Posts Tagged ‘psychiatry’

A new study using machine learning has identified brain-based dimensions of mental health disorders, an advance towards much-needed biomarkers to more accurately diagnose and treat patients. A team at Penn Medicine led by Theodore D. Satterthwaite, MD, an assistant professor in the department of Psychiatry, mapped abnormalities in brain networks to four dimensions of psychopathology: mood, psychosis, fear, and disruptive externalizing behavior. The research is published in Nature Communications this week.

Currently, psychiatry relies on patient reporting and physician observations alone for clinical decision making, while other branches of medicine have incorporated biomarkers to aid in diagnosis, determination of prognosis, and selection of treatment for patients. While previous studies using standard clinical diagnostic categories have found evidence for brain abnormalities, the high level of diversity within disorders and comorbidity between disorders has limited how this kind of research may lead to improvements in clinical care.

“Psychiatry is behind the rest of medicine when it comes to diagnosing illness,” said Satterthwaite. “For example, when a patient comes in to see a doctor with most problems, in addition to talking to the patient, the physician will recommend lab tests and imaging studies to help diagnose their condition. Right now, that is not how things work in psychiatry. In most cases, all psychiatric diagnoses rely on just talking to the patient. One of the reasons for this is that we don’t understand how abnormalities in the brain lead to psychiatric symptoms. This research effort aims to link mental health issues and their associated brain network abnormalities to psychiatric symptoms using a data-driven approach.”

To uncover the brain networks associated with psychiatric disorders, the team studied a large sample of adolescents and young adults (999 participants, ages 8 to 22). All participants completed both functional MRI scans and a comprehensive evaluation of psychiatric symptoms as part of the Philadelphia Neurodevelopmental Cohort (PNC), an effort lead by Raquel E. Gur, MD, Ph.D., professor of Psychiatry, Neurology, and Radiology, that was funded by the National Institute of Mental Health. The brain and symptom data were then jointly analyzed using a machine learning method called sparse canonical correlation analysis.

This analysis revealed patterns of changes in brain networks that were strongly related to psychiatric symptoms. In particular, the findings highlighted four distinct dimensions of psychopathology—mood, psychosis, fear, and disruptive behavior—all of which were associated with a distinct pattern of abnormal connectivity across the brain.

The researchers found that each brain-guided dimension contained symptoms from several different clinical diagnostic categories. For example, the mood dimension was comprised of symptoms from three categories, e.g. depression (feeling sad), mania (irritability), and obsessive-compulsive disorder (recurrent thoughts of self-harm). Similarly, the disruptive externalizing behavior dimension was driven primarily by symptoms of both Attention Deficit Hyperactivity Disorder(ADHD) and Oppositional Defiant Disorder (ODD), but also included the irritability item from the depression domain. These findings suggest that when both brain and symptomatic data are taken into consideration, psychiatric symptoms do not neatly fall into established categories. Instead, groups of symptoms emerge from diverse clinical domains to form dimensions that are linked to specific patterns of abnormal connectivity in the brain.

“In addition to these specific brain patterns in each dimension, we also found common brain connectivity abnormalities that are shared across dimensions,” said Cedric Xia, a MD-Ph.D. candidate and the paper’s lead author. “Specifically, a pair of brain networks called default mode network and frontal-parietal network, whose connections usually grow apart during brain development, become abnormally integrated in all dimensions.”

These two brain networks have long intrigued psychiatrists and neuroscientists because of their crucial role in complex mental processes such as self-control, memory, and social interactions. The findings in this study support the theory that many types of psychiatric illness are related to abnormalities of brain development.

The team also examined how psychopathology differed across age and sex. They found that patterns associated with both mood and psychosis became significantly more prominent with age. Additionally, brain connectivity patterns linked to mood and fear were both stronger in female participants than males.

“This study shows that we can start to use the brain to guide our understanding of psychiatric disorders in a way that’s fundamentally different than grouping symptoms into clinical diagnostic categories. By moving away from clinical labels developed decades ago, perhaps we can let the biology speak for itself,” said Satterthwaite. “Our ultimate hope is that understanding the biology of mental illnesses will allow us to develop better treatments for our patients.”

