Therapeutic (DOT), could revolutionize treatment for drug-resistant depression and other psychiatric or neurological disorders by providing a therapeutic alternative that offers greater patient autonomy and accessibility than current neurostimulation-based therapies and is less invasive than other brain-computer interfaces (BCIs).
“In this paper we show that our device, the size of a pea, can activate the motor cortex, which results in the patient moving their hand,” said Robinson, a professor of electrical and computer engineering and of bioengineering at Rice. “In the future, we can place the implant above other parts of the brain, like the prefrontal cortex, where we expect to improve executive functioning in people with depression or other disorders.”
Existing implantable technologies for brain stimulation are powered by relatively large batteries that need to be placed under the skin elsewhere in the body and connected to the stimulating device via long wires. Such design limitations require more surgery and subject the individual to a greater burden of hardware implantation, risks of wire breakage or failure and the need for future battery replacement surgeries.
“We eliminated the need for a battery by wirelessly powering the device using an external transmitter,” explained Joshua Woods, an electrical engineering graduate student in the Robinson lab and lead author on the study published in Science Advances. Amanda Singer, a former graduate student in Rice’s applied physics program who is now at Motif Neurotech, is also a lead author.
The technology relies on a material that converts magnetic fields into electrical pulses. This conversion process is very efficient at small scales and has good misalignment tolerance, meaning it does not require complex or minute maneuvering to activate and control. The device has a width of 9 millimeters and can deliver 14.5 volts of stimulation.
“Our implant gets all of its energy through this magnetoelectric effect,” said Robinson, who is founder and CEO of Motif, a startup formed through the Rice Biotech Launch Pad that is working to bring the device to market. “The physics of that power transfer makes this much more efficient than any other wireless power transfer technologies under these conditions.”
Motif is one of several neurotech companies that are probing the potential of BCIs to revolutionize treatments for neurological disorders.
“Neurostimulation is key to enabling therapies in the mental health space where drug side effects and a lack of efficacy leave many people without adequate treatment options,” Robinson said.
The researchers tested the device temporarily in a human patient, using it to stimulate the motor cortex ⎯ the part of the brain responsible for movement ⎯ and generating a hand movement response. They next showed the device interfaces with the brain stably for a 30-day duration in pigs.
“This has not been done before because the quality and strength of the signal needed to stimulate the brain through the dura were previously impossible with wireless power transfer for implants this small,” Woods said.
Robinson envisions the technology being used from the comfort of one’s home. A physician would prescribe the treatment and provide guidelines for using the device, but patients would retain complete control over how the treatment is administered.
“Back home, the patient would put on their hat or wearable to power and communicate with the implant, push ‘go’ on their iPhone or their smartwatch and then the electrical stimulation from that implant would activate a neuronal network inside the brain,” Robinson said.
Implantation would require a minimally invasive 30-minute procedure that would place the device in the bone over the brain. Both the implant and the incision would be virtually invisible, and the patient would go home the same day.
“When you think about a pacemaker, it’s a very routine part of cardiac care,” said Sheth, professor and vice-chair of research, McNair Scholar and Cullen Foundation Endowed Chair of Neurosurgery at the Baylor College of Medicine.
“In neurological and psychiatric disorders, the equivalent is deep brain stimulation (DBS), which sounds scary and invasive. DBS is actually quite a safe procedure, but it’s still brain surgery, and its perceived risk will place a very low ceiling on the number of people who are willing to accept it and may benefit from it. Here’s where technologies like this come in. A 30-minute minor procedure that is little more than skin surgery, done in an outpatient surgery center, is much more likely to be tolerated than DBS. So if we can show that it is about as effective as more invasive alternatives, this therapy will likely make a much larger impact on mental health.”
For some conditions, epilepsy for example, the device may need to be on permanently or most of the time, but for disorders such as depression and OCD, a regimen of just a few minutes of stimulation per day could suffice to bring about the desired changes in the functioning of the targeted neuronal network.
