Tag Archives: #schizophrenia

Researchers Discovered How Levels Of A Protein Could be Used in the Future To Diagnose Schizophrenia (Psychiatry)

Scientists at Sanford Burnham Prebys have discovered how levels of a protein could be used in the future as a blood-based diagnostic aid for schizophrenia. The activity of the protein, which is found in both the brain and blood, affects neural connections in human brains and is uniquely imbalanced in people diagnosed with the condition. The research also provides guidance for future analyses into the molecular basis of this serious, disabling mental disorder.

The study, an international collaboration among groups at Yokohama City University Graduate School of Medicine in Japan and the Department of Psychiatry at Harvard Medical School in Belmont, Massachusetts, was recently published in PNAS.

“This study examined the activity of CRMP2, a protein found in the brain (called a ‘cytoskeletal protein’) that regulates how neurons make connections with each other,” says Evan Y. Snyder, M.D., Ph.D., director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys and co-senior author of the study. “CRMP2 also happens to be expressed in lymphocytes in the blood and can therefore be readily sampled in people by doing nothing more than a simple venipuncture.

“There was an abundance of CRMP2 levels in samples from people with schizophrenia compared to people without the disorder. We also saw structural abnormalities in the dendrites of neurons that could potentially be disabling because dendrites play an important role in receiving impulses from other nerve cells in the brain.”

Previous research has shown that most people maintain an even balance between the two forms of CRMP2: its active, non-phosphorylated form and its inactive, phosphorylated form. The new research first examined postmortem brain tissue and then blood samples from people with schizophrenia. The research team compared these levels to those in people without the disorder.

The findings indicated that the amount of active CRMP2 was too high in people with schizophrenia and, at least in young people with schizophrenia, was not balanced by an appropriate amount of increased inactive CRMP2. That imbalance between active and inactive CRMP2 could account for some dysfunctions in neural connections.

Measuring an abundance of active CRMP2, particularly if its ratio with inactive CRMP2 is too low, could become a format for a rapid, minimally invasive blood test to support the diagnosis of schizophrenia.

“Schizophrenia can be challenging to diagnose early on or in young patients for a number of reasons,” says Snyder. “Pairing a blood test with psychiatric and neurobehavioral exams could help doctors distinguish schizophrenia from other conditions that have somewhat similar symptomologies, such as the manic phase of bipolar disorder or other behavioral, personality, or thought disorders.

“Our results were most striking in people under the age of 40, and even more so in people under the age of 30. An early diagnosis could improve the clinical management of affected individuals as well as accelerate the development of new therapeutic options,” Snyder adds.

The researchers now want to dig deeper into the molecular biology of the disease to discover the “regulator” that keeps most people’s CRMP2 levels on an even keel. They also want to conduct a larger, multi-center clinical study that compares schizophrenia with other psychiatric disorders. Future research will aim to include a wider range of ethnicities and age groups.

Featured image: Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.

Reference: Munetaka Nomoto el al., “Clinical evidence that a dysregulated neural network modulator may aid in diagnosing schizophrenia,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2100032118

Provided by Sanford Burnham Prebys Medical Discovery Institute

Lipidomics Research Provides Clues for Drug Resistance in Schizophrenia (Psychiatry)

Researchers from Skoltech and the Mental Health Research Center have found 22 lipids in the blood plasma of people with schizophrenia that were associated with lower symptom improvement over time during treatment. These can help track resistance to medication that affects over a third of patients. The paper was published in the journal Biomolecules.

Studies suggest that up to 34% of people living with schizophrenia can be resistant to two or more antipsychotic medications used to treat the disorder. Individual responses vary greatly, and there are no satisfactory biomarkers of treatment response yet, which can often turn finding the right medication into a painful and protracted guessing game.

Recently researchers have turned to studying lipids and the important function they are now known to play in both the properties and functionality of the brain, such as membrane fluidity and permeability, retrograde signaling, neural plasticity, and neurotransmitter release modulation. “Lipidomics is a growing field, and a lot remains unknown about lipid metabolism and its alteration in disease, which makes lipidomics a promising field for new discoveries,” the paper’s lead author, Anna Tkachev of the Skoltech Center for Neurobiology and Brain Restoration (CNBR), says.

