Tag Archives: Psychiatry

Scientists Use Genetic Engineering to Explore Mechanisms Involved in Psychiatric Disorders (Psychiatry)

Researchers used genetic engineering tools to create a virus that can enter specific neurons and insert into the prefrontal cortex a new genetic code that induces the production of modified proteins. In tests with mice, the alteration of these proteins was sufficient to modify brain activity, indicating a potential biomarker for the diagnosis of psychiatric disorders such as schizophrenia and autism.

Sometimes referred to as the “executive brain”, the prefrontal cortex is the region that governs higher-level cognitive functions and decision making. Studies of tissue from this brain region in patients with schizophrenia have detected alterations in two proteins: BDNF (brain-derived neurotrophic factor) and trkB (tyrosine receptor kinase B).

The relationship between BDNF and trkB is important during brain development. When these proteins bind to each other, they trigger a cascade of intracellular signals that are essential to neuronal maturation and growth. Imbalances in this kind of signaling may be associated with the manifestation of certain disorders.

A group of researchers affiliated with the Federal University of Minas Gerais (UFMG) and the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil, and with Sweden’s Karolinska Institute, have created a virus capable of carrying the genetic code for a mutant form of trkB. When the modified trkB binds to BDNF, the intracellular signaling cascade is blocked, reproducing characteristics observed in brain tissue from schizophrenia patients.

The research, conducted with funding from FAPESP and the Ministry of Education’s Coordination for the Improvement of Higher Education Personel (CAPES), involved parvalbumin-expressing inhibitory interneurons, or PV interneurons for short. Interneurons connect spinal motor and sensory neurons, and can also communicate with each other, forming circuits of various complexity. Firing at relatively high frequencies in the gamma range (30-80 Hertz), they resemble the conductor of an orchestra, regulating excitation and inhibition in the central nervous system. 

PV is a protein that plays a role in many processes, such as cell-cycle regulation and muscle contraction, among others. PV interneurons are the most common interneurons in the cortex, and are involved in attention, social memory, and more. Dysfunction of PV interneurons disrupting cortical information processing and cognitive behavior has been detected in psychiatric patients.

The neurons and interneurons in the human brain communicate via electrical and chemical signals to activate or inhibit nearby neurons as well as circuits in distant brain regions. The organized activity of these different circuits gives rise to consciousness, feelings and behavior.

“Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice,” the researchers write in an article published in February in the Journal of Neuroscience.

In the study, the genetically modified virus was introduced into the brain tissue of adult transgenic mice using Cre-Lox recombination, a site-specific recombinase technology for inserting or deleting target DNA sequences. The researchers then recorded electrical activity in the prefrontal cortex and found alterations in the excitation-inhibition balance, as well as changes in brain waves and neuronal activity resulting in more aggressive behavior and anxiety.

Specific circuits in the cortex were manipulated in an innovative manner using the technique, explained Cleiton Lopes Aguiar, a professor at UFMG’s Institute of Biological Sciences and co-principal investigator for the study alongside Marie Carlén, a professor at Karolinska Institute.

“The results show that manipulating BDNF/trkB in adults can alter not only brain activity but also complex behaviors that depend on the prefrontal cortex,” Aguiar said. “It can be inferred that BDNF/trkB signaling is necessary to development, and to maintain mature neural networks.”

According to Leonardo Rakauskas Zacharias, a co-author of the article and a researcher at FMRP-USP’s Epilepsy Research Laboratory, the new technique enhances the study of the developed adult brain.

The role of interneurons

In the same issue of the Journal of Neuroscience, the group published another article on synchronous activity of cortical inhibitory interneurons expressing parvalbumin. “Brain oscillations are fundamental to the coordination of neuronal activity across neurons and structures. Gamma oscillations (30-80 Hz) have received particular attention through their association with perceptual and cognitive processes. (…) [Here we] show how deficient PV inhibition can lead to increased and asynchronous excitatory firing, contaminating the local field potential and manifesting as increased gamma power. Thus, increased gamma power does not always reflect a genuine rhythm. Further, we show that ketamine-induced gamma increases are caused by separate network mechanisms,” the authors explain.

According to Nicolas Gustavo Guyon, a member of the group and a researcher at Karolinska Institute, their analysis of brain oscillations in genetically modified mice detected asynchronous activity due to the inability of PV interneurons to respond to all excitatory stimuli generated by other neurons.

For Aguiar, what both articles have in common is the search for a deeper understanding of the role played by interneurons in the prefrontal cortex and how the brain organizes the excitation-inhibition balance. “We’re exploring the normal brain in order to achieve a deeper understanding of psychiatric disorders such as schizophrenia,” he said. “We show that if there are alterations in certain specific aspects of these normal animals, they display symptoms that could be initial clues to the mechanisms underlying the disorders.”

According to the Pan American Health Organization (PAHO-WHO), mental illness accounts for more than a third of total disability in the Americas, yet investment in mental health programs falls well short of what is required to address the needs of psychiatric patients. The term covers mental disorders such as dementia and schizophrenia, as well as depression. Over 300 million people live with depression, 60 million with bipolar disorders, and 23 million with schizophrenia-related disorders (including 1.5 million Brazilians), the WHO estimates.

Zacharias points out that the group’s research projects have been in progress for more than seven years and their results could contribute to the development of potential treatments. “We work with basic science to understand the mechanisms of the brain, and our findings can help all those concerned understand psychiatric disorders a little better,” he said.

