Tag: College of Medicine

Brain Disruptions Similar In Many Emotional Disorders

Dr. Scott Langenecker, Dr. Olusola Ajilore and Lisanne Jenkins pose in front of an image of the brain in UIC’s Electronic Visualization Laboratory. Photo: Vibhu Rangavasan.

Dr. Scott Langenecker, Dr. Olusola Ajilore and Lisanne Jenkins pose in front of an image of the brain in UIC’s Electronic Visualization Laboratory. Photo: Vibhu Rangavasan.

Researchers have long known that emotional disorders have a lot in common. Many often occur together, like depression and social anxiety disorder. Treatments also tend to work across multiple disorders, suggesting shared underlying elements. But perhaps the most common shared characteristic is that almost all emotional disorders involve persistent negative thinking.

In an analysis of existing studies that used MRI images to study the brain’s white matter, researchers from the University of Illinois at Chicago describe common brain abnormalities found in multiple emotional disorders. Their findings are published in the journal NeuroImage: Clinical.

“This study provides important insights into mechanisms shared across multiple emotional disorders, and could provide us with biomarkers that can be used to more rapidly diagnose these disorders,” says Dr. Scott Langenecker, associate professor of psychiatry and psychology in the UIC College of Medicine and senior author of the paper. Those disorders, he said, can sometimes take many years to be diagnosed accurately.

The most common difference in white matter structure that Langenecker’s group found — present in every emotional disorder they looked at — was disruption in a region of the brain that connects different parts of the “default-mode network,” which is responsible for passive thoughts not focused on a particular task. That area is the left superior longitudinal fasciculus. The superior longitudinal fasciculus, or SLF, also connects the default-mode network and the cognitive control network, which is important in task-based thinking and planning and tends to work in alternation with the default-mode network.

The constant negative thoughts or ruminations associated with most emotional disorders appear to be due to a hyperactive default-mode network, Langenecker said.

“If the part of the brain that helps rein in the default-mode network isn’t as well-connected through the SLF, this could explain why people with emotional disorders have such a hard time modulating or gaining control of their negative thoughts,” he said.

The researchers systematically searched the scientific literature for studies that performed whole-brain “diffusion tensor” imaging on adults with major depressive disorder, bipolar disorder, social anxiety disorder, obsessive-compulsive disorder, or posttraumatic stress disorder, as well as healthy control participants. Thirty-seven studies met those criteria and included a combined 962 participants with emotional disorders and 892 healthy control subjects.

The researchers then performed a meta-analysis to determine which white-matter alterations may be common across multiple mood disorders and which are unique for a particular mood disorder. White matter includes the long nerve fibers called axons that transmit electrical signals.

Diffusion tensor imaging, or DTI, measures the degree to which water molecules move in one direction rather than randomly diffusing in all directions. It provides “an indirect measurement of the microstructure of white matter, and can give information about connectivity of different parts of the brain,” said Lisanne Jenkins, postdoctoral research fellow in psychiatry in the UIC College of Medicine and first author on the paper.

“If you think of white matter as the highways of the brain, connecting all the different regions and networks,” Jenkins said, an area with highly directional water movement “could be a major superhighway where all the cars are moving along quickly with little traffic.” An area with less-directed water movement could be “a two-lane road, with several exits and stop signs, maybe even some potholes, which slow down traffic.”

Brain regions connected by these slower pathways “may not communicate as well as they would in someone where this road looks more like a superhighway,” said Dr. Olusola Ajilore, associate professor of psychiatry in the UIC College of Medicine and a co-author on the paper.

In the 37 studies the researchers looked at, participants with emotional disorders had less directed water movement in their white matter compared to participants who did not have emotional disorders.

One of the most surprising findings to Langenecker was that people with obsessive-compulsive disorder shared the most brain abnormalities with people with other emotional disorders.

“We would have expected … OCD to look very different from other emotional disorders, because the symptoms are so unique and distinct,” Langenecker said. “But this kind of flips how we see OCD, which clearly has more in common with other emotional disorders than we think.”

The traditional diagnosis for OCD, he said, is repetitive thoughts about specific objects or tasks — thoughts that pertain to the world outside the self. The thoughts can also be internally-directed.