In terms of next steps, Robinson said that on the research side he is “really interested in the idea of creating networks of implants and creating implants that can stimulate and record, so that they can provide adaptive personalized therapies based on your own brain signatures.” From the therapeutic development standpoint, Motif Neurotech is in the process of seeking FDA approval for a long-term clinical trial in humans. Patients and caregivers can sign up on the Motif Neurotech website to learn when and where these trials will begin.
Virtual reality for pain management in hospitalized patients with cancer: A randomized controlled trial
by Groninger H, Violanti D, Mete M. in Cancer
A new study has used virtual reality (VR) to help reduce cancer pain for hospitalized patients, potentially providing a non-invasive and non-pharmacologic approach to improve the quality of life for people with cancer.
People with cancer can experience high levels of pain, caused not only by the disease itself but also by its treatment. Strong painkillers such as opioids are often required to manage these high levels of pain. However, these come with their own risks and side effects.
New, non-invasive and non-pharmacologic approaches are needed to treat these types of pain and improve patients’ quality of life. But how can we achieve this? Enter the power of VR.
VR headsets are a common sight in the homes of many gamers, helping to create a more immersive gaming experience by placing users into new environments and exploring virtual worlds — and it is this immersive experience that is being harnessed by pain researchers.
VR approaches have been investigated for some conditions as a type of distraction therapy to draw attention away from pain. But not much has been achieved on this front for cancer pain, explains the study’s lead author, Dr. Hunter Groninger.
“Researchers have continued to look at VR to improve acute procedure-related pain and chronic low back pain,” said Groninger, a professor of medicine at Georgetown University and director of the Section of Palliative Care at MedStar Washington Hospital Center. “But there have been few developments in the space of cancer-related pain, something that is important to me as a palliative care researcher and certainly important to our patients living with cancer pain.”
In the new study, Groninger and colleagues enrolled 128 hospitalized cancer patients experiencing moderate to severe pain. They compared the effects of 10 minutes of immersive VR distraction therapy against 10 minutes of 2D guided imagery distraction therapy using a tablet device.
Patients scored their pain from 0–10 (10 being the most severe). This revealed that those in the VR group self-reported sustained and significant decreases in pain severity — dropping by 1.4 on average — compared to the 2D imagery, which led to an average decrease of 0.7.
Surprisingly, some of the benefits of VR therapy also extended 24 hours after the treatment — pain scores the next day were sustained at 1.7 points lower than baseline for the VR group and 0.3 lower for the 2D imagery group.
“Why this sustained benefit happens is unclear right now,” explained Groninger. “Perhaps the immersive nature of VR experiences impacts pain pathways in the body somehow. Whatever the mechanism may be, this phenomenon is an important part of our ongoing and future research. These differences are important to tease out how pain impacts our daily lived experience, particularly since pain remains so subjective,” said Groninger.
Further optimization is required before clinical use
Next, the researchers are interested in expanding on their findings by studying the effects of VR therapy “dosing” to determine if it works better if used when needed, or as part of a regular schedule.
“For example, we are interested to learn what might happen if we administer VR pain therapy every day, similar to how we administer a traditional pain medication,” Groninger explained.
However, it will take time before the therapy can be integrated into clinical practice.
“We need to learn more before knowing the future of VR in this setting,” Groninger said. “Who benefits from VR pain therapies the most? Do some VR experiences work better than others? What is the neural mechanism by which immersive VR can improve acute or chronic pain? Most of all, what do our patients want from VR, and how we can support them?”
Neuron type-specific proteomics reveals distinct Shank3 proteoforms in iSPNs and dSPNs lead to striatal synaptopathy in Shank3B–/– mice
by Wang YZ, Perez-Rosello T, Smukowski SN, Surmeier DJ, Savas JN. in Mol Psychiatry
Northwestern Medicine investigators have developed a method to measure protein expression in an individual neuron, a discovery that will enable scientists to study how this process goes awry in disease, according to a study published in Molecular Psychiatry.
Neurons in the brain communicate primarily through chemical signals and disruption in neuronal communication can lead to disorders such as autism, Parkinson’s and Alzheimer’s disease. Previously, scientists had no way of measuring protein expression within a single type of neuron, which limited how closely they could study dysfunctional neurons.