Anna Tkachev and her colleagues measured the blood lipid abundances for 322 blood plasma lipids in 92 individuals diagnosed with schizophrenia and undergoing treatment in a hospital. They studied the associations between symptom improvement and individual changes in blood plasma lipid levels by collecting blood plasma at two distinct time points: at the beginning and at the end of a hospital stay that lasted for 37 days on average.

Doctors used the Positive and Negative Syndrome Scale (PANSS) to assess the condition of the patients; a higher score corresponds to more severe symptoms, so researchers were looking for a drop in PANSS score over time. All but one patient showed improvement, but the extent was different. “We found that, for patients with the least improvement in symptom severity, 22 lipids, including 20 triglyceride species, were increased at the second time point, while patients with most improvement did not demonstrate the same increase in lipid levels,” the authors write.

Anna Tkachev notes that a lot remains uncertain about the role of lipids in disease, and the role of lipids in schizophrenia in particular. “Typically, in a clinical setting, only total triglycerides are measured in the blood. In our study, we assessed lipids at a more detailed level of individual triglyceride species. The lipids we find significant in our study (shorter chain triglycerides) are not among the most abundant triglycerides, and any variation in their levels would probably remain undetected at the level of total triglyceride measurement. Because many studies in the past have focused on total triglyceride levels and not detailed level of individual lipid species, it is difficult to say for now what these alterations signify,” she says.

The lipids the team found seem to be related to metabolic alterations: they have been reported to be affected in diabetes and non-alcohol fatty liver disease. “Metabolic abnormalities are, unfortunately, common in patients suffering from schizophrenia, and managing these metabolic abnormalities is an important part of managing the psychiatric disorder. However, there seems to be a complex interplay between metabolic abnormalities and psychiatric health. The role these metabolic abnormalities play in schizophrenia is not well understood, and the cause-effect relationship between the two is unclear as well,” Tkachev explains.

Since the researchers were looking at individual changes in lipid levels and not the levels of lipids at baseline, their results cannot be used for a predictive model of treatment response. “Our results show that different levels of symptom improvement are associated with different alterations in lipid levels. Rather than providing a predictive biomarker, we hope that our results can help further the understanding of the underlying mechanisms of disease manifestation and treatment response,” Tkachev says.

Provided by SKOLTECH

Partners of People With Schizophrenia and Bipolar Disorder Have Often A Mental Disorder (Psychiatry)

Almost half of the parents who have children together with a parent with schizophrenia or bipolar disorder, are themselves burdened by psychological issues. This can affect family life and the children. This is shown in the research result from the major Danish psychiatry project iPSYCH.

We typically choose a partner who resembles us in relation to social status, education and, to some extent, also income. Research has previously established this. A new study now shows that almost half of the parents who have children with a partner who suffers from schizophrenia or bipolar disorder themselves meet the criteria for a mental disorder. By comparison, this is 18 percent for parents in the control group. 

The results stem from The Danish High-Risk and Resilience Study, which is part of iPSYCH. A total of 872 parents participated in the study. The parental couples were selected such that one of the parents was registered in the National Patient Register with a diagnosis of schizophrenia or bipolar disorder. Their partner and the parents from the control group were not registered with these disorders. At the time of the study, all of the parents had a seven-year-old child. 

Met the criteria themselves

“In the Danish registers we used, each child only had one parent registered with a mental disorder, but the diagnostic interview carried out as part of our study showed that almost half of the partners also fulfilled the criteria for such a disorder. In addition, the partners had a lower functional level compared to the control group,” says PhD and Psychologist Aja Neergaard Greve, who is behind the study.

“The most frequent diagnosis among the partners was depression. We were surprised that six per cent of the partners to people with schizophrenia also met the diagnostic criteria for schizophrenia themselves. In the control group, it was only one per cent,” she says.

Care is often dependent on the other person

According to the researcher, the results – which have been published in the scientific journal Schizophrenia Bulletin – indicate possible risk factors for children who grow up in families with a parent with schizophrenia or bipolar disorder.

“When one of the parents has a severe mental disorder, caring for the child will often be more dependent on the other parent, who perhaps also has much of their attention directed towards the ill parent. If the parent who we thought was healthy and well-functioning also in some cases has a mental disorder, and/or has a lower functional level and is emotionally and practically burdened by the general family situation, then this can have significance for the whole family’s well-being,” explains Aja Neergaard Greve.

Already at increased risk

Children born to parents with schizophrenia and bipolar disorder have an increased risk of themselves developing mental disorders – in fact, the familial risk is the highest known risk factor for later development of these disorders. If both parents have a mental disorder, the overall risk for the children increases.