“Other emotional disorders, like depression, social anxiety, and panic disorder — the repetitive thoughts are directed at the self,” Ajilore said. “So our finding that OCD is more like the other emotional disorders makes sense, and we may now be able to further examine commonalities between these disorders that could improve our treatment of them individually.”

The disorder that stood out and shared the fewest white-matter characteristics with the others was post-traumatic stress disorder.

PTSD is triggered by a traumatic event and involves being reminded of that event at unwelcome times, not unlike the repetitive negative thinking in other emotional disorders. But people with PTSD had several areas of low white-matter connectivity that weren’t seen in the other emotional disorders, Langenecker said.

“While milder forms of trauma is common in other conditions, like major depression or generalized anxiety, it is possible that the brain regions we saw that were distinctly affected in PTSD participants are related to the experience of severe trauma or the re-experiencing of that trauma,” he said.

In bipolar disorder, characterized by periods of both depression and mania, the researchers saw generally decreased water-directionality in the right side of the brain, including the right SLF, the area that connects the default-mode network and the cognitive control network.

“All emotional disorders had disruptions more so in the left hemisphere, but for bipolar disorder, we saw disruptions in white matter in both the right and left sides of the brain,” Langenecker said.

Older studies of stroke patients have shown that abnormalities in the right hemisphere are associated with externally-focused symptoms, like mania, while left hemisphere involvement — which the current study found in most emotional disorders — was more often associated with inwardly-focused symptoms, like depression. Langenecker said the bilateral changes his team observed in bipolar disorder may reflect vulnerability to mania and to depression and anxiety.

Alyssa Barba, Miranda Campbell, Melissa Lamar, Stewart Shankman and Dr. Alex Leow, all of UIC, are the remaining co-authors on the paper.

By Sharon Parmet
sparmet@uic.edu


Medicare To Cover stem cell transplantation for sickle cell disease

Medicar story graphicThe Centers for Medicare & Medicaid Services recently ruled that they will pay most medical costs for clinical trials that use stem cell transplantation to treat sickle cell disease, multiple myeloma and myelofibrosis for people covered by Medicare. The expanded coverage will begin this summer.

The decision puts a new potential cure for sickle cell disease within reach of more adult patients at the University of Illinois Hospital & Health Sciences System through an ongoing clinical trial.

The new technique, pioneered by clinicians at the National Institutes of Health in Bethesda, Maryland, and offered only at the NIH and UI Health, eliminates the need for chemotherapy to prepare a patient to receive healthy stem cells from a donor.

Children have been cured of sickle cell disease using bone marrow stem cell transplants for many years. Their young bodies are able to handle the chemotherapy. In adults, such cures have not been possible, because the preparative chemotherapy is too dangerous.

In the new procedure, patients receive immunosuppressive drugs just before the transplant, along with a very low dose of total body irradiation – a treatment much safer than chemotherapy. Donor cells from a tissue-matched healthy sibling are then transfused into the patient. Stem cells from the donor soon produce new blood cells in the patient and eventually eliminate symptoms without the need for regular blood transfusions. In many cases, sickle cells can no longer be detected. Patients must continue to take immunosuppressant drugs for at least a year after the transplant.

“Like any other transplant procedure, the patient undergoes an extensive screening process to determine if they are a good candidate,” said Dr. Damiano Rondelli, chief of hematology/oncology and director of the blood and marrow transplant program at UI Health. Patients must have a tissue-matched donor, usually a sibling, to provide the stem cells that will be used in the transplant. Determining a patient’s ability to pay for the transplant is also a necessary part of the screening.

“Prior to Medicare’s decision, adult patients insured by Medicare weren’t able to get the chemo-free transplant because of its cost – about $200,000 for the transplant and medications,” said Rondelli. Medicare coverage, he said, “means that many more that would likely have died relatively young from the disease now have hope for a full life.”

Last September, Rondelli and colleagues published a paper in the journal Biology of Blood & Marrow Transplantation validating the NIH’s sickle cell procedure in 12 patients treated and cured at UI Health.

Patients eligible for the new coverage must be covered under Medicare. People 65 and older and those getting disability benefits from Social Security or certain disability benefits from the Railroad Retirement Board for 24 months are eligible for Medicare.