The article “Adult trkB signaling in parvalbumin interneurons is essential to prefrontal network dynamics” can be retrieved from: www.jneurosci.org/content/early/2021/02/10/JNEUROSCI.1848-20.2021

The article “Network asynchrony underlying increased broadband gamma power” can be retrieved from: www.jneurosci.org/content/early/2021/02/10/JNEUROSCI.2250-20.2021

Featured image: The research group created a virus capable of acting on specific adult brain regions, helping to elucidate the role of key neurons in the prefrontal cortex. They tested the technique on mice (interneuron, stained green, with positive markings for trkB.DN, stained orange, and parvalbumina, stained blue. These results prove that trkB.DN-expressing inhibitory interneurons were successfully inserted by the viral vector; image: Nicolas Guyon)


Provided by FAPESP

Insomnia Associated With More Suicidal Thoughts, Worse Disease Symptoms in Schizophrenia (Psychiatry)

Insomnia is a common problem in patients with schizophrenia, and a new study reinforces a close association between insomnia, more suicidal thoughts and actions and increased problems like anxiety and depression in these patients.

It also provides more evidence that keeping tabs on how patients are sleeping — and intervening when needed — is important to their overall care.

“We are now aware that significant insomnia is putting our patients at even higher risk for suicide, so if they are having changes in sleep patterns, if they are having significant insomnia, then we really need to hone in on those questions even more related to suicidal thinking and do what we can to help,” says Dr. Brian Miller, psychiatrist and schizophrenia expert at the Medical College of Georgia at Augusta University.

Schizophrenia is clearly associated with an increased risk of suicide, with a 5-10% lifetime risk of death by suicide, that is likely the greatest within the first year of diagnosis, Miller says.

The new study in The Journal of Clinical Psychiatry looked at associations between insomnia, suicidal thoughts and attempts and disease severity in a large group of patients, 1,494 individuals diagnosed at 57 sites in the country, and enrolled in a comparative study of five different antipsychotics.

Miller and his colleagues looked at patient reports of insomnia and suicidal thoughts within the most recent two weeks, suicide attempts in the past six months and the state of their psychiatric illness when they enrolled in the study.

Nearly half of patients reported problems falling asleep or broken sleep, termed initial and middle insomnia, and 27% reported terminal insomnia where they wake up too early and cannot get back asleep.

They found insomnia a common symptom in patients with schizophrenia, with waking up too early particularly associated with current suicidal thoughts, and trouble falling and staying asleep significantly increasing the odds of a suicide attempt in the past six months.

Waking up too early was also most associated with more severe schizophrenia, including symptoms like anxiety and depression. But no matter which type of insomnia, it’s bad for patients’ overall health and disease, Miller says.

Studies indicate that 23-44% of patients with schizophrenia — both those taking and not taking medications– report problems with insomnia. Sleep architecture is a pattern of normal sleep, and sleep disturbances and abnormal sleep architecture have been found early in the schizophrenia disease process, findings which may correlate with disease severity. Disturbances in the natural body clocks, or circadian rhythms that help regulate sleep and wakefulness and other essential body functions, are known to be present in schizophrenia and are suspected to be a factor in patients’ related sleep problems. A generally heightened state of arousal in patients who are hearing voices and/or paranoid also is likely a factor. Insomnia has been implicated as a predictor of hallucinations in patients, and there seems to be a bidirectional relationship between insomnia and paranoia, the investigators write.

“If you are hearing voices that are constantly saying negative, horrible things, berating you, interfering with your thinking and your activities, it can be hard to fall asleep,” he says.

Miller says insomnia in his patients cuts across all ages, sexes and races.

While he has always been diligent asking patients at each visit about their sleep and counseling them on how to improve their sleep, the increasing evidence of the association with suicide and disease severity has heightened his diligence. While Miller says his colleagues across the country also tend to be diligent in regularly talking with patients about sleep, surveys have indicated that while patients with schizophrenia commonly report problems with insomnia, less than 20% of clinicians formally evaluate patients for it.

The new study suggests that insomnia is an important treatment target in schizophrenia. Interventions Miller offers include ensuring habits like avoiding caffeine as well as blue light from commons sources like televisions and smartphones, particularly in the hours before bedtime, as well as prescription and over-the-counter sleep aids.

Adjustments also can be made to the antipsychotic medication used to treat their schizophrenia since some, like clozapine, also have sedative effects. In fact, there is some evidence that insomnia and suicidal thoughts and actions are less likely in patients taking antipsychotics known to also have a sedative effect, they write, but just how needs exploration.

While he has not yet done a formal study, Miller has noted anecdotally that when his patients’ sleep improves, generally their schizophrenia does as well.

“I can’t think of anyone who says I am sleeping better and now my illness is worse. When you get a bad night’s sleep, the world just isn’t quite the same place the next day,” Miller says. “It affects the way we think about things, the judgements we make, it affects our emotions.” In fact, insomnia and increased suicide risk are associated with a variety of mental health issues, including depression.

The current study is the third group of patients in which Miller and his colleagues have found an association between insomnia and suicidal thoughts and actions.

Other investigators have associated sleep disturbances with suicidal thoughts in these patients but not actual suicide; others have shown, for example, nearly five times the risk of suicide attempts in patients experiencing insomnia at least three times a week.

Read the full study.