“We were motivated to make these new tools to actually study how synaptic proteins are changed and how these processes could contribute to the functional deficits seen in specific neurological disorders,” said Jeffrey Savas, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Behavioral Neurology and senior author of the study.
In the study, Savas and his collaborators developed synaptic probes, which consisted of a virus activated by a protein present in a specific type of neuron. Once inside a mouse and activated, the virus would release a protein capable of “tagging” other proteins expressed by the neuron, allowing investigators to pinpoint, monitor, and quantify the proteins expressed in a particular type of neuron.
First, the investigators studied two types of neurons in the striatum, an area of the brain involved in decision-making functions, such as motor control, emotion and habit formation. According to the study, they found that protein expression was similar in both direct and indirect pathway spiny projection neurons (dSPNs and iSPNs), two of the major neuron types in the striatum.
“The surprise was that while the protein identities were not dissimilar, the expression of the isoforms was,” Savas said. “Isoforms are like cousins of proteins that are related, but they might be shorter or longer but are still encoded from the same gene.”
In particular, the isoforms produced by the gene SHANK3 in neurons were starkly different, Savas said. SHANK3 has long been thought to play a key role in autism spectrum disorders, but confounded scientists studying it because mutations in the gene led to markedly different symptoms across individuals.
By tracking neuronal protein expression with their new probes in Shank3b knockout mice, the investigators discovered that several SHANK3 isoforms were expressed by dSPNs but were undetectable in iSPNs, which resulted in hampered neuronal communication in mice. Notably, these dSPNs appeared healthier than the iSPNs, a difference that contributed to an imbalance in synaptic transmission within the basal ganglia. Remarkably, by reintroducing Shank3b isoforms in the knockout mice, investigators were able to rescue many of the synaptic deficits, according to the study.
The findings may also explain why people with autism caused by SHANK3 mutations can present with a wide range of symptoms, Savas said.
“This highlights a new aspect of molecular specificity in the mammalian brain,” Savas said. “Human patients who have mutations in the SHANK3 gene phenotypically look very different, but the mutations are in the same gene.
The most compelling possibility by which that happens is that those different mutations affect isoform-specific expression of SHANK3 protein isoforms in a cell-type-specific manner. The manifestation of that mutation impacts different parts of the brain and then those different parts of the brain are responsible for different phenotypes associated with autism.”
“Currently, we are applying these probes, to additional synapses, cell types, and different mouse models to see if we can elucidate similar mechanisms in the context of other neurological disorders,” Savas said.
A systematic review and multivariate meta-analysis of the physical and mental health benefits of touch interventions
by Packheiser J, Hartmann H, Fredriksen K, Gazzola V, Keysers C, Michon F. in Nature Human Behaviour
Through a large-scale analysis, researchers at the Netherlands Institute for Neuroscience have uncovered the ways in which consensual touch can benefit a person’s physical and mental wellbeing.
You might recognize the comforting feeling when someone offers you a hug at the end of a stressful day or strokes your shoulder when you’re feeling down. But the question remains: can touch really help you feel better, and does it matter who it’s from or how they touch you? To explore these questions, researchers from the Social Brain Lab at the Netherlands Institute for Neuroscience and the University Hospital Essen conducted a large-scale analysis of studies exploring touch interventions.
Does touch truly improve someone’s wellbeing? It is an easy question to ask but more complicated to answer. Individual studies often only focus on specific instances and may contradict each other. Combining all these studies together for a large-scale analysis offers a clearer answer: yes, touch substantially improves both physical and mental wellbeing, for example via reduction of pain, anxiety, depression, and stress in adults. But in fact, those with physical or mental health problems (and therefore most in need of support) benefit even more from touch than healthy adults. “This is especially relevant considering how often touch interventions are overlooked” Packheiser, first author, adds.
“A key question of our study is to leverage the hundreds of individual studies out there to identify what type of touch works best,” adds professor Keysers, director of the Social Brain Lab. “What if you don’t have a friend or partner close by to hug you? Would touch from a stranger or even a machine also help? And how often?. The study clearly shows that touch can indeed be optimized, but the most important factors are not necessarily those we suspect.”