“This increased risk is both genetic and environmental. Cognitive functions such as intelligence are e.g. hereditary, but if the parents have cognitive difficulties there will also be an effect on the environment the child grows up in if  the parents therefore don’t have the opportunity to create good stable routines and predictability or to stimulate the child sufficiently,” she says and continues:

“Some of these families are particularly vulnerable and struggle with more than one issue and they therefore need extra help and support. Our study suggests that there is a need for increased attention on some of the families where one or both parents have a mental disorder. There is a need for specialised and targeted efforts for families already early in the child’s life,” says Aja Neergaard Greve.

The researchers will follow the families from the study up through the child’s upbringing and hope to learn more about how the children develop, as well as which factors have greatest importance for the well-being of the families.

Background for the results

  • The Danish High-Risk and Resilience Study is a nationwide, representative group consisting of 522 children born to parents with schizophrenia, bipolar disorder or parents from the control group. The children and both the child’s biological parents have been interviewed and examined. The results of this study stem from data from 872 parents.
  • The study is a collaboration between adult psychiatry in the Central Denmark Region and adult and child and adolescent psychiatry in the Capital Region of Denmark.
  • The study is financed by the Lundbeck Foundation, Aarhus University, the Central Denmark Region, the Capital Region of Denmark and the Beatrice Surovell Haskell Foundation for Child Mental Health Research of Copenhagen.
  • The scientific article is published in Schizophrenia Bulletin

Reference: Aja Neergaard Greve, Rudolf Uher, Thomas Damm Als, Jens Richardt Møllegaard Jepsen, Erik Lykke Mortensen, Ditte Lou Gantriis, Jessica Ohland, Birgitte Klee Burton, Ditte Ellersgaard, Camilla Jerlang Christiani, Katrine S Spang, Nicoline Hemager, Kerstin J Plessen, Anne A E Thorup, Vibeke Bliksted, Merete Nordentoft, Ole Mors, A Nationwide Cohort Study of Nonrandom Mating in Schizophrenia and Bipolar Disorder, Schizophrenia Bulletin, 2021;, sbab021, https://doi.org/10.1093/schbul/sbab021

Provided by Aarhus University

The Immune Link Between A Leaky Blood-brain Barrier and Schizophrenia (Psychiatry)

Research from the the School of Veterinary Medicine, Perelman School of Medicine, and Children’s Hospital of Philadelphia points to the involvement of the brain vasculature as a contributor to mental disorders such as schizophrenia.

Like a stern bodyguard for the central nervous sytem, the blood-brain barrier keeps out anything that could lead to disease and dangerous inflammation—at least when all is functioning normally.

That may not be the case in people with schizophrenia and other mental disorders, suggest new findings from a team led by researchers from the School of Veterinary MedicinePerelman School of Medicine, and Children’s Hospital of Philadelphia (CHOP). In these individuals, a more permissive barrier appears to allow the immune system to get improperly involved in the central nervous system, the researchers showed. The inflammation that arises likely contributes to the clinical manifestations of neuropsychiatric conditions.

“Our hypothesis was that, if the immune function of the blood-brain barrier is compromised, the resulting inflammation will have an impact on the central nervous system,” says Jorge Iván Alvarez, an assistant professor at Penn Vet and senior author on the work, published in the journal Brain. “With that in mind, we think these findings could also be used to understand how the blood-brain barrier and neurological processes impact not only schizophrenia but mental disorders at large.”

The research team pursued the study focused on a rare condition called 22q11.2 deletion syndrome (22qDS), in which people are born missing a small portion of DNA from chromosome 22. Roughly a quarter of people with this syndrome go on to develop schizophrenia. Penn and CHOP have a community of researchers who study the condition, often as a way of probing deeper into the mysteries of schizophrenia.

This disorder had not been a focus for the Alvarez lab, however, until he gave a talk at CHOP on his area of expertise—the blood-brain barrier—and was approached by an attendee afterward.

“We started talking about the fact that, in this deletion syndrome, one of the missing genes is very important for blood-brain barrier function,” Alvarez says.

That attendee, Stewart Anderson of CHOP, had been studying 22qDS, and together he and Alvarez began collaborating to evaluate whether the blood-brain barrier and its effect on the immune system were playing a role in the condition.