Featured image: Dr. Brian Miller © Augusta University


Reference: Brian J. Miller, Joseph P. McEvoy, and William V. McCall, “Insomnia, Suicidal Ideation, and Suicide Attempts in the Clinical Antipsychotic Trials of Intervention Effectiveness”, J Clin Psychiatry. 2021;82(3):20m13338. Link doi: https://doi.org/10.4088/JCP.20m13338


Provided by Augusta University

Pilot Study Finds Evidence of Bartonella Infection in Schizophrenia Patients (Psychiatry)

A pilot study from North Carolina State University and the University of North Carolina at Chapel Hill has found evidence of Bartonella infection in the blood of people with schizophrenia and schizoaffective disorder.

“Researchers have been looking at the connection between bacterial infection and neuropsychiatric disease for some time,” says Dr. Erin Lashnits, a former veterinary internist at NC State, current faculty member at the University of Wisconsin and first author of the study.

“Specifically, there has been research suggesting that cat ownership is associated with schizophrenia due to the zoonotic parasite Toxoplasma gondii, but to date there has been no conclusive evidence in support of a causative role for this parasite. So we decided to look at another cat-associated infectious agent, Bartonella, to see if there could be a connection.”

Bartonella are bacteria historically associated with cat-scratch disease, which until recently was thought to be solely a short-lived (or self-limiting) infection. Cats can become infected with Bartonella via exposure to fleas and potentially ticks, which are natural vectors of the bacteria. The cat is a host for at least three of the 40 known Bartonella species: Bartonella henselaeBartonella clarridgeiae and Bartonella koehlerae.

“While there is emerging understanding of neuropsychiatric illnesses such as schizophrenia as disorders of brain networks, the question about the actual causes remains unanswered,” says corresponding author Flavio Frohlich, associate professor of psychiatry at the UNC School of Medicine. “It was an exciting opportunity for us in the UNC Department of Psychiatry to team up with the leading experts on Bartonella to pursue this innovative idea of a potential link to schizophrenia. To our knowledge, this is the very first work that examines a potential role of Bartonella in schizophrenia.”

The research team enrolled a group of 17 people with stable, medically managed schizophrenia or schizoaffective disorder, and a control group of 13 healthy adults, to test for evidence of Bartonella infection.

All participants filled out questionnaires on severity of symptoms and potential Bartonella exposure. Blood samples were taken from participants twice in a one-week period. The samples were cultured in a growth medium, and both cultured and whole blood samples underwent qPCR and droplet digital, or ddPCR testing, at seven-, 14- and 21-day intervals, to look for evidence of Bartonella organism-specific DNA. Blood samples were also tested for Bartonella species-specific antibodies.

Of the 17 patients with schizophrenia, 12 had Bartonella DNA in their blood, as compared to only one of 13 in the control group. According to the questionnaires, both patients and controls reported similar pet ownership and flea exposures.

Bartonella ddPCR, a very new diagnostic technology, provides a more sensitive molecular test than we’ve previously had access to,” says Dr. Ed Breitschwerdt, Melanie S. Steele Distinguished Professor of Internal Medicine at NC State and study coauthor. “If we had not used ddPCR to test this cohort of individuals, we would not have found Bartonella DNA in any of the participants, either case or control.”

“It is important to remember that our study was by design not able to demonstrate a causal link between Bartonella infection and schizophrenia,” Frohlich says. “However, we believe this initial observational study strongly supports the need for follow-up research.”

The researchers plan to proceed with a larger study to see whether their preliminary results are borne out.

“Many of these patients have been undergoing care for years,” Breitschwerdt says. “What we’re starting to see is a pattern – Bartonella can persist for a long time. And for the subset of people who can’t eliminate the infection, the bacteria can cause chronic or progressive illness.”

The research appears in Vector Borne and Zoonotic Diseases and was supported in part by the National Institutes of Health (grants UL1TR002489 and T32OD011130). Ricardo Maggi and Julie Bradley of NC State, as well as L. Fredrik Jarskog of UNC-Chapel Hill, contributed to the work.


Reference: Erin Lashnits, Ed Breitschwerdt, Ricardo Maggi, Julie Bradley, North Carolina State Univerity; L. Fredrik Jarskog, Flavio Frolich, University of North Carolina at Chapel Hill, “Schizophrenia and Bartonella spp. infection: a pilot case-control study”, Vector-Borne and Zoonotic Diseases 2021. DOI: 10.1089/vbz.2020.2729


Provided by NC State University

How Pregnancy Turns the Stress Response on its Head? (Psychiatry)

Researchers seek elusive link between prenatal stress and offspring mental health

The link between psychological stress and physical health problems generally relates to a stress-induced immune response gone wild, with inflammation then causing damage to other systems in the body. It’s a predictable cascade – except in pregnancy, research suggests.

Scientists exploring the negative effects of prenatal stress on offspring mental health set out to find the immune cells and microbes in stressed pregnant mice most likely to trigger inflammation in the fetal brain – the source for anxiety and other psychological problems identified in previous research.

Tamar Gur © OSU

Instead, the researchers found two simultaneous conditions in response to stress that made them realize just how complex the cross-talk between mom and baby is during gestation: Immune cells in the placenta and uterus were not activated, but significant inflammation was detected in the fetal brain.

They also found that prenatal stress in the mice led to reductions in gut microbial strains and functions, especially those linked to inflammation.

“I thought it was going to be a fairly straightforward tale of maternal inflammation, changes in microbes and fetal inflammation. And while the changes in microbes are there, the inflammation part is more complex than I had anticipated,” said Tamar Gur, senior author of the study and assistant professor of psychiatry and behavioral healthneuroscience, and obstetrics and gynecology at The Ohio State University.