Interestingly, the person touching you, how they touch you, and the duration of their touch doesn’t make a difference in terms of impact. A long-lasting massage by a therapist could therefore be just as effective as a quick hug offered by a friend. That is, until the frequency of the intervention is considered. The more often a touch intervention is offered, the greater the impact. A quick hug could therefore be even more impactful than a massage if it is offered more frequently.
The next question was whether touch intervention needs to be human at all. As it turns out, object or robot interventions can be equally effective at improving physical wellbeing.
“There are lots of people in need of wellbeing improvements, perhaps because they’re lonely but also because they may be inflicted by clinical conditions. These results indicate that a touch-robot, or even a simple weighted blanket has the potential to help those people”, last author Frédéric Michon explains. However, the benefits of robot and object interventions are less effective for mental wellbeing. Mental health disorders like anxiety or depression might therefore require human touch after all, “perhaps suggestive of the importance for an emotional component associated with the touch”, Michon point out.
While the researchers were equally curious about human-to-animal contact, studies exploring this question are still lacking.
“It would be useful to see whether an animal’s or pet’s touch could improve wellbeing, and inversely if they also benefit from it, but unfortunately there simply aren’t enough studies, or properly controlled ones, for us to draw any general conclusions on these topics”, Michon clarifies.
When the team looked into the impact of touch on newborns, they found out that newborns also benefited significantly from touch. However, the person conducting the touch intervention was more important: the benefits of touch are higher when done by a parent instead of a healthcare worker.
“This finding could be impactful”, Packheiser adds. “Death rates due to premature births are high in some countries and the knowledge that a baby benefits more from the touch of their own parent offers another easily implementable form of support for the baby’s health”.
Due to a lack of studies, it proved difficult to draw conclusions about children and teenagers.
“Large scale studies like this help us draw more general conclusions but they also help us identify where research is lacking”, Michon explains. “We hope that our findings can steer future research to explore lesser-known questions. This includes animal touch, but also touch across ages, and in specific clinical settings like autistic patients, another category that has not been explored extensively”.
Childhood adverse life events and skeletal muscle mitochondrial function
by Duchowny KA, Marcinek DJ, Mau T, et al. in Science Advances
A University of Michigan study has shown that traumatic experiences during childhood may get “under the skin” later in life, impairing the muscle function of people as they age. The study examined the function of skeletal muscle of older adults paired with surveys of adverse events they had experienced in childhood. It found that people who experienced greater childhood adversity, reporting one or more adverse events, had poorer muscle metabolism later in life. The research, led by University of Michigan Institute for Social Research scientist Kate Duchowny, is published in Science Advances.
Duchowny and her co-authors used muscle tissue samples from people participating in the Study of Muscle, Mobility and Aging, or SOMMA. The study includes 879 participants over age 70 who donated muscle and fat samples as well as other biospecimens. The participants also were given a variety of questionnaires and physical and cognitive assessments, among other tests.
The researchers examined muscle biopsies to determine two key features of muscular function: the production of adenosine triphosphate, or ATP, and another measure called oxidative phosphorylation, a process that helps produce ATP. Produced by organelles within cells called mitochondria, ATP provides the chemical energy to fuel cellular function.
The researchers also used data from questionnaires that included a set of questions such as: Did a close family member use drugs or alcohol in a way that caused you to worry? Did an adult or parent in your household insult you or put you down? Were you physically abused by a parent or adult in your household? Did you feel loved, important or special in your family? Were either of your parents absent for a portion of your life?
Duchowny found that about 45% of the sample reported experiencing one or more adverse childhood events, and that both men and women who reported adverse childhood events had poorer ATP max production — that is, they weren’t producing as much ATP as people who experienced fewer or no adverse events in childhood.
“What these results suggest is that these early formative childhood experiences have the ability to get under the skin and influence skeletal muscle mitochondria, which is important because mitochondrial function is related to a host of aging-related outcomes,” Duchowny said. “If you have compromised mitochondrial function, that doesn’t bode well for a range of health outcomes, including everything from chronic conditions to physical function and disability limitations.”