As a first step, the group used a technique whereby stem cells from 22qDS patients diagnosed with schizophrenia, as well as healthy controls, are coaxed to develop into blood-brain barrier endothelial cells, the cells that form a tightly regulated “wall.” In experiments led by Vet School doctoral student Alexis Crockett, they found that the barrier function in cells derived from 22qDS patients was more impaired than those derived from the healthy controls, which were more restrictive. They confirmed these findings in mice bred to have a version of 22qDS, finding that their blood-brain barrier was likewise leaky compared to normal mice.

The brain is typically considered “immune privileged,” meaning that the surveillance carried out by immune cells and immune mediators on the central nervous system is not only regulated by the physical blockade of the blood-brain barrier but also by endothelial cells making the barrier express lower levels of immune signaling molecules.

To see if 22qDS compromised this immune privilege, the researchers again looked to patient stem cells induced to grow into blood-brain barrier cells and to their mouse model. In both cases, they observed impairments in the immune privilege properties of the barrier, with more immune cells and pro-inflammatory molecules able to cross it.

As a final validation of their findings, the researchers examined post-mortem brain tissue from three 22qDS patients and three controls. Similar to their work in cultured cells and the mouse model, they found evidence of impairment in the blood-brain barrier’s physical and immune protective functions.

“This was the corroboration process, replicating all of these observations in human tissues,” Alvarez says.

The work adds to a growing body of evidence suggesting that schizophrenia and certain other neuropsychiatric conditions may be in part neuroinflammatory disorders. It’s also the first study to assess blood-brain barrier function in 22qDS, making an important link between neuroinflammation due to barrier dysfunction and neuropsychiatric disorders.

“Because 25% of 22q patients develop schizophrenia, it may be possible that these mechanisms taking place in 22q are applicable to idiopathic schizophrenia,” Alvarez says. “And when 22q patients are studied in detail, up to 80% are found to have some form of mental disorder, so these findings may well extend to other disorders as well,” including perhaps depression or autism, he says.

In future work, Alvarez and colleagues will be exploring the role of the blood-brain barrier further, narrowing in on what processes are involved in the barrier’s increased permeability, including a look at astrocytes, cells that normally enhance barrier function.

Further insights into the connection between inflammation and neuropsychiatric disease, Alvarez says, may one day lead to therapies that address inflammation by manipulating the immune response.

Alvarez’s and Anderson’s coauthors, from Penn Vet, the Children’s Hospital of Philadelphia, and the Perelman School of Medicine, were Alexis M. Crockett, Sean K. Ryan, Adriana Hernández Vásquez, Caroline Canning, Nickole Kanyuch, Hania Kebir, Guadalupe Ceja, James Gesualdi, Elaine Zackai, Donna McDonald-McGinn, Angela Viaene, Richa Kapoor, Naïl Benallegue, and Raquel Gur. Alvarez was senior author, and Crockett was first author.

Jorge Iván Alvarez is an assistant professor in the Department of Pathobiology at the University of Pennsylvania School of Veterinary Medicine.

Stewart Anderson is a professor in the Department of Psychiatry at Penn’s Perelman School of Medicine and director of Research for the Department of Child and Adolescent Psychiatry and Behavioral Services of the Children’s Hospital of Philadelphia.

Alexis Crockett is a doctoral student at Penn’s School of Veterinary Medicine.

The study was supported by the National Institutes of Health (grants 5K01NS097519-03, MH110185-03, MH066912, MH191719, MH087636, MH119738, MH119219, and MH101719) and the Penn/CHOP Lifespan Brain Institute.

Featured image: A genetic condition known as 22q.11.2 deletion syndrome is associated with an increased risk of schizophrenia. A Penn Vet-led team found that a leaky blood-brain barrier, allowing inappropriate immune involvement in the central nervous system, may contribute to this or perhaps other neuropsychiatric conditions. (Image: Courtesy of Jorge Iván Alvarez)

Reference: Alexis M Crockett, Sean K Ryan, Adriana Hernandez Vásquez, Caroline Canning, Nickole Kanyuch, Hania Kebir, Guadalupe Ceja, James Gesualdi, Elaine Zackai, Donna McDonald-McGinn, Angela Viaene, Richa Kapoor, Naïl Benallegue, Raquel Gur, Stewart A Anderson, Jorge I Alvarez, Disruption of the blood−brain barrier in 22q11.2 deletion syndrome, Brain, 2021;, awab055, https://doi.org/10.1093/brain/awab055

Provided by Penn Today

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

Seeing Schizophrenia: X-rays Shed Light on Neural Differences, Point Toward Treatment (Psychiatry)

An international research team used the ultrabright X-rays of the Advanced Photon Source to examine neurons in the brains of schizophrenia patients. What they learned may help neurologists treat this harmful brain disorder.