“The complex interplay between the stress response and the immune system is dysregulated by stress, which is problematic for the developing fetus. There are key changes during this critical window that can help shape the developing brain, so we want to figure out how we could potentially intervene to help regulate these systems.”

The study was published recently in Scientific Reports.

Most attention paid to the negative effects of prenatal stress on offspring mental health focus on disruptive major life events or exposure to disaster, but evidence also suggests that up to 84% of pregnant women experience some sort of stress.

In a previous study, Gur’s lab found that prenatal stress’s contributions to life-long anxiety and cognitive problems in mouse offspring could be traced to changes in microbial communities in both mom and baby.

Gur focuses on the intrauterine environment in her search for factors that increase the risk for prenatal stress’s damaging effects, and this newer study opened her eyes to how complicated that environment is.

“The dogma would be that we’re going to see an influx of immune cells to the placenta. The fact that it’s suppressed speaks to the powerful anti-inflammatory response of the mom. And that makes sense – a fetus is basically a foreign object, so in order to maintain pregnancy we need to have some level of immunosuppression,” said Gur, also an investigator in Ohio State’s Institute for Behavioral Medicine Research and a maternal-fetal psychiatrist at Ohio State Wexner Medical Center.

“We want to figure out what is at the interface between mom and baby that is mediating the immunosuppressive effect on the maternal side and the inflammation on the fetal side. If we can get at that, we’ll get really important keys to understanding how best to prevent the negative impact of prenatal stress.”

Prevention could come in the form of prebiotics or probiotics designed to boost the presence of beneficial microbes in the GI tract of pregnant women. Maternal microbes affect the brains and immune systems of developing offspring by producing a variety of chemicals the body uses to manage physiological processes.

“I think microbes hold really important clues and keys, making them a tantalizing target for intervention. We can do things about individuals’ microbes to benefit both mom and baby,” Gur said.

To mimic prenatal stress during the second and early third trimesters, pregnant mice in her lab are subjected to two hours of restraint for seven days to induce stress. Control mice are left undisturbed during gestation.

In this recent study, the researchers found stress in mice activated steroid hormones throughout the body – the sign of a suppressed immune system – and resulted in lower-than-expected populations of immune cells in reproductive tissue, suggesting that the uterus was effectively resisting the effects of the stress.

An examination of colon contents showed differences in microbial communities between stressed and non-stressed mice, with one family of microbes that influences immune function markedly decreased in stressed mice. The researchers found that stress showed few signs of gene-level changes in the colon that could let bacteria escape to the bloodstream – one way that microbes interfere with body processes.

“There are absolutely changes in microbes that might help explain key pathways that are important for health and the immune system, especially when it comes to the placenta and the mom’s immune system,” Gur said.

In future studies, her lab will examine immune cells in the fetal brain and monitor how gene expression changes in cells in the placenta in response to stress. She is also leading an ongoing observational study in women, tracking microbes, inflammation and stress levels during and after pregnancy.

This work was supported by grants from the National Institutes of Health and startup funds from Ohio State. Co-authors, all from Ohio State, include Adrienne Antonson, Morgan Evans, Jeffrey Galley, Helen Chen, Therese Rajasekera, Sydney Lammers, Vanessa Hale and Michael Bailey.

Featured image: Evidence suggests that up to 84% of pregnant women experience some sort of stress. Photo: Shutterstock.com


Reference: Antonson, A.M., Evans, M.V., Galley, J.D. et al. Unique maternal immune and functional microbial profiles during prenatal stress. Sci Rep 10, 20288 (2020). https://www.nature.com/articles/s41598-020-77265-x https://doi.org/10.1038/s41598-020-77265-x


Provided by OSU

For Breakthroughs in Slowing Aging, Scientists Must Look Beyond Biology (Psychiatry / Psychology)

Incorporating social and behavioral factors alongside biological mechanisms is critical for improving aging research, according to a trio of studies by leading social scientists

A trio of recent studies highlight the need to incorporate behavioral and social science alongside the study of biological mechanisms in order to slow aging.

The three papers, published in concert in Ageing Research Reviews, emphasized how behavioral and social factors are intrinsic to aging. This means they are causal drivers of biological aging. In fact, the influence of behavioral and social factors on how fast people age are large and meaningful. However, geroscience–the study of how to slow biological aging to extend healthspan and longevity–has traditionally not incorporated behavioral or social science research. These papers are by three pioneers in aging research and members of the National Academy of Medicine who study different aspects of the intersection of biology and social factors in shaping healthy aging through the lifespan.

Improving translation of aging research from mice to humans

Exciting biological discoveries about rate of aging in non-human species are sometimes not applicable or lost when we apply them to humans. Including behavioral and social research can support translation of geroscience findings from animal models to benefit humans, said Terrie Moffitt, the Nannerl O. Keohane University Professor of Psychology and Neuroscience at Duke University.

“The move from slowing fundamental processes of aging in laboratory animals to slowing aging in humans will not be as simple as prescribing a pill and watching it work,” Moffitt said. “Compared to aging in laboratory animals, human aging has many behavioral/social in addition to cellular origins and influences. These influences include potential intervention targets that are uniquely human, and therefore are not easily investigated in animal research.”

Several of these human factors have big impacts on health and mortality: stress and early life adversity, psychiatric history, personality traits, intelligence, loneliness and social connection, and purpose in life are connected to a variety of late-life health outcomes, she explained. These important factors need to be taken into account to get a meaningful prediction of human biological aging.