Study co-author Anthony Molina, professor of medicine at the University of California San Diego, provided expertise in muscle bioenergetics. He and the team looked at images of participants’ muscles taken during exercise and during rest inside an MRI machine. Using a technique called 31 PMR spectroscopy, SOMMA researchers were able to determine the rate of ATP synthesis by looking at how fast the muscle was able to synthesize ATP after it was depleted by exercise.
In addition, SOMMA researchers looked at the muscle biopsies of participants. The researchers teased apart the fiber bundles that compose muscle, and examined them using high-resolution mitochondrial respirometry. This technique allowed the researchers to look at the oxygen consumption rate in the muscle fiber bundle and generate a precise readout of muscle mitochondrial function.
“You can think about oxygen consumption rate as a way to measure the flow of electrons that’s going through the electron transport train, and it’s these electrons that generate the membrane potential that drives the synthesis of ATP,” Molina said. “It’s a really precise way of assessing mitochondrial bioenergetic capacity.”
Previous studies have shown that these measures are closely related to the physical abilities of older adults, Molinda says.
The researchers say the effects of childhood adverse events remained significant even after they controlled for other factors that could potentially impact muscle function such as age, gender, educational attainment, parental education, body mass index, number of depressive symptoms, smoking status and physical activity.
“All of my previous studies have been focused on contemporaneous measures: mitochondria and physical function, mitochondria and cognitive function,” Molina said. “These studies have shown that these measures are strongly related to our strength, fitness and numerous conditions that impact physical ability.
“I’ve also shown that these measures are related to cognitive ability and dementia. But here’s the first time we’re looking backwards, at what kinds of things that could lead to those differences in mitochondrial function that we know can drive differences in healthy aging outcomes among older adults.”
Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial
by Wang S, Deng CM, Zeng Y, et al. in BMJ
A single low dose of esketamine — the active form of the anesthetic drug, ketamine — can reduce depressive episodes when given immediately after childbirth, a new study has found. The research, published in The British Medical Journal, suggests esketamine treatment could be considered after birth for those with depressive symptoms in pregnancy.
Depression in pregnancy and shortly after birth — known as perinatal depression — is relatively common, with a prevalence of 6–13% in high-income countries and 26% in low-income countries.
It is a strong indicator of later postpartum depression and can have negative health implications for parents as well as babies.
However, when it comes to treating perinatal depression, traditional antidepressants are of limited benefit as they can take several weeks to work and some may present risks to the newborn.
On the other hand, drugs such as ketamine have shown rapid antidepressant effects for treatment-resistant depression — but it is unclear if the same may be true for perinatal depression.
In the new study, researchers recruited 361 new mothers preparing for childbirth across 5 Chinese hospitals. The participants had no medical history of depression but had scores consistent with mild prenatal depression on the Edinburgh postnatal depression scale.
Participants were randomly assigned to receive an IV infusion of either esketamine or a placebo shortly after birth. They were then interviewed 18–30 hours after birth, and again at 7 and 42 days.
By 42 days after birth, 6.7% of the participants given esketamine had experienced a major depressive episode compared to 25.4% of those given the placebo. This suggests that esketamine reduced the relative risk of a depressive episode by around three-quarters.
Based on these results, the researchers estimate that one major depressive episode would be prevented for every five participants given esketamine.
“This is a well-powered study that shows convincing evidence for the use of esketamine in the prevention of postpartum depression in mothers with some depression symptoms before birth,” said Dr. Camilla Nord, an assistant professor of cognitive neuroscience at the University of Cambridge, who was not involved in the study.
However, the large treatment effect also came with a high number of adverse events. The most frequent were dizziness and double vision — occurring in 44% of the esketamine group and 22% of the placebo group — though these lasted less than a day and did not require drug treatment.
“This study is an important, well-designed replication of previous work, all of which has come from China,” said Dr. Rupert McShane, an associate professor in the University of Oxford’s Department of Psychiatry, who was not involved in the study. “A single dose of intravenous esketamine (which is the active component of ketamine) is extraordinarily safe, effective and cheap for women at risk of worsening depression after childbirth.”
There are, however, several important limitations to the study. For example, participants in similar studies investigating ketamine and psychedelics are often able to tell if they were in the treatment or the placebo group, with their results potentially skewed by participants’ expectations.