Schizophrenia, a chronic, neurological brain disorder, affects millions of people around the world. It causes a fracture between a person’s thoughts, feelings and behavior. Symptoms include delusions, hallucinations, difficulty processing thoughts and an overall lack of motivation. Schizophrenia patients have a higher suicide rate and more health problems than the general population, and a lower life expectancy.

There is no cure for schizophrenia, but the key to treating it more effectively is to better understand how it arises. And that, according to Ryuta Mizutani, professor of applied biochemistry at Tokai University in Japan, means studying the structure of brain tissue. Specifically, it means comparing the brain tissues of schizophrenia patients with those of people in good mental health, to see the differences as clearly as possible.

“There are only a few places in the world where you can do this research. Without 3D analysis of brain tissues this work would not be possible.”

— Ryuta Mizutani, professor, Tokai University

“The current treatment for schizophrenia is based on many hypotheses we don’t know how to confirm,” Mizutani said. ​“The first step is to analyze the brain and see how it is constituted differently.”

To do that, Mizutani and his colleagues from several international institutions collected eight small samples of brain tissue — four from healthy brains and four from those of schizophrenia patients, all collected post-mortem — and brought them to beamline 32-ID of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE’s Argonne National Laboratory.

At the APS, the team used powerful X-rays and high-resolution optics to capture three-dimensional images of those tissues. (Researchers collected similar images at the Super Photon Ring 8-GeV [SPring-8] light source facility in Japan.) The resolution of the X-ray optics used at the APS can be as high as 10 nanometers. That’s about 700 times smaller than the width of the average red blood cell, and there are five million of those cells in a drop of blood.

“There are only a few places in the world where you can do this research,” Mizutani said. ​“Without 3D analysis of brain tissues this work would not be possible.”

According to Vincent De Andrade, physicist in Argonne’s X-ray Science Division, capturing images at high resolution presents a challenge, since the neurons being imaged can be centimeters long. The neuron is the basic working unit of the brain, a cell within the nervous system that transmits information to other cells to control body functions. The human brain has roughly 100 billion of these neurons, in various sizes and shapes.

“The sample has to move through the X-ray beam to trace the neurons through the sample,” De Andrade explained. ​“The field of view of our X-ray microscope is about 50 microns, about the width of a human hair, and you need to follow these neurons over several millimeters.”

What these images showed is that the structures of these neurons are uniquely different in each schizophrenia patient, which Mizutani said is evidence that the disease is associated with those structures. Images of healthy neurons were relatively similar, while neurons from schizophrenia patients showed far more deviation, both from the healthy brains and from each other.

More study is needed, Mizutani said, to figure out exactly how the structures of neurons are related to the onset of the disease and to devise a treatment that can alleviate the effects of schizophrenia. As X-ray technology continues to improve — the APS, for example, is scheduled to undergo a massive upgrade that will increase its brightness up to 500 times — so will the possibilities for neuroscientists.

“The APS upgrade will allow for better sensitivity and resolution for imaging, making the process of mapping neurons in the brain faster and more precise,” De Andrade said. ​“We would need resolutions of better than 10 nanometers to capture synaptic connections, which is the holy grail for a comprehensive mapping of neurons, and those should be achievable with the upgrade.”

De Andrade also noted that while electron microscopy has been used to map the brains of small animals — fruit flies, for instance — that technique would take a long time to image the brain of a larger animal, such as a mouse, let alone a full human brain. Ultrabright, high energy X-rays like those at the APS, he said, could speed up the process, and advances in technology will help scientists get a more complete picture of brain tissue.

For neuroscientists like Mizutani, the end goal is fewer people suffering with brain diseases like schizophrenia.

“The differences in brain structure between healthy and schizophrenic people must be linked to mental disorders,” he said. ​“We must find some way to make people healthy.”

Mizutani and his team reported their results in Translational Psychiatry.