More information: Cedric Huchuan Xia et al, Linked dimensions of psychopathology and connectivity in functional brain networks, Nature Communications (2018). DOI: 10.1038/s41467-018-05317-y



Young people suffering from treatment-resistant depression (TRD) showed a significant reduction of their symptoms after being administered ketamine injections, according to a study published in the Journal of Child and Adolescent Psychopharmacology.

Researchers from the University of Minnesota (UM) and the nonprofit Mayo Clinic found that ketamine caused an average decrease of 42 percent on the Children’s Depression Rating Scale (CDRS)—the most widely used rating scale in research trials for assessing the severity of depression and change in depressive symptoms among adolescents.

Ketamine is perhaps best known for being a popular recreational drug and a useful medical anesthetic, but a growing body of research is indicating that the compound could be an effective treatment for depression. Several recent studies have shown that even a single dose in adults can lead to rapid reductions in depressive symptoms. However, relatively little research has been conducted into ketamine’s antidepressant effects in adolescents.

“Adolescence is a very important time for studying depression, first because depression often starts during these years, and second because it is an important time for brain development,” Kathryn Cullen, from the Department of Psychiatry at UM, told Newsweek.

“When adolescent depression persists without successful treatment, it can interfere with achieving important developmental milestones. Finding the right treatment is critical to allow the restoration of healthy brain development and prevent negative outcomes like chronic depression, disability and suicide.”

Unfortunately, about 40 percent of adolescents do not respond to their first intervention and only half of nonresponders respond to the second treatment, according to the researchers.

“Standard antidepressant treatments do not work for everyone and take weeks to months to take effect, a time period when patients are at risk for continued suffering and suicide attempts,” Cullen said. “The field is in need of new treatment options. Ketamine has a very different mechanism of action than standard treatments.”

The latest study involved 13 young people ages 12 to 18 who had failed two previous trials of antidepressants. During a two-week period, the researchers gave them six ketamine infusions.

They found that the treatment was well tolerated, with the participants showing an average decrease in CDRS scores of 42.5 percent. Five of the participants met the criteria for clinical response and remission. Of these, three were still in remission after six weeks, while the remaining two relapsed within two weeks.

According to the scientists, the results demonstrate the potential role for ketamine in treating adolescents with TRD. However, they note that the study was limited by its small sample size, so future research will be needed to confirm these results.

“The purpose of our study was to investigate the effects of ketamine for TRD in younger patients for whom this indication for ketamine administration is not well studied,” Mark Roback, a professor of pediatrics at the University of Minnesota, told Newsweek.

“I think our results show promise for this population, however this study is just a beginning. The study serves to point out the need for further, rigorous, study designed to answer the many questions that remain about ketamine for TRD, such as optimal dosing and route of administration, dosing interval and treatment length, and long-term effects—just to name a few.”

James Stone, a clinical senior lecturer from the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, who was not involved in the study, told Newsweek that there is “a lot of potential for the use of ketamine as a second or third line antidepressant where other treatments have failed.”

“Although ketamine is potentially a huge breakthrough in the treatment of depression, we still don’t know about the long-term safety, or about how to keep people well from depression without requiring regular ketamine dosing,” Stone added. “Further studies are needed to address these questions.”

Researchers believe that large cells called nucleus gigantocellularis neurons, pictured here, modulate blood flow by releasing nitric oxide.

There is no shortage of wonders that our central nervous system produces—from thought and language to movement to the five senses. All of those dazzling traits, however, depend on an underappreciated deep brain mechanism that Donald Pfaff, head of the Laboratory of Neurobiology and Behavior at The Rockefeller University, calls generalized arousal, or GA for short. GA is what wakes us up in the morning and keeps us aware and in touch with ourselves and our environment throughout our conscious hours.

“It’s so fundamental that we don’t pay attention to it,” says Pfaff, “and yet it’s so important that we should.”

Pfaff and his team of researchers certainly do. Now, in a series of experiments involving a particular type of brain cell, they have advanced our understanding of the roots of consciousness. Their work may potentially prove relevant in the study of some psychiatric diseases.