Additionally, the study excluded those with mood disorders before their pregnancy, potentially affecting the validity of the results in the relatively short follow-up period. It also remains unclear whether esketamine would work for those with more severe depression, as most of the participants experienced mild depression.
“Overall, however, this study provides a strong indication that esketamine has treatment potential for preventing postpartum depression in mothers with mild prenatal depression,” Nord summarized.
Robust and replicable functional brain signatures of 22q11.2 deletion syndrome and associated psychosis: a deep neural network-based multi-cohort study
by Kaustubh Supekar, Carlo de los Angeles, Srikanth Ryali, Leila Kushan, Charlie Schleifer, Gabriela Repetto, Nicolas A. Crossley, Tony Simon, Carrie E. Bearden, Vinod Menon in Molecular Psychiatry
Inside the brains of people with psychosis, two key systems are malfunctioning: a “filter” that directs attention toward important external events and internal thoughts, and a “predictor” composed of pathways that anticipate rewards.
Dysfunction of these systems makes it difficult to know what’s real, manifesting as hallucinations and delusions.
The findings come from a Stanford Medicine-led study, publishing in Molecular Psychiatry, that used brain scan data from children, teens and young adults with psychosis. The results confirm an existing theory of how breaks with reality occur.
“This work provides a good model for understanding the development and progression of schizophrenia, which is a challenging problem,” said lead author Kaustubh Supekar, PhD, clinical associate professor of psychiatry and behavioral sciences.
The findings, observed in individuals with a rare genetic disease called 22q11.2 deletion syndrome who experience psychosis as well as in those with psychosis of unknown origin, advance scientists’ understanding of the underlying brain mechanisms and theoretical frameworks related to psychosis.
During psychosis, patients experience hallucinations, such as hearing voices, and hold delusional beliefs, such as thinking that people who are not real exist. Psychosis can occur on its own and is a hallmark of certain serious mental illnesses, including bipolar disorder and schizophrenia. Schizophrenia is also characterized by social withdrawal, disorganized thinking and speech, and a reduction in energy and motivation.
It is challenging to study how schizophrenia begins in the brain. The condition usually emerges in teens or young adults, most of whom soon begin taking antipsychotic medications to ease their symptoms. When researchers analyze brain scans from people with established schizophrenia, they cannot distinguish the effects of the disease from the effects of the medications. They also do not know how schizophrenia changes the brain as the disease progresses.
To get an early view of the disease process, the Stanford Medicine team studied young people aged 6 to 39 with 22q11.2 deletion syndrome, a genetic condition with a 30% risk for psychosis, schizophrenia or both.
Brain function in 22q11.2 patients who have psychosis is similar to that in people with psychosis of unknown origin, they found. And these brain patterns matched what the researchers had previously theorized was generating psychosis symptoms.
“The brain patterns we identified support our theoretical models of how cognitive control systems malfunction in psychosis,” said senior study author Vinod Menon, PhD, the Rachael L. and Walter F. Nichols, MD, Professor; a professor of psychiatry and behavioral sciences; and director of the Stanford Cognitive and Systems Neuroscience Laboratory.
Thoughts that are not linked to reality can capture the brain’s cognitive control networks, he said.
“This process derails the normal functioning of cognitive control, allowing intrusive thoughts to dominate, culminating in symptoms we recognize as psychosis.”
Normally, the brain’s cognitive filtering system — aka the salience network — works behind the scenes to selectively direct our attention to important internal thoughts and external events. With its help, we can dismiss irrational thoughts and unimportant events and focus on what’s real and meaningful to us, such as paying attention to traffic so we avoid a collision.
The ventral striatum, a small brain region, and associated brain pathways driven by dopamine, play an important role in predicting what will be rewarding or important.
For the study, the researchers assembled as much functional MRI brain-scan data as possible from young people with 22q11.2 deletion syndrome, totaling 101 individuals scanned at three different universities. (The study also included brain scans from several comparison groups without 22q11.2 deletion syndrome: 120 people with early idiopathic psychosis, 101 people with autism, 123 with attention deficit/hyperactivity disorder and 411 healthy controls.)