Elissa Epel, professor and vice chair in the Department of Psychiatry at UC San Francisco © R Searcy

“Geroscience can be augmented through collaboration with behavioral and social science to accomplish translation from animal models to humans, and improve the design of clinical trials of anti-aging therapies,” Moffitt said. “It’s vital that geroscience advances be delivered to everyone, not just the well-to-do, because individuals who experience low education, low incomes, adverse early-life experiences, and prejudice are the people who age fastest and die youngest.”

Social factors associated with poor aging outcomes

“Social hallmarks of aging” can be strongly predictive of age-related health outcomes – in many cases, even more so than biological factors, said USC University Professor and AARP Chair in Gerontology Eileen Crimmins. While the aging field commonly discusses the biological hallmarks of aging, we don’t tend to include the social and behavioral factors that lead to premature aging. Crimmins has called the main five factors below “the Social Hallmarks of aging” and poses that these should not be ignored in any sample of humans and the concepts should be incorporated where possible into non-human studies.

Crimmins examined data that was collected in 2016 from the Health and Retirement Study, a large, nationally representative study of Americans over the age of 56 that incorporates both surveys regarding social factors and biological measurements, including a blood sample for genetic analysis. For the study, she focused the five social hallmarks for poor health outcomes:

  1. low lifetime socioeconomic status, including lower levels of education
  2. adversity in childhood and adulthood, including trauma and other hardships
  3. being a member of a minority group
  4. adverse health behaviors, including smoking, obesity and problem drinking
  5. adverse psychological states, such as depression, negative psychological outlook and chronic stress

The presence of these five factors were strongly associated with older adults having difficulty with activities of daily living, experiencing problems with cognition, and multimorbidity (having five or more diseases). Even when controlling for biological measurements – including blood pressure, genetic risk factors, mitochondrial DNA copy number and more – the social differences, as well as demographic factors such as age and gender, explained most of the differences in aging outcomes between study subjects, she said. However, biological and social factors aren’t completely independent from one another, Crimmins added, which is why she advocates for further incorporation of social and behavioral factors in aging biology research.

Terrie Moffitt, the Nannerl O. Keohane University Professor of Psychology and Neuroscience at Duke University. Courtesy Terrie Moffitt

“Variability in human aging is strongly related to the social determinants of aging; and it remains so when extensive biology is introduced as mediating factors. This means that the social variability in the aging process is only partly explained by the biological measures researchers currently use,” she said. “Our hypothesis is that if we could fully capture the basic biological mechanisms of aging, they would even more strongly explain the social variability in the process of aging, as social factors need to ‘get under the skin’ through biology.”

Understanding stress and stress resilience

Elissa Epel, professor and vice chair in the Department of Psychiatry and Behavioral Sciences at UC San Francisco, detailed how research on stress and resilience needs to incorporate psychosocial factors in order to understand how different kinds of stress affect aging. Not all types of stress are equal and in fact some are salutary.

The social hallmarks of aging can shape the rate of aging in part through toxic stress responses, she said. While acute responses to minor or moderate stressors, including infection or injury, is critical to survival, chronic exposure to high amounts of stress–including long-term psychological stressors such as abuse–can prove toxic and result in poor health outcomes.

“Brief, intermittent, low-dose stressors can lead to positive biological responses, improving resistance to damage, which is called hormesis,” Epel explained. For example, physiological hormetic stressors include short term exposure to cold, heat, exercise, or hypoxia. Hormetic stress turns on mechanisms of cell repair and rejuvenation. “In contrast, a high dose of a chronic exposure can override these mechanisms, resulting in damage or death,” she added. Thus, toxic stress can accelerate biological aging processes, whereas hormetic stress can slow aging.

However, the types, timing, and frequency of hormetic stress need to be better delineated in order to be useful to human aging research and interventions, Epel said.

“Stress resilience, an umbrella term including hormetic stress, can be measured across cellular, physiological, and psychosocial functioning,” she said. “Developing a deeper understanding of stress resilience will lead to more targeted innovative interventions.” Stress resilience can also include social interventions that protect from the malleable social hallmarks of aging, including safe neighborhoods to reduce trauma and violence, and social support programs to combat loneliness and depression.

Geroscience is now more important than ever, both to our aging global demography but also to the health challenges we face going forward, and stress resilience is an especially important topic at the moment, Epel added. “In our new era, we have dramatically increasing temperature extremes, wildfires and small particle pollution, and new zoonotic viruses to contend with intermittently,” she said. “Reducing social disparities, improving stress resilience and bolstering immune function have become critical public health goals.”

In sum, the three papers together point to a promising decade ahead for aging research.

Humans, as complex social mammals, age together in response to social conditions and behavioral factors that are partly malleable. Epel explains “As we discover and test biological processes of aging that we can manipulate, we can do this in tandem with capitalizing on the natural levers of healthy aging that are powerful, interactive, and cannot be ignored. In this way, the fountain of youth becomes more attainable.”

“Behavioral and Social Research to Accelerate the Geroscience Translation Agenda” by Terrie E. Moffitt was supported by the National Institute on Aging (AG032282, R01 AG049789) and the U.K. Medical Research Council (P005918). “Social hallmarks of aging: Suggestions for geroscience research” by Eileen Crimmins was funded by grants from the National Institute on Aging (U01 AG009740, P30 AG017265, and R01 AG AG060110). “The geroscience agenda: Toxic stress, hormetic stress, and the rate of aging” by Elissa Epel was funded by National Institute on Aging grant R24 AG048024.