The big cells in the black box

The findings, published this month in Proceedings of the National Academy of Sciences, shed light on an area of the brainstem that is so little understood the first author of the paper, Inna Tabansky, a research associate in Pfaff’s lab, calls it “the black box.” That term is certainly simpler than its actual name—the nucleus gigantocellularis (NGC), which is part of a structure called the medullary reticular formation.

In her work, using mice, Tabansky focused on a subtype of extremely large neurons in the NGC with links to virtually the entire nervous system, including the thalamus, where neurons can activate the entire cerebral cortex. “If you just look at the morphology of NGC neurons, you know they’re important,” Pfaff says. “It’s just a question of what they’re important for. I think they’re essential for the initiation of any behavior.”

To discover what role the NGC neurons might play in GA, Tabansky and her colleagues, including Joel Stern, a visiting professor in the Pfaff lab, began by identifying the genes that these neurons express. They used a technique known as “retro-TRAP,” developed in the lab of Rockefeller scientist Jeffrey Friedman.

To Tabansky’s surprise, the NGC neurons were found to express the gene for an enzyme, endothelial nitric oxide synthase (eNOS), which produces nitric oxide, which in turn relaxes blood vessels, increasing the flow of oxygenated blood to tissue. (No other neurons in the brain are known to produce eNOS.) They also discovered that the eNOS-expressing NGC neurons are located close to blood vessels.

In Pfaff’s view, the neurons are so critical for the normal functions of the central nervous system that they have evolved the ability to control their own blood supply directly. ‘“We’re pretty sure that if these neurons need more oxygen and glucose, they will release nitric oxide into these nearby blood vessels in order to get it,” he says.

The circumstances that would prompt such a response were the subject of further experiments. The scientists found evidence that changes in the environment, such as the introduction of novel scents, activated eNOS in the NGC neurons and produced increased amounts of nitric oxide in mice.

“There is some low level of production when the animal is in a familiar setting,” says Tabansky, “which is what you expect as they maintain arousal. But it is vastly increased when the animal is adapting to a new environment.” This activation of the NGC neurons supports the case for their central role in arousal, Tabansky says.

From cells to psychiatry

Going forward, Tabansky says she’s interested in exploring if their findings might help fill a gap in the understanding of certain disorders, such as bipolar disorder, suicidality, and ADHD. Some genetic research has implicated a role for the neurons she studied in these diseases, but the mechanism behind this link is not known.

“By showing that this gene and its associated pathways have a particular role, at least in the rodent brain, that relates to a fundamental function of the nervous system, is a hint about how this gene can cause psychiatric disease,” she says. “It’s very preliminary, and there is a lot more work to be done, but it potentially opens a new way to study how this gene can alter an individual’s psychology.”

A study by scientists of the German Center for Neurodegenerative Diseases (DZNE) points to a novel potential approach against Alzheimer’s disease. In studies in mice, the researchers were able to show that blocking a particular receptor located on astrocytes normalized brain function and improved memory performance. Astrocytes are star-shaped, non-neuronal cells involved in the regulation of brain activity and blood flow. The findings are published in the Journal of Experimental Medicine (JEM).

Alzheimer’s disease is a common and currently incurable brain disorder leading to dementia, whose mechanisms remain incompletely understood. The disease appears to be sustained by a combination of factors that include pathological changes in blood flow, neuroinflammation and detrimental changes in brain cell activity.

“The brain contains different types of cells including neurons and astrocytes”, explains Dr. Nicole Reichenbach, a postdoc researcher at the DZNE and first author of the paper published in JEM. “Astrocytes support brain function and shape the communication between neurons, called synaptic transmission, by releasing a variety of messenger proteins. They also provide metabolic and structural support and contribute to the regulation of blood flow in the brain.”

Glitches in network activity

Similar to neurons, astrocytes are organized into functional networks that may involve thousands of cells. “For normal brain function, it is crucial that networks of brain cells coordinate their firing rates. It’s like in a symphony orchestra where the instruments have to be correctly tuned and the musicians have to stay in synchrony in order to play the right melody”, says Professor Gabor Petzold, a research group leader at the DZNE and supervisor of the current study. “Interestingly, one of the main jobs of astrocytes is very similar to this: to keep neurons healthy and to help maintain neuronal network function. However, in Alzheimer’s disease, there is aberrant activity of these networks. Many cells are hyperactive, including neurons and astrocytes. Hence, understanding the role of astrocytes, and targeting such network dysfunctions, holds a strong potential for treating Alzheimer’s.”