The genetic condition, characterized by deletion of part of the 22nd chromosome, affects 1 in every 2,000 to 4,000 people. In addition to the 30% risk of schizophrenia or psychosis, people with the syndrome can also have autism or attention deficit hyperactivity disorder, which is why these conditions were included in the comparison groups.
The researchers used a type of machine learning algorithm called a spatiotemporal deep neural network to characterize patterns of brain function in all patients with 22q11.2 deletion syndrome compared with healthy subjects. With a cohort of patients whose brains were scanned at the University of California, Los Angeles, they developed an algorithmic model that distinguished brain scans from people with 22q11.2 deletion syndrome versus those without it. The model predicted the syndrome with greater than 94% accuracy. They validated the model in additional groups of people with or without the genetic syndrome who had received brain scans at UC Davis and Pontificia Universidad Católica de Chile, showing that in these independent groups, the model sorted brain scans with 84% to 90% accuracy.
The researchers then used the model to investigate which brain features play the biggest role in psychosis. Prior studies of psychosis had not given consistent results, likely because their sample sizes were too small.
Comparing brain scans from 22q11.2 deletion syndrome patients who had and did not have psychosis, the researchers showed that the brain areas contributing most to psychosis are the anterior insula (a key part of the salience network or “filter”) and the ventral striatum (the “reward predictor”); this was true for different cohorts of patients.
In comparing the brain features of people with 22q11.2 deletion syndrome and psychosis against people with psychosis of unknown origin, the model found significant overlap, indicating that these brain features are characteristic of psychosis in general.
A second mathematical model, trained to distinguish all subjects with 22q11.2 deletion syndrome and psychosis from those who have the genetic syndrome but without psychosis, selected brain scans from people with idiopathic psychosis with 77.5% accuracy, again supporting the idea that the brain’s filtering and predicting centers are key to psychosis.
Furthermore, this model was specific to psychosis: It could not classify people with idiopathic autism or ADHD.
“It was quite exciting to trace our steps back to our initial question — ‘What are the dysfunctional brain systems in schizophrenia?’ — and to discover similar patterns in this context,” Menon said. “At the neural level, the characteristics differentiating individuals with psychosis in 22q11.2 deletion syndrome are mirroring the pathways we’ve pinpointed in schizophrenia. This parallel reinforces our understanding of psychosis as a condition with identifiable and consistent brain signatures.” However, these brain signatures were not seen in people with the genetic syndrome but no psychosis, holding clues to future directions for research, he added.
In addition to supporting the scientists’ theory about how psychosis occurs, the findings have implications for understanding the condition — and possibly preventing it.
“One of my goals is to prevent or delay development of schizophrenia,” Supekar said. The fact that the new findings are consistent with the team’s prior research on which brain centers contribute most to schizophrenia in adults suggests there may be a way to prevent it, he said. “In schizophrenia, by the time of diagnosis, a lot of damage has already occurred in the brain, and it can be very difficult to change the course of the disease.”
“What we saw is that, early on, functional interactions among brain regions within the same brain systems are abnormal,” he added. “The abnormalities do not start when you are in your 20s; they are evident even when you are 7 or 8.”
The researchers plan to use existing treatments, such as transcranial magnetic stimulation or focused ultrasound, targeted at these brain centers in young people at risk of psychosis, such as those with 22q11.2 deletion syndrome or with two parents who have schizophrenia, to see if they prevent or delay the onset of the condition or lessen symptoms once they appear.
The results also suggest that using functional MRI to monitor brain activity at the key centers could help scientists investigate how existing antipsychotic medications are working.
Visualizing the invisible tie: Linking parent–child neural synchrony to parents’ and children’s attachment representations
by Trinh Nguyen, Melanie T. Kungl, Stefanie Hoehl, Lars O. White, Pascal Vrtička in Developmental Science
More synchrony between parents and children may not always be better, new research has revealed.
For the first time a new University of Essex study looked at behavioural and brain-to-brain synchrony in 140 families with a special focus on attachment. It looked at how they feel and think about emotional bonds whilst measuring brain activity as mums and dads solved puzzles with their kids.