Featured image: These 3D images of neurons in the brain of a schizophrenia patient show wavy, distorted neurites, which indicate that the condition may be linked to the shape of the neurons. X-ray images were taken at the Advanced Photon Source. (Image by Ryuta Mizutani.)

Reference: Mizutani, R., Saiga, R., Yamamoto, Y. et al. Structural diverseness of neurons between brain areas and between cases. Transl Psychiatry 11, 49 (2021). https://www.nature.com/articles/s41398-020-01173-x https://doi.org/10.1038/s41398-020-01173-x

Provided by Argonne National University

How Does the Immune System Keep Tabs on the Brain? (Neuroscience)

Study finds site of immune surveillance of the brain, points to new ways to target brain inflammation.

Alzheimer’s disease, multiple sclerosis, autism, schizophrenia and many other neurological and psychiatric conditions have been linked to inflammation in the brain. There’s growing evidence that immune cells and molecules play a key role in normal brain development and function as well. But at the core of the burgeoning field of neuroimmunology lies a mystery: How does the immune system even know what’s happening in the brain? Generations of students have been taught that the brain is immunoprivileged, meaning the immune system largely steers clear of it.

Now, researchers at Washington University School of Medicine in St. Louis believe they have figured out how the immune system keeps tabs on what’s going on in the brain. Immune cells are stationed in the meninges — the tissue that covers the brain and spinal cord — where they sample fluid as it washes out of the brain. If the cells detect signs of infection, disease or injury, they are prepared to initiate an immune response to confront the problem, the researchers said.

The findings, published Jan. 27 in the journal Cell, open up the possibility of targeting immune cells at such surveillance sites as a means of treating conditions driven by brain inflammation.

“Every organ in the body is being surveilled by the immune system,” said senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology. “If there’s a tumor, an injury, an infection anywhere in the body, the immune system has to know about it. But people say the exception is the brain; if you have a problem in the brain, the immune system just lets it happen. That never made sense to me. What we’ve found is that there is indeed immune surveillance of the brain — it’s just happening outside the brain. Now that we know where it’s happening, that opens up lots of new possibilities for modulating the immune system.”

In 2015, Kipnis and colleagues found a network of vessels that drains fluid and small molecules from the brain into the lymph nodes, where immune responses are initiated. The discovery demonstrated a direct physical connection between the brain and the immune system. But the network of vessels represented an exit from the brain. It remained unclear where immune cells entered or surveilled the brain.

Kipnis and Justin Rustenhoven, PhD, a postdoctoral researcher and the first author on the new paper, set out to find the immune system’s gateway to the brain. They saw a clue in the fact that the vessels containing fluid leaving the brain run alongside sinuses in the dura mater, the tough outer layer of the meninges just underneath the skull. Dural sinuses, which contain blood that carries immune cells, lack the tight barrier that elsewhere keeps blood separate from the brain.

Experiments showed that the dural sinuses were packed with molecules from the brain and immune cells that had been carried in with blood. Multiple kinds of immune cells were represented, including some that pick up and display suspect molecules from the blood and others that scan the suspect molecules and respond to them by mounting a defense.

“Imagine if your neighbors went through your trash every day,” said Kipnis, also a professor of neurosurgery, of neurology and of neuroscience. “If they start finding blood-stained towels in your trash, they know something is wrong. It’s the same thing with the immune system. If patrolling immune cells see tumor antigens or signs of infection from the brain, the cells know there’s a problem. They will take that evidence to immune headquarters, which is the lymph nodes, and initiate an immune response.”

The findings suggest that the immune system surveils the brain from a distance and only enters when it finds a problem. This could explain why the brain was thought for so long to be immunoprivileged.

“Immune activity in the brain can be highly detrimental,” Rustenhoven said. “It can kill neurons and cause swelling. The brain can’t tolerate much swelling because the cranium is a fixed volume. So immune surveillance is pushed to the borders, where the cells can still monitor the brain but don’t risk damaging it.”

Multiple sclerosis is a degenerative condition in which the immune system attacks the protective sheath on nerves, causing communication problems between the brain and the rest of the body. The cause is unknown. Using a mouse model of multiple sclerosis, the researchers showed that initiation of disease triggered a massive accumulation of activated immune cells in the dural sinuses, suggesting that harmful immune responses may begin in the dura mater and spread to the brain.

Further work is needed to verify the role of dural sinuses in neuroinflammatory conditions. But the location of the sinuses just on the inside of skull on the accessible side of the blood-brain barrier suggests possibilities for targeting the immune system in that area.