Astrocyte-targeted treatment alleviated memory impairment

Petzold and colleagues tested this approach in an experimental study involving mice. Due to a genetic disposition, these rodents exhibited certain symptoms of Alzheimer’s similar to those that manifest in humans with the disease. In the brain, this included pathological deposits of proteins known as “Amyloid-beta plaques” and aberrant network activity. In addition, the mice showed impaired learning ability and memory.

In their study, the DZNE scientists targeted a cell membrane receptor called P2Y1R, which is predominately expressed by astrocytes. Previous experiments by Petzold and colleagues had revealed that activation of this receptor triggers cellular hyperactivity in mouse models of Alzheimer’s. Therefore, the researchers treated groups of mice with different P2Y1R antagonists. These chemical compounds can bind to the receptor, thus switching it off. The treatment lasted for several weeks.

“We found that long-term treatment with these drugs normalized the brain’s network activity. Furthermore, the mice’s learning ability and memory greatly improved”, Petzold says. On the other hand, in a control group of wild type mice this treatment had no significant effect on astrocyte activity. “This indicates that P2Y1R inhibition acts quite specifically. It does not dampen network activity when pathological hyperactivity is absent.”

New approaches for research and therapies?

Petzold summarizes: “This is an experimental study that is currently not directly applicable to human patients. However, our results suggest that astrocytes, as important safeguards of neuronal health and normal network function, may hold the potential for novel treatment options in Alzheimer’s disease.” In future studies, the scientists intend to identify additional novel pathways in astrocytes and other cells as potential drug targets.

Reichenbach, N., Delekate, A., Breithausen, B., Keppler, K., Poll, S., Schulte, T., . . . Petzold, G. C. (2018). P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. The Journal of Experimental Medicine. doi:10.1084/jem.20171487

On the heels of one failed drug trial after another, a recent study suggests people with early Alzheimer’s disease could reap modest benefits from a device that uses magnetic fields to produce small electric currents in the brain.

Alzheimer’s is a degenerative brain disorder that afflicts more than 46 million people worldwide. At present there are no treatments that stop or slow its progression, although several approved drugs offer temporary relief from memory loss and other cognitive symptoms by preventing the breakdown of chemical messengers among nerve cells.

The new study tested a regimen that combines computerized cognitive training with a procedure known as repetitive transcranial magnetic stimulation (rTMS). The U.S. Food and Drug Administration has cleared rTMS devices for some migraine sufferers as well as for people with depression who have not responded to antidepressant medications.

Israel-based Neuronix reported results of a phase III clinical trial of its therapy system, known as neuroAD, in Alzheimer’s patients. More than 99 percent of Alzheimer’s drug trials have failed. The last time a phase III trial for a wholly new treatment succeeded (not just a combination of two already approved drugs) was about 15 years ago. The recent study did not test a drug but rather a device, which usually has an easier time gaining FDA clearance. NeuroAD has been approved for use in Europe and the U.K., where six weeks of therapy costs about $6,700. The system is not commercially available in the U.S., but based on the latest results the company submitted an application for FDA clearance last fall.

The neuroAD setup resembles a dental chair fitted with a touch screen and flexible arms, which generate magnetic fields from metal coils positioned near the person’s scalp. The magnetic fields produce electric currents within the brain that influence the activity of neurons. The procedure can reportedly speed up learning by strengthening synaptic connections between neurons while the person performs tasks that engage those particular brain cells. In the cognitive training that accompanies rTMS, when study participants see a picture of a strawberry and touch the screen to identify it as “fruit” or “furniture,” for instance, the system stimulates Wernicke’s area, the brain region responsible for language comprehension.

For its latest rTMS trial, the company enrolled about 130 people with mild to moderate Alzheimer’s at 10 sites—nine in the U.S. and one in Israel. Four out of five participants were already taking symptom-relieving therapies. At the start of the trial, each person took a cognitive battery—a 30-minute paper-and-pencil test commonly used to gauge mental function in Alzheimer’s studies—and was randomly assigned to receive the rTMS-cognitive therapy or a sham treatment for six weeks. The sessions lasted about an hour each day, five days per week.

