Brain scan can reveal the risk of psychiatric hospitalisation
One in four psychiatric patients in Denmark are readmitted and that carries major personal and societal costs. But can we predict who will be readmitted, while others return to everyday life without symptoms? That is exactly what Professor Kamilla Miskowiak aims to support through her latest research.
She is a professor of cognitive neuropsychiatry at the Department of Clinical Medicine at the University of Copenhagen, and in a new study she and her colleagues examined people with major depressive disorder or bipolar disorder and identified clear neurological and behavioural patterns that may help reveal who is at particular risk of readmission.
“Our study suggests that the brain’s reaction to emotional stimuli may be an important piece of the puzzle when trying to understand who is at risk of a deterioration in their illness. And it may help guide future treatment,” says Kamilla Miskowiak.
The brain’s alarm button
In the first part of the study, 112 participants with depression or bipolar disorder were put in an fMRI scanner while being shown images of happy or fearful faces. The researchers then measured activity in the amygdala – the brain’s “alarm button”, which alerts us to danger.
The second part of the study took place outside the scanner. Here, participants were shown faces expressing different emotions – fear, happiness, sadness, anger, surprise, and disgust – and the researchers recorded how quickly they identified each one.
In both cases, it was clear that some people reacted more strongly to negative emotions than others.
Vulnerability across diagnoses
The researchers then followed participants over the course of a year and found a link between emotional reactivity and risk of hospitalisation. Participants with a strong amygdala response to fearful faces had a significantly higher risk of being admitted.
Those who identified negative emotions more quickly than positive ones also were at higher risk of admission. In both cases, this applied to people with depression as well as bipolar disorder.
“So this is a vulnerability marker that cuts across diagnoses, and it suggests that we have found broader neurological changes in people with affective disorders,” says Kamilla Miskowiak.
In other words, participants’ brains had a negativity bias and misinterpreted signals in the environment that were not actually threatening. For each small increase in the brain’s response to fear, the risk of hospitalisation rose by 17%.
“Psychiatric disorders such as depression can feel like invisible illnesses, and some people may feel it is their own fault or are told to simply pull themselves together. But we can actually see that there is a real neurological vulnerability. The good thing is that we can then treat this vulnerability,” says Kamilla Miskowiak.
A strong need for identifying the right patients
Depression costs Danish society almost DKK 10 billion annually in treatment, care and medication, and DKK 25 billion in lost productivity, according to figures from the Danish Health Authority from 2022. That same year, there were more than 58,000 psychiatric hospitalisations in Denmark, and a quarter of patients were readmitted within 30 days, according to Local Government Denmark. So there is a strong need to identify who requires extra support.
Although MRI scanning is expensive and unlikely to be used for routine assessment of all patients with depression or bipolar disorder, it is easy to carry out a simple test of people’s reactions to facial expressions – one that does not require a brain scanner. The researchers are already developing an online tool that will make it easy for clinicians to administer and interpret the test.
“Of course, it needs to be used alongside an assessment of other factors in someone’s life, such as previous hospitalisations. But it may be a way to screen for who is at increased risk,” says Kamilla Miskowiak.
We still do not fully understand what happens in the brain when some people develop mental disorders. That is why Kamilla Miskowiak and her team work to identify so‑called biomarkers – measurable signs that something is beginning to go awry.
“At the GP, you can have a throat swab to see whether an infection is caused by a virus or bacteria and get the right treatment. But in psychiatry we lack that kind of biomarker. So, if this finding can become a biomarker that predicts prognosis, it would be hugely important,” she says.
Journal
Neuropsychopharmacology
Article Title
Amygdala reactivity to threat, negative facial perception, and risk of future psychiatric hospitalizations: a longitudinal study in major depressive and bipolar disorders
Article Publication Date
15-Dec-2025
COI Statement
Competing interests KWM has served as consultant for Janssen, and Angelini. BO states that part of his salary while working on this project was covered by a grant from Novo Nordisk A/S. HLK has served as a consultant for Lundbeck. VHD has served as lecturer for H. Lundbeck. GMK has served as consultant for Sanos, Onsero, Pangea Botanica, Gilgamesh, and Seaport, and additionally served as lecturer for Abbvie, Angelini and H. Lundbeck. LVK has within the last three years served as a consultant for Lundbeck and Teva. VGF has served as consultant for Sage therapeutics, and additionally as lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. All other authors declare no conflict of interest.
Scientists engineer a tool to “edit” brain circuits and enhance memory
A new molecular tool called SynTrogo harnesses astrocytes to selectively dismantle synaptic connections
Institute for Basic Science
image:
Synthetic Trogocytosis (SynTrogo) enables the "nibbling" of neuronal membranes by astrocytes through engineered ligand and receptor proteins. Upon SynTrogo induction, the synaptic density of the target CA3-CA1 hippocampal circuit was significantly reduced by ~27%. Conversely, the remaining synapses underwent structural and functional remodeling – characterized by the enlargement of pre- and post-synaptic compartments, enhanced long-term potentiation (LTP), and improved memory formation and retention.
view moreCredit: Institute for Basic Science
Every thought, memory, and feeling we experience depends on trillions of tiny connection points in the brain called synapses. These are the junctions where one neuron passes signals to another, forming the vast communication network known as the connectome—the brain’s wiring diagram. Although scientists have developed powerful tools to increase or decrease neural activity, directly redesigning the brain’s physical wiring has remained far more difficult.
A research team led by Dr. LEE Sangkyu and Director C. Justin LEE at the Center for Memory and Glioscience within the Institute for Basic Science (IBS), in collaboration with Dr. LEE Kea Joo of the Korea Brain Research Institute (KBRI), has now developed a molecular tool that makes such structural editing possible. The new platform, called SynTrogo (Synthetic Trogocytosis), enables researchers to induce astrocytes to selectively remodel synaptic connections in a targeted brain circuit.