“If this is a gateway to the brain, we can attempt to manipulate the area with therapies aimed at preventing over-activated immune cells from entering the brain,” Kipnis said. “The dura is close to the surface, so we may even be able to deliver drugs through the skull. In theory, you could come up with an ointment that diffuses through the skull bone and reaches the dura. We might have found where inflammatory responses for many neuroimmunological conditions start, and there’s so much we can do with that.”

Featured image: Immune cells (yellow and purple) fill a sinus (teal) in the outer layer of the meninges, the tissue that surrounds the brain and spinal cord. Researchers at Washington University School of Medicine in St. Louis have found that immune cells stationed in such sinuses monitor the brain and initiate an immune response if they detect a problem. © Justin Rustenhoven

Reference: Justin Rustenhoven, Antoine Drieu, Tornike Mamuladze et al., “Functional characterization of the dural sinuses as a neuroimmune interface”, Cell, 2021. https://doi.org/10.1016/j.cell.2020.12.040

Provided by Washington University School of Medicine

Research Supports Association of Neurological Soft Signs and Cerebellar-cerebral Functional Connectivity in Schizophrenia (Neuroscience)

Neurological soft signs (NSS) have been shown to be the important biomarkers for schizophrenia. These signs, including motor coordination, sensory integration and disinhibition, were conventionally thought to be minor neurological anomalies without any specific brain regions corresponding for the observed behavioral manifestations. Accumulating imaging findings have suggested these signs are actually associating with specific brain functional network. However, most of these studies have specifically focused on the association of motor coordination signs in patients with schizophrenia and general brain functional connectivity within the cerebral cortex.

More recently, evidence suggests that the cerebellum plays an important node in multiple function networks accounting for various cognitive and perceptual impairments observed in patients with schizophrenia. However, little is known about the underlying cerebellar-cerebral functional connectivity associating with sensory integration signs in patients with schizophrenia.

Dr. Raymond Chan and his team from the Institute of Psychology of the Chinese Academy of Sciences have shown that cerebellar hypoactivation was associated with sensory integration in patients with schizophrenia and their unaffected siblings.

Importantly, the cerebellar activation underlying sensory integration is heritable. Based on these findings, Dr. Chan and his team have recently conducted another study to further examine the specific relationship of NSS and cerebellar-cerebral resting-state functional connectivity (rsFC) in 51 patients with schizophrenia and 50 healthy controls.

Their findings showed that positive correlations between NSS and rsFC of the cerebellum with the inferior frontal gyrus and the precuneus, and negative correlations between NSS and rsFC of the cerebellum with the inferior temporal gyrus in patients with schizophrenia.

Moreover, they also found that cerebellar-prefrontal rsFC was also positively correlated with negative symptoms in schizophrenia patients. More importantly, similar findings were replicated in another sample of 34 patients with schizophrenia and 34 healthy controls.

“These findings demonstrate the important role of cerebellum and its connection to cerebral cortex contributing to both the NSS manifestations and negative symptoms in patients with schizophrenia. Such altered cerebellar-cerebral functional connectivity may share the same neural mechanism for NSS and negative symptoms in this clinical group,” said Dr. Chan.

Besides, the cerebellar activation underlying sensory integration is heritable that suggested its role as a candidate endophenotype of schizophrenia.

This study was supported by a grant from the National Key Research and Development Programme, Beijing Municipal Science & Technology Commission Grant, the CAS Key Laboratory of Mental Health, Institute of Psychology, and the Philip KH Wong Foundation.

This study has been published online in a paper entitled “Neurological soft signs are associated with altered cerebellar-cerebral functional connectivity in schizophrenia” on Schizophrenia Bulletin on Jan. 22, 2021.

Reference: Xin-Lu Cai, Yong-Ming Wang, Yi Wang, Han-Yu Zhou, Jia Huang, Ya Wang, Simon S Y Lui, Arne Møller, Karen S Y Hung, Henry K F Mak, Pak C Sham, Eric F C Cheung, Raymond C K Chan, Neurological Soft Signs Are Associated With Altered Cerebellar-Cerebral Functional Connectivity in Schizophrenia, Schizophrenia Bulletin, 2021;, sbaa200, https://doi.org/10.1093/schbul/sbaa200

Provided by Chinese Academy of Sciences