A week after the six-week regimen, and again five weeks later, participants retook the paper-and-pencil test to see if their cognition improved. Despite the elaborate protocol, study adherence was high. More than 90 percent of participants completed at least 90 percent of their visits, says Babak Tousi, who heads the Clinical Trials Program at Cleveland Clinic Lou Ruvo Center for Brain Health and reported the trial’s results at the Vienna meeting.

Based on past studies of the neuroAD system in smaller groups (none had more than 30 participants), the company expected to see a cognitive benefit after six weeks of treatment. Curiously, though, the recent study revealed no significant difference in test scores between active and sham groups at the seven-week time point. (The sham group sat in the chair and saw pictures on the screen but received no cognitive training or exposure to magnetic fields.) At week 12—six weeks after the therapy ended—the active group did show an 1.8-point test score advantage over the sham group. “That is a pretty small effect,” says Lon Schneider, who directs the State of California Alzheimer’s Disease Center at the University of Southern California in Los Angeles and heard the study results presented in Vienna. By comparison, he says, drugs currently approved to treat Alzheimer’s symptoms have shown a 2.5- to 3-point improvement in six-month clinical trials. And in a study reported last fall, a leading pharmaceutical candidate tested in more than 2,100 people seemed to work about as well (a roughly 1.5-point improvement) but failed to achieve statistical significance.

Plus, the modest effect seen with the new rTMS trial only turned up in participants with mild Alzheimer’s, Tousi reported. People with more advanced cases did not improve on the therapy. “We’ve got that typical problem of a small study that does seem to give outcomes, but the outcomes are either unclear or not fully evaluable,” Schneider says, adding it is unclear, for instance, if the test scores improved because of the cognitive training or resulted from possible mood-enhancing effects of the rTMS, because some Alzheimer’s patients have depression or other psychiatric symptoms.

John-Paul Taylor, a neuropsychiatrist at Newcastle University in England who was not involved with the study and researches TMS’s prospects for treating visual hallucinations in dementia, agrees that it is hard to tell if the cognitive improvement was indeed “a real TMS effect.” He says, however, this technology is “ripe for more investigation.”

Taylor is working with colleagues who are trying to use computational modeling to get a better idea how rTMS works. “That’s where it’s going to get really interesting,” he says. “I suspect you’ll have to tailor the stimulation to individual patients.” Consistent with that idea, earlier this year researchers reported using brain imaging to identify different types of depression—and patients in one of those subgroups responded especially well to rTMS.

With the computational modeling, one could imagine feeding in a person’s brain scan “and the computer would say, you need to be in this position at this stimulation intensity to equal what another person would receive,” Taylor says. “That’s not that far off.” Ultimately, though, “we want a therapeutic that still works across everybody to some degree,” he says. “There’s a hint of that in this trial. I’m cautiously optimistic.”

Pinpoint stimulation of a cluster of nerve cells in the brains of mice encouraged timid responses to a perceived threat, whereas stimulation of an adjacent cluster induced boldness and courage.

Researchers at the Stanford University School of Medicine have identified two adjacent clusters of nerve cells in the brains of mice whose activity level upon sighting a visual threat spells the difference between a timid response and a bold or even fierce one.

Located smack-dab in the middle of the brain, these clusters, or nuclei, each send signals to a different area of the brain, igniting opposite behaviors in the face of a visual threat. By selectively altering the activation levels of the two nuclei, the investigators could dispose the mice to freeze or duck into a hiding space, or to aggressively stand their ground, when approached by a simulated predator.

People’s brains probably possess equivalent circuitry, said Andrew Huberman, PhD, associate professor of neurobiology and of ophthalmology. So, finding ways to noninvasively shift the balance between the signaling strengths of the two nuclei in advance of, or in the midst of, situations that people perceive as threatening may help people with excessive anxiety, phobias or post-traumatic stress disorder lead more normal lives.