The study — published in Developmental Science — discovered that mums with insecure attachment traits showed more brain-to-brain synchrony with their children.
Dr Pascal Vrticka, from the Department of Psychology, said: “For secure child attachment development, sensitive and mutually attuned interactions with parents are crucial.
“If the parent, here the mother, has more insecure attachment traits it may be more difficult for the dyad to achieve optimal behavioural synchrony. Increased brain-to-brain synchrony may reflect a neural compensation mechanism to overcome otherwise less attuned interaction elements.”
The study also discovered different behavioural and brain-to-brain synchrony patterns depending on whether the parent was a mum or a dad.
Fathers and children showed stronger brain-to-brain synchrony, whereas mums and their kids had stronger behavioural synchrony.
These findings suggest higher father-child brain-to-brain synchrony may reflect a neural compensation strategy to counteract a relative lack of behavioural synchrony. It hopes this research will springboard studies into parent-child relationships and open new avenues for intervention and prevention.
It comes as Dr Vrticka prepares to work with the NHS to explore family relationships.
He added: “Together with the East Suffolk and North Essex NHS Foundation Trust, we will soon start looking at synchrony within families with neurodivergent children and children with experiences of care and adoption.
“Our aim is to find behavioural and neurobiological correlates of an optimal range of synchrony to help all families with their relationships and child attachment development. In doing so, we must appreciate that not only low but also high synchrony can signal interaction and relationship difficulties.”
Attachment was assessed in parents with an interview and in children with a story completion task.
Brain-to-brain synchrony between parents and children was derived from functional near-infrared spectroscopy (fNIRS) hyperscanning.
Finally, the parent-child interaction was video-recorded and coded for behavioural synchrony.
Spindle oscillations in communicating axons within a reconstituted hippocampal formation are strongest in CA3 without thalamus
by Wang M, Lassers SB, Vakilna YS, Mander BA, Tang WC, Brewer GJ. in Sci Rep.
University of California, Irvine biomedical engineering researchers have uncovered a previously unknown source of two key brain waves crucial for deep sleep: slow waves and sleep spindles. Traditionally believed to originate from one brain circuit linking the thalamus and cortex, the team’s findings, published today in Scientific Reports, suggest that the axons in memory centers of the hippocampus play a role.
For decades, slow waves and sleep spindles have been identified as essential elements of deep sleep, measured through electroencephalography recordings on the scalp. However, the UC Irvine-led team revealed a novel source of these brain waves within the hippocampus and were able to measure them in single axons.
The study demonstrates that slow waves and sleep spindles can originate from axons within the hippocampus’ cornu ammonis 3 region. These oscillations in voltage occur independently of neuronal spiking activity, challenging existing theories about the generation of these brain waves.
“Our research sheds light on a previously unrecognized aspect of deep sleep brain activity,” said lead author Mengke Wang, former UC Irvine undergraduate student in biomedical engineering who is now a graduate student at Johns Hopkins University (Wang conducted the study while at UC Irvine). “We’ve discovered that the hippocampus, typically associated with memory formation, plays a crucial role in generating slow waves and sleep spindles, offering new insights into how these brain waves support memory processing during sleep.”
The team utilized innovative techniques — including in vitro reconstructions of hippocampal subregions and microfluidic tunnels for single axon communication — to observe spontaneous spindle waves in isolated hippocampal neurons. These findings suggest that spindle oscillations originate from active ion channels within axons, rather than through volume conduction as previously thought.
“The discovery of spindle oscillations in single hippocampal axons opens new avenues for understanding the mechanisms underlying memory consolidation during sleep,” said co-author Gregory Brewer, adjunct professor of biomedical engineering. “These findings have significant implications for sleep research, potentially paving the way for new approaches to treating sleep-related disorders.”
Brewer’s other research affiliations include the Institute for Memory Impairment and Neurological Disorders and the Center for Neurobiology of Learning and Memory.
By uncovering the hippocampus’s role in generating slow waves and sleep spindles, this research expands our understanding of the brain’s activity during deep sleep and its impact on memory processing. The findings offer a promising foundation for future studies exploring the therapeutic potential of targeting hippocampal activity to improve sleep quality and cognitive function.
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