Featured image: USC University Professor and AARP Chair in Gerontology Eileen Crimmins © John Skalicky/USC


Reference: Eileen M. Crimmins, Social hallmarks of aging: Suggestions for geroscience research, Ageing Research Reviews, Volume 63, 2020, 101136, ISSN 1568-1637, https://doi.org/10.1016/j.arr.2020.101136. (https://www.sciencedirect.com/science/article/pii/S1568163720302713)


Provided by University of South California

FSU Researcher Examines Ways Cocaine Alters Gene Expression (Psychiatry)

New research from Florida State University identifies a novel gene that plays a functional role in cocaine addiction.  

In a new paper in the journal Biological Psychiatry, Assistant Professor of Biological Science Jian Feng and his colleagues reveal that cocaine use in mice resulted in changes to what’s called long noncoding RNA (lncRNA), a major type of ribonucleic acid that is transcribed, but not translated into protein. While the functional significance of lncRNAs remains elusive, scientists do know, however, that they play a regulatory role in gene expression.

“Though gene expression underlies various forms of brain function and disorders, scientists have mostly focused on coding genes, the ones that are translated into proteins. The role of long noncoding RNA in the brain, particularly drug addiction, is not well understood yet,” Feng said. “Over the past decade, people recognized tens of thousands of lncRNAs, with many of them expressed specifically in the brain, which suggests their pivotal role in neural function.”  

In the experiments, scientists observed that cocaine specifically affected a long noncoding RNA named Gas5. When cocaine was administered, it decreased the expression of this gene. In contrast, if Gas5 was manipulated to overperform, it led to decreased cocaine intake and decreased compulsive-like behavior to acquire cocaine.  

“We saw this decrease in gene expression with cocaine and so then we really wanted to understand the molecular underpinnings of that,” Feng said.  

In this study, they demonstrate that Gas5 alone mediates numerous gene expression changes, which significantly overlap with the ones altered by cocaine administration.  

Feng’s laboratory at FSU focuses mostly on epigenetics and genes affected by drug addiction. In this study, he is particularly interested in the role long noncoding RNA plays in that process, something that could have long-term implications in how scientists and health care professionals investigate treatment and rehabilitation.  

“We really want to improve people’s understanding of what this RNA does and hopefully that will lead to more studies and eventually better treatments,” Feng said.  

About 14.7% of Americans ages 12 and older have tried cocaine at some point in their life, according to the research from the National Institute on Drug Abuse.  

Reference: Haiyang Xu, Amber N. Brown, Nicholas J. Waddell, Xiaochuan Liu, Graham J. Kaplan, Javed M. Chitaman, Victoria Stockman, Rachel L. Hedinger, Ryan Adams, Kristen Abreu, Li Shen, Rachael Neve, Zuoxin Wang, Eric J. Nestler, Jian Feng, “Role of Long Noncoding RNA Gas5 in Cocaine Action”, Biological Psychiatry, Volume 88, Issue 10, 2020, Pages 758-766, ISSN 0006-3223,
https://doi.org/10.1016/j.biopsych.2020.05.004.
(http://www.sciencedirect.com/science/article/pii/S0006322320315894)

Provided by FSU

A Pursuit of Better Testing to Sort Out the Complexities of ADHD (Psychiatry)

Review of cognitive testing studies reveals how adding computer simulations could help.

The introduction of computer simulation to the identification of symptoms in children with attention deficit/hyperactivity disorder (ADHD) has potential to provide an additional objective tool to gauge the presence and severity of behavioral problems, Ohio State University researchers suggest in a new publication.

Computational psychiatry could be an important supplement to the diagnostic process for ADHD, researchers suggest in a new publication. Illustration: Getty Images

Most mental health disorders are diagnosed and treated based on clinical interviews and questionnaires – and, for about a century, data from cognitive tests has been added to the diagnostic process to help clinicians learn more about how and why people behave in a certain way.

Cognitive testing in ADHD is used to identify a variety of symptoms and deficits, including selective attention, poor working memory, altered time perception, difficulties in maintaining attention and impulsive behavior. In the most common class of performance tests, children are told to either press a computer key or avoid hitting a key when they see a certain word, symbol or other stimulus.

For ADHD, however, these cognitive tests often don’t capture the complexity of symptoms. The advent of computational psychiatry – comparing a computer-simulated model of normal brain processes to dysfunctional processes observed in tests – could be an important supplement to the diagnostic process for ADHD, the Ohio State researchers report in a new review published in the journal Psychological Bulletin.

The research team reviewed 50 studies of cognitive tests for ADHD and described how three common types of computational models could supplement these tests.

It is widely recognized that children with ADHD take longer to make decisions while performing tasks than children who don’t have the disorder, and tests have relied on average response times to explain the difference. But there are intricacies to that dysfunction that a computational model could help pinpoint, providing information clinicians, parents and teachers could use to make life easier for kids with ADHD.

“We can use models to simulate the decision process and see how decision-making happens over time – and do a better job of figuring out why children with ADHD take longer to make decisions,” said Nadja Ging-Jehli, lead author of the review and a graduate student in psychology at Ohio State.

Ging-Jehli completed the review with Ohio State faculty members Roger Ratcliff, professor of psychology, and L. Eugene Arnold, professor emeritus of psychiatry and behavioral health.