“This opens the door to future work on how to shift us from paralysis and fear to being able to confront challenges in ways that make our lives better,” said Huberman, the senior author of a paper describing the experimental results. It was published online May 2 in Nature. Graduate student Lindsey Salay is the lead author.

Perilous life of a mouse
There are plenty of real threats in a mouse’s world, and the rodents have evolved to deal with those threats as best they can. For example, they’re innately afraid of aerial predators, such as a hawk or owl swooping down on them. When a mouse in an open field perceives a raptor overhead, it must make a split-second decision to either freeze, making it harder for the predator to detect; duck into a shelter, if one is available; or to run for its life.

To learn how brain activity changes in the face of such a visual threat, Salay simulated a looming predator’s approach using a scenario devised some years ago by neurobiologist Melis Yilmaz Balban, PhD, now a postdoctoral scholar in Huberman’s lab. It involves a chamber about the size of a 20-gallon fish tank, with a video screen covering most of its ceiling. This overhead screen can display an expanding black disc simulating a bird-of-prey’s aerial approach.

Looking for brain regions that were more active in mice exposed to this “looming predator” than in unexposed mice, Salay pinpointed a structure called the ventral midline thalamus, or vMT.

Salay mapped the inputs and outputs of the vMT and found that it receives sensory signals and inputs from regions of the brain that register internal brain states, such as arousal levels. But in contrast to the broad inputs the vMT receives, its output destination points were remarkably selective. The scientists traced these outputs to two main destinations: the basolateral amygdala and the medial prefrontal cortex. Previous work has tied the amygdala to the processing of threat detection and fear, and the medial prefrontal cortex is associated with high-level executive functions and anxiety.

Further inquiry revealed that the nerve tract leading to the basolateral amygdala emanates from a nerve-cell cluster in the vMT called the xiphoid nucleus. The tract that leads to the medial prefrontal cortex, the investigators learned, comes from a cluster called the nucleus reuniens, which snugly envelopes the xiphoid nucleus.

Next, the investigators selectively modified specific sets of nerve cells in mice’s brains so they could stimulate or inhibit signaling in these two nerve tracts. Exclusively stimulating xiphoid activity markedly increased mice’s propensity to freeze in place in the presence of a perceived aerial predator. Exclusively boosting activity in the tract running from the nucleus reuniens to the medial prefrontal cortex in mice exposed to the looming-predator stimulus radically increased a response seldom seen under similar conditions in the wild or in previous open-field experiments: The mice stood their ground, right out in the open, and rattled their tails, an action ordinarily associated with aggression in the species.

Thumping tails

This “courageous” behavior was unmistakable, and loud, Huberman said. “You could hear their tails thumping against the side of the chamber. It’s the mouse equivalent of slapping and beating your chest and saying, ‘OK, let’s fight!’” The mice in which the nucleus reuniens was stimulated also ran around more in the chamber’s open area, as opposed to simply running toward hiding places. But it wasn’t because nucleus reuniens stimulation put ants in their pants; in the absence of a simulated looming predator, the same mice just chilled out.

In another experiment, the researchers showed that stimulating mice’s nucleus reuniens for 30 seconds before displaying the “looming predator” induced the same increase in tail rattling and running around in the unprotected part of the chamber as did vMT stimulation executed concurrently with the display. This suggests, Huberman said, that stimulating nerve cells leading from the nucleus reunions to the prefrontal cortex induces a shift in the brain’s internal state, predisposing mice to act more boldly.

Another experiment pinpointed the likely nature of that internal-state shift: arousal of the autonomic nervous system, which kick-starts the fight, flight or freeze response. Stimulating either the vMT as a whole or just the nucleus reuniens increased the mice’s pupil diameter — a good proxy of autonomic arousal.

On repeated exposures to the looming-predator mockup, the mice became habituated. Their spontaneous vMT firing diminished, as did their behavioral responses. This correlates with lowered autonomic arousal levels.

Human brains harbor a structure equivalent to the vMT, Huberman said. He speculated that in people with phobias, constant anxiety or PTSD, malfunctioning circuitry or traumatic episodes may prevent vMT signaling from dropping off with repeated exposure to a stress-inducing situation. In other experiments, his group is now exploring the efficacy of techniques, such as deep breathing and relaxation of visual fixation, in adjusting the arousal states of people suffering from these problems. The thinking is that reducing vMT signaling in such individuals, or altering the balance of signaling strength from their human equivalents of the xiphoid nucleus and nucleus reuniens may increase their flexibility in coping with stress.