By: Sharon Parmet
sparmet@uic.edu


Potential Vaccine For Herpes Being Developed

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Zinc oxide tetrapod nanoparticles. Credit: Deepak Shukla

An effective vaccine against the virus that causes genital herpes has evaded researchers for decades. But now, researchers from the University of Illinois at Chicago working with scientists from Germany have shown that zinc-oxide nanoparticles shaped like jacks can prevent the virus from entering cells, and help natural immunity to develop.

Results of the study are published in The Journal of Immunology.

“We call the virus-trapping nanoparticle a microbivac, because it possesses both microbicidal and vaccine-like properties,” says corresponding author Deepak Shukla, professor of ophthalmology and microbiology & immunology in the UIC College of Medicine. “It is a totally novel approach to developing a vaccine against herpes, and it could potentially also work for HIV and other viruses,” he said.

The particles could serve as a powerful active ingredient in a topically-applied vaginal cream that provides immediate protection against herpes virus infection while simultaneously helping stimulate immunity to the virus for long-term protection, explained Shukla.

Herpes simplex virus-2, which causes serious eye infections in newborns and immunocompromised patients as well as genital herpes, is one of the most common human viruses. According to the Centers for Disease Control and Prevention, about 15 percent of people from ages 14-49 carry HSV-2, which can hide out for long periods of time in the nervous system. The genital lesions caused by the virus increase the risk for acquiring human immunodeficiency virus, or HIV.

“Your chances of getting HIV are three to four times higher if you already have genital herpes, which is a very strong motivation for developing new ways of preventing herpes infection,” Shukla said.

Treatments for HSV-2 inczoten-Mechanism2-590x393lude daily topical medications to suppress the virus and shorten the duration of outbreaks, when the virus is active and genital lesions are present. However, drug resistance is common, and little protection is provided against further infections. Efforts to develop a vaccine have been unsuccessful because the virus does not spend much time in the bloodstream, where most traditional vaccines do their work.

The tetrapod-shaped zinc-oxide nanoparticles, called ZOTEN, have negatively charged surfaces that attract the HSV-2 virus, which has positively charged proteins on its outer envelope. ZOTEN nanoparticles were synthesized using technology developed by material scientists at Germany’s Kiel University and protected under a joint patent with UIC.

When bound to the nanoparticles, HSV-2 cannot infect cells. But the bound virus remains susceptible to processing by immune cells called dendritic cells that patrol the vaginal lining. The dendritic cells “present” the virus to other immune cells that produce antibodies. The antibodies cripple the virus and trigger the production of customized killer cells that identify infected cells and destroy them before the virus can take over and spread.

The researchers showed that female mice swabbed with HSV-2 and an ointment containing ZOTEN had significantly fewer genital lesions than mice treated with a cream lacking ZOTEN. Mice treated with ZOTEN also had less inflammation in the central nervous system, where the virus can hide out.

The researchers were able to watch immune cells pry the virus off the nanoparticles for immune processing, using high-resolution fluorescence microscopy.

“It’s very clear that ZOTEN facilitates the development of immunity by holding the virus and letting the dendritic cells get to it,” Shukla said.

If found safe and effective in humans, a ZOTEN-containing cream ideally would be applied vaginally just prior to intercourse, Shukla said. But if a woman who had been using it regularly missed an application, he said, she may have already developed some immunity and still have some protection. Shukla hopes to further develop the nanoparticles to work against HIV, which like HSV-2 also has positively charged proteins embedded in its outer envelope.

ZOTEN particles are uniform in size and shape, making them attractive for use in other biomedical applications. The novel flame transport synthesis technology used to make them allows large-scale production, said Rainer Adelung, professor of nanomaterials at Kiel University. And, because no chemicals are used, the production process is green.

Adelung hopes to begin commercial production of ZOTEN through a startup company that will be run jointly with his colleagues at UIC.

Co-authors on the study are Bellur Prabhakar, Tibor Valyi-Nagy, Thessicar Antoine, Satvik Hadigal, Abraam Yakoub, Palash Bhattacharya, and Christine Haddad of UIC and Yogendra Kumar Mishra of Kiel University. The research was supported by National Institutes of Health grants AI103754 and EY001792 and German Research Foundation grant Ad/183/10-1.

By Sharon Parmet
sparmet@uic.edu