The researchers offer recommendations for testing and clinical practice to achieve three principal goals: better characterizing ADHD and any accompanying mental health diagnoses such as anxiety and depression, improving treatment outcomes (about one-third of patients with ADHD do not respond to medical treatment), and potentially predicting which children will “lose” the ADHD diagnosis as adults.

Decision-making behind the wheel of a car helps illustrate the problem: Drivers know that when a red light turns green, they can go through an intersection – but not everyone hits the gas pedal at the same time. A common cognitive test of this behavior would repeatedly expose drivers to the same red light-green light scenario to arrive at an average reaction time and use that average, and deviations from it, to categorize the typical versus disordered driver.

This approach has been used to determine that individuals with ADHD are typically slower to “start driving” than those without ADHD. But that determination leaves out a range of possibilities that help explain why they’re slower – they could be distracted, daydreaming, or feeling nervous in a lab setting. The broad distribution of reactions captured by computer modeling could provide more, and useful, information.

“In our review, we show that this method has multiple problems that prevent us from understanding the underlying characteristics of a mental-health disorder such as ADHD, and that also prevent us from finding the best treatment for different individuals,” Ging-Jehli said. “We can use computational modeling to think about the factors that generate the observed behavior. These factors will broaden our understanding of a disorder, acknowledging that there are different types of individuals who have different deficits that also call for different treatments.

“We are proposing using the entire distribution of the reaction times, taking into consideration the slowest and the fastest reaction times to distinguish between different types of ADHD.”

The review also identified a complicating factor for ADHD research going forward – a broader range of externally evident symptoms as well as subtle characteristics that are hard to detect with the most common testing methods. Understanding that children with ADHD have so many biologically based differences suggests that a single task-based test is not sufficient to make a meaningful ADHD diagnosis, the researchers say.

“ADHD is not only the child who is fidgeting and restless in a chair. It’s also the child who is inattentive because of daydreaming. Even though that child is more introverted and doesn’t express as many symptoms as a child with hyperactivity, that doesn’t mean that child doesn’t suffer,” Ging-Jehli said. Daydreaming is especially common in girls, who are not enrolled in ADHD studies nearly as frequently as boys, she said.

Ging-Jehli described computational psychiatry as a tool that could also take into account – continuing the analogy – mechanical differences in the car, and how that could influence driver behavior. These dynamics can make it harder to understand ADHD, but also open the door to a broader range of treatment options.

“We need to account for the different types of drivers and we need to understand the different conditions to which we expose them. Based on only one observation, we cannot make conclusions about diagnosis and treatment options,” she said.

“However, cognitive testing and computational modeling should not be seen as an attempt to replace existing clinical interviews and questionnaire-based procedures, but as complements that add value by providing new information.”

According to the researchers, a battery of tasks gauging social and cognitive characteristics should be assigned for a diagnosis rather than just one, and more consistency is needed across studies to ensure the same cognitive tasks are used to assess the appropriate cognitive concepts.

Finally, combining cognitive testing with physiological tests – especially eye-tracking and EEGs that record electrical activity in the brain – could provide powerful objective and quantifiable data to make a diagnosis more reliable and help clinicians better predict which medicines would be most effective.

Ging-Jehli is putting these suggestions to the test in her own research, applying a computational model in a study of a specific neurological intervention in children with ADHD.

“The purpose of our analysis was to show there’s a lack of standardization and so much complexity, and symptoms are hard to measure with existing tools,” Ging-Jehli said. “We need to understand ADHD better for children and adults to have a better quality of life and get the treatment that is most appropriate.”

This research was supported by the Swiss National Science Foundation and the National Institute on Aging.

Reference: Ging-Jehli, N. R., Ratcliff, R., & Arnold, L. E. (2020). Improving neurocognitive testing using computational psychiatry—A systematic review for ADHD. Psychological Bulletin. Advance online publication. https://doi.org/10.1037/bul0000319 https://psycnet.apa.org/record/2020-99592-001

Provided by Ohio State University

Schizophrenia May be Similar to Immune Disorders, Show Scientists (Psychiatry)

A study by clinical scientists at the University of Manchester has shown that schizophrenia may—in some part—be caused by disordered functioning of the immune system.

©WebMD

The first ever trial in schizophrenia of the powerful immune suppressant drug, Methotrexate, produced what the team described as ‘promising’ effects on what are known as positive symptoms, such as hearing voices.

Though the team stress the sample size was too small to show if Methotrexate could work as an add-on treatment for schizophrenia, they found a ‘puzzling’ therapeutic effect on symptoms of early schizophrenia.

And that, they argue, warrants further investigation.

The findings published in the Journal of Translational Psychiatry shed new light on the devastating and difficult to treat condition, which causes distress and disability worldwide.

Schizophrenia is categorized by so called ‘positive symptoms’ such as hearing voices (hallucinations) and ‘negative symptoms’ (disordered thinking, poor motivation, poor social function).

Negative symptoms, which contribute significantly to the disability associated with schizophrenia are hard to treat with currently available medication.

The study was funded by the Stanley Medical Research Institute in the United States in collaboration with the Pakistan Institute of Living and Learning.

The trial took place in Pakistan, led by Professor Imran Chaudhry from The University of Manchester who after years of service to the NHS relocated to Pakistan to continue to practice psychiatry.

The lack of available treatments for these symptoms encouraged Professor Chaudhry’s team to investigate new treatment options for schizophrenia.