Salay, L. D., Ishiko, N., & Huberman, A. D. (2018). A midline thalamic circuit determines reactions to visual threat. Nature. doi:10.1038/s41586-018-0078-2

A research team at University of Copenhagen including a researcher from the Faculty of Health and Medical Sciences has discovered a circuit in the brains of mice connecting circadian rhythm to aggressive behaviour. The discovery is particularly interesting to Alzheimer’s patients who experience increased aggression at night. The researchers have developed special protein tools capable of turning off the cells in the brain causing the behaviour.

Each year around 8,000 Danes are diagnosed with a form of dementia. Alzheimer’s disease is one of them. The disease manifests itself in memory difficulties in particular, but can also result in personality changes and mood swings.

When the sun sets 20 per cent of all Alzheimer’s patients experience increased bewilderment, anxiety, unease, disorientation, irritation and aggression. This phenomenon is called ‘sundowning’ or sundown syndrome. At worst, the condition can mean that the patient must be left in professional care, as it can be difficult for family members to handle. The cause of the condition is unknown, but previous research has suggested that it is connected to the circadian rhythm.

A research team including a researcher from the Department of Drug Design and Pharmacology at the University of Copenhagen is now able to confirm this connection. The researchers have identified and mapped a circuit between the part of the brain containing the circadian clock or circadian rhythm and a part of the brain controlling aggression.

’We have shown that the circadian clock in mice is closely linked to an aggression centre in the mouse brain by a cell circuit. The human brain has those same groups of cells that the circuit goes through. With this knowledge, we are now enabled to target this circuit pharmacologically and target cells that make people aggressive at the end of the day’, says Assistant Professor Timothy Lynagh from the Department of Drug Design and Pharmacology at the University of Copenhagen.

Turn off the Aggression
The inner clock or circadian rhythm is located in the part of the brain called suprachiasmatic nucleus. One of the parts of the brain that control aggressive behaviour is called the ventromedial hypothalamus. Researchers have previously observed a connection between the two parts of the brain, though none have had knowledge of the specific circuit connecting them.

Using electrophysiology and microscopy, the researchers measured the activity of the brain cells at main author Clifford Saper’s laboratory in Boston. They also turned off parts of the cell circuit in the brains of mice to map the circuit and to identify the cells connecting the two parts of the brain. To map circuits in the brain you need a protein tool that can turn off the various cells to determine their function. Assistant Professor Timothy Lynagh has designed precisely such a tool.

‘We take a receptor and mutate it, so that it is not sensitive to anything in the brain, but very sensitive to a particular drug. The tool works like an on/off switch. When you put the protein tool in the mouse brain, under normal circumstances, nothing will happen. But when you give the animal the drug, the cells that have the receptor on them will be turned off’, Timothy Lynagh explains.

Using this tool, the researchers can thus in theory turn off the cells that cause people suffering from sundown syndrome to become more aggressive at night.

May Be Used on Humans 20 Years into the Future
The tool can also be used in other contexts than sundown syndrome. In other studies, Tim Lynagh’s tool has been used to turn off cells in rats linked to anxiety and fear.

‘If you can start understanding which cells in the brain lead to which problems, you can then put this tool into any of those parts of the brain. The person who takes the drug will then have the cells causing the problem turned off’, Timothy Lynagh says.

Even though the study was conducted on mice, the tool and the knowledge the research has generated can potentially be used in the treatment of humans.

‘Because of the huge advances that are coming along with CRISPR, I would be tempted to say that based on a recent demonstration of gene therapy for brain disease, potentially, it could be used in the human brain in 20 years’ time. Of course it needs a lot more research’, he says.

Todd, W. D., Fenselau, H., Wang, J. L., Zhang, R., Machado, N. L., Venner, A., … & Lowell, B. B. (2018). A hypothalamic circuit for the circadian control of aggression. Nature neuroscience, 1.