The brain already has a natural mechanism for refining its wiring. During development and throughout life, unneeded or weak connections are removed in a process known as synaptic pruning, much like trimming unnecessary branches from a tree. This pruning is partly carried out by astrocytes—star-shaped glial cells that closely surround synapses and help maintain the neural environment. When this process becomes dysregulated, either through too much or too little pruning, it has been linked to disorders such as schizophrenia, autism spectrum disorder, and Alzheimer’s disease.
Until now, however, there has been no method for deliberately triggering this kind of structural remodeling at a chosen location in the brain without also altering the electrical activity of the circuit. Existing techniques such as optogenetics and chemogenetics can modulate how strongly neurons fire, but they largely act on synapses that are already there. By contrast, SynTrogo is designed to act on the physical connections themselves.
The system works like a molecular lock-and-key mechanism. Neurons in the target circuit are engineered to display a molecular “tag” on their surface (a lock), while nearby astrocytes are engineered with a matching binding partner (a key). When the two cells come into contact, the astrocyte is induced to “nibble” part of the neuronal membrane and nearby synaptic material through a trogocytosis-like process—a form of partial cellular uptake seen in several biological systems. By harnessing this process synthetically, the researchers created a way to selectively reduce synaptic connectivity in a defined neural circuit.
Dr. LEE Sangkyu, Junior Chief Investigator at the IBS Center for Memory and Glioscience said, “This is the first demonstration that brain circuits can be directly edited by engineering physical interactions between neurons and astrocytes, independent of neuronal activity. It opens the possibility of ‘connectome editing’ and provides a new platform for studying and reshaping the physical architecture of neural circuits.”
To test the method in the brain, the team applied SynTrogo to the hippocampus, a region essential for learning and memory. They expressed the synthetic ligand in CA3 excitatory neurons and the matching receptor in CA1 astrocytes, targeting one of the best-known memory circuits in the mammalian brain. Three weeks later, the number of excitatory synapses in the targeted region had decreased by about 27 percent.
At first glance, fewer synapses might be expected to impair brain function. However, the researchers found the opposite. The surviving synapses became structurally and functionally stronger: presynaptic boutons enlarged, synaptic vesicle numbers increased, and the remaining connections transmitted signals more efficiently. Electrophysiological experiments further showed that long-term potentiation (LTP)—a key cellular process underlying learning and memory—was significantly enhanced. The remaining synapses also exhibited coordinated remodeling on both the presynaptic and postsynaptic sides, and rather than causing widespread degeneration, the process appeared to be spatially restricted and self-limiting.
To directly examine the structural basis of these changes, the researchers used high-resolution imaging techniques, including correlative light and electron microscopy. These analyses revealed unusually tight interfaces between astrocytes and neuronal axons, along with localized membrane deformation and partial enclosure of axonal regions. Consistent with the functional results, targeted axons contained fewer synapses, while the remaining synapses displayed clear ultrastructural remodeling.
This finding was especially important because it showed that reducing synapse number does not necessarily mean weakening the circuit. Instead, the brain appears capable of compensatory refinement: when some connections are removed, the remaining ones can reorganize and become more effective.
Dr. LEE Kea Joo, Principal Investigator at KBRI said, “We found that the brain can adapt and strengthen its function even when the total number of synaptic connections is reduced. This gives us new insight into how neural circuits maintain performance and may offer clues for restoring cognitive function in brain disorders.”
The team then asked whether these cellular changes translated into behavioral effects. In contextual fear-conditioning experiments, mice with SynTrogo-modified hippocampal circuits showed stronger memory than control animals. They displayed enhanced recall both two days after learning and 23 days later, indicating improvements in both recent and remote memory. Importantly, these mice also remained capable of extinction learning—the process by which previously learned fear responses are reduced when they are no longer appropriate—suggesting that SynTrogo strengthened memory without sacrificing cognitive flexibility.
Further analysis suggested that SynTrogo may place synapses into a more plastic, learning-ready state. Before learning, AMPA receptor-mediated synaptic responses were reduced, but after fear conditioning they recovered to control-like levels. This implies that the remodeled circuit may be particularly poised for experience-dependent strengthening when new learning occurs.
Director C. Justin LEE of the IBS Center for Memory and Glioscience said, “This study shows that selectively reducing a subset of synapses can paradoxically enhance circuit function by promoting adaptive remodeling of the remaining connections. It also lays the groundwork for a new strategy to study and potentially treat brain disorders associated with abnormal synapse numbers.”
Beyond its value as a neuroscience tool, SynTrogo may have broad biomedical implications. Many neurological and psychiatric disorders—including autism spectrum disorder, schizophrenia, Alzheimer’s disease, and brain injury—have been associated with abnormal synapse numbers or disrupted circuit organization. Yet researchers have lacked a way to directly manipulate synaptic connectivity in living mammalian brains with cell-type specificity. By enabling targeted structural remodeling through engineered neuron-astrocyte interactions, SynTrogo provides a foundation for future efforts in connectome editing and may eventually help guide therapeutic strategies aimed at restoring healthy circuit function.
Perhaps the most fundamental message of the study is that the brain is not simply strongest when it has the greatest possible number of synapses. Under some conditions, removing selected connections can trigger the network to reorganize itself in a more efficient and adaptable way. This resilience has long been difficult to isolate experimentally. SynTrogo now offers a way to study that process directly.
The study was published online in Nature Communications in 2026.
Journal
Nature Communications
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Remodeling Synaptic Connections via Engineered Neuron-Astrocyte Interactions
Article Publication Date
15-Apr-2026