Methotrexate is often used to treat inflammatory diseases such as rheumatoid arthritis and Crohn’s disease.

Inflammatory and autoimmune conditions are more common in patients with schizophrenia, possibly indicating that there is a shared underlying cause to these diseases.

“Methotrexate is thought to help treat autoimmune disorders by resetting the way T cells—an important part of the immune system—work,” said Professor Chaudhry.

“This action on the central nervous system may account for the improvement in symptoms we found in our study,” he added.

They used a low 10mg dose of the drug, which was given alongside the patients’ routine psychiatric medication.

No significant side-effects were reported by the patients taking Methotrexate, suggesting it was relatively well tolerated.

Nusrat Husain, Professor of Psychiatry and Director of Research in Global Mental Health at The University of Manchester added: “We used the lowest clinically effective dose in autoimmune disorders which often needs to be increased so higher doses could produce a more powerful effect in schizophrenia.

“However, the health risks of methotrexate are substantial and require careful monitoring which is why we would rule out large unfocussed trials.”

Psychiatrist Dr. Omair Husain, who is an honorary researcher at The University of Manchester and an Assistant Professor based at The University of Toronto said: “Immune systems could be involved in schizophrenia and that raises fascinating questions.

“Perhaps one day we might be able to identify subsets of people with schizophrenia who may respond to treatments that act on the immune system.

“The small, unexpected effect we found in our study warrants further investigation which we now believe is feasible.

“Future work needs to focus on identifying these subgroups possibly through studies that use advanced brain imaging techniques and state of the art immune profiling techniques.”

Reference: I. B. Chaudhry et al. A randomized clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis, Translational Psychiatry (2020). DOI: 10.1038/s41398-020-01095-8 https://www.nature.com/articles/s41398-020-01095-8

Provided by University of Manchester

Genetic Differences Important in Alzheimer’s Diagnosis (Psychiatry)

The two used methods for detecting amyloid pathology in Alzheimer’s disease do not give unambiguous results, with the risk of incorrect or delayed care interventions. Now, researchers at Karolinska Institutet in Sweden have found genetic explanations for the differences. The study is published in Molecular Psychiatry and may be important for more individual diagnostics and the development of future drugs.

Schematic illustration of how brain imaging resp. cerebrospinal fluid measures the accumulation of amyloid protein. ©The research team.

Alzheimer’s disease is the most common dementia disease and leads to gradual memory loss and premature death. Approximately 120,000 people in Sweden have Alzheimer’s and there are approximately 50 million people worldwide. According to Hjärnfonden, the number will increase by 70 percent in 50 years, partly because we are living longer and longer.

One of the earliest signs of Alzheimer’s is a pathological accumulation of amyloid protein forming insoluble deposits in the brain, also called plaques. This process can last for many years without appreciably affecting the person’s cognitive ability.

Amyloid plaques are present in the brain from an early stage of Alzheimer’s disease, already before mild cognitive impairment. At the same time, an early diagnosis is important for care interventions that could dampen the course of the disease.

Today, brain imaging of amyloid plaques with a PET camera and analysis of cerebrospinal fluid, CSF, from the spinal cord are the accepted methods for detecting pathological accumulations of amyloid.

But in up to 20 percent of cases, especially at early stages of the disease, the methods show different results. These differences can have implications for the patient for early diagnosis and treatment.

Now, researchers at Karolinska Institutet and Vita-Salute San Raffaele University in Milano have identified two alternative pathways for the development of amyloid pathology in Alzheimer’s disease.

The results are based on PET imaging and CSF analyses in 867 participants, including patients with mild cognitive impairment, Alzheimer’s dementia and healthy controls. For two years, the amyloid accumulation in a subset of nearly 300 participants had been documented with both a PET camera and CSF analysis.

The results show that pathological changes in some individuals are first detected in the brain with a PET camera, and in other individuals first with CSF analysis. In the latter group, the researchers also saw a higher incidence of Alzheimer’s genetic risk factor and faster accumulation of amyloid plaques in the brain compared to the former group.

According to the researchers, the results reveal two different groups of patients, with different genetics and speed of amyloid plaque accumulation in the brain.

“The results may be important as amyloid biomarkers play a significant role as early diagnostic markers for clinical diagnosis. Today, CSF-analysis and PET are considered equivalent to determine the degree of amyloid accumulation, but the study indicates that the two methods should rather be seen as complementary to each other,” says first author Arianna Sala, currently a post-doctoral fellow at the University of Liège, Belgium and Technical University of Munich, Germany.

“The differences in the results for biomarkers in the brain and CSF provide unique biological information and the opportunity for earlier and more individualized diagnosis and treatment for Alzheimer’s disease in the future. The results may also be important for the design of clinical trials of new drugs against amyloid accumulation in the brain,” says last author Elena Rodriguez-Vieitez, senior researcher at the Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet.

The study was funded by the European Union Innovative Medicines Initiative AMYPAD, the Alzheimer’s Foundation, the Brain Foundation, the Dementia Foundation, the Foundation for Strategic Research (SSF), the Swedish Research Council, the Ake Wiberg Foundation and Region Stockholm. There are no reported conflicts of interest.

Reference: Arianna Sala, Agneta Nordberg, Elena Rodriguez Vieitez,”Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity”, Molecular Psychiatry, online December 11, 2020, doi: 10.1038/s41380-020-00950-w. https://www.nature.com/articles/s41380-020-00950-w

Provided by Karolinska Institutet