Category: Neuroscience

— In the cerebral cortex, the balance between excitation (pyramidal neurons) and inhibition (interneurons) is thought to be mediated by the primary mode of neuronal communication: "all-or-none" action potentials, or spikes. However, Dr. Yousheng Shu's research group at the Institute of Neuroscience of Chinese Academy of Sciences has discovered a new strategy by which the cortex can maintain this balance, by showing that the amount of inhibition depends on the membrane potentials (Vm) in pyramidal cells, which represents an "analog" strategy.

Their results are published in the online, open access journal PLoS Biology.

The cortex consists of recurrent networks, where pyramidal cells send action potentials down their axons to excite interneurons, which in turn inhibit the pyramidal cells through disynaptic inhibitory postsynaptic potentials (IPSPs). This back-and-forth process serves to keep a stable excitation/inhibition ratio critical for proper cortical function. In the classic view, these action potentials are delivered if and only if the Vm crosses a certain threshold and are invariable in their shape, which is the all-or-none fashion of rapid neuron-to-neuron communication. But is there an analog component?

Using paired recording from two pyramidal cells within a recurrent circuit, Dr. Shu and colleagues discovered that a slight positive shift (depolarization) in Vm of the first pyramidal cell could increase the disynaptic IPSPs received by the second one. In other words, this study provides the first evidence demonstrating that an analog change of excitation can regulate feedback inhibition, with the information carriers no longer stereotyped.

"This type of regulation could be a key mechanism for the cortex to maintain a dynamic balance of excitation and inhibition, and generate appropriate cortical rhythms under different behavioral states," said Dr. Shu, "It may also play an important role in preventing abnormal cortical activities including epileptiform activity during seizures."

Therefore, future studies may focus on whether the Vm-dependent modulation of inhibition has an impact on information processing under both normal and pathological conditions, and whether the analog signaling influences the operation of other cortical circuits. Nevertheless, to what extent these findings may influence the conceptual framework of a "digital brain" is still open to further computational and theoretical investigation.

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Journal Reference:

1. Jie Zhu, Man Jiang, Mingpo Yang, Han Hou, Yousheng Shu. Membrane Potential-Dependent Modulation of Recurrent Inhibition in Rat Neocortex. PLoS Biology, 2011; 9 (3): e1001032 DOI: 10.1371/journal.pbio.1001032

A long term study reports about the effectiveness of replacing bone marrow, purposely destroyed by chemotherapy, with autologous (self) stem cell rescue for people with aggressive forms of multiple sclerosis (MS). The study is published in the March 22, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology.

For the treatment, chemotherapy drugs are used to kill all of the patient's blood cells, including the immune cells that are believed to be attacking the body's own central nervous system. Bone marrow stem cells removed from the patient are purified and transplanted back into the body, which saves life by replacing the blood cells and also is proposed to 'reboot' the immune system.

The study followed 35 people for an average of 11 years after transplant. The study involved people with rapidly progressive MS who had tried a number of other treatments for MS with little or no effect. All were severely disabled by the disease, with an average score of six on a scale of disease activity that ranges from zero being a normal neurological examination to 10 meaning death due to MS. A score of six means able to walk with a cane or crutch; a seven is mainly in a wheelchair. All had worsened by at least one point on the scale in the year prior to the transplant.

After the transplants, the probability of participants having no worsening of their disease for 15 years was 25 percent. The probability was higher-44 percent-for those who had active brain lesions, which are a sign of disease activity, at the time of the transplant.

For 16 people, symptoms improved by an average of one point on the scale after the transplant, and the improvements lasted for an average of two years. The participants also had a reduction in the number and size of lesions in their brains. Two people (six percent) died from complications related to the transplant at two months and 2-1/2 years post-transplant.

Study author Vasilios Kimiskidis, MD, of Aristotle University of Thessaloniki Medical School in Thessaloniki, Greece noted that more research is needed on this treatment, including studies that compare people receiving the treatment to a control group that does not receive the treatment.

"Keeping that in mind, our feeling is that stem cell transplants may benefit people with rapidly progressive MS," he said. "This is not a therapy for the general population of people with MS but should be reserved for aggressive cases that are still in the inflammatory phase of the disease."

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Journal Reference:

1. A. Fassas, V. K. Kimiskidis, I. Sakellari, K. Kapinas, A. Anagnostopoulos, V. Tsimourtou, K. Sotirakoglou, A. Kazis. Long-term results of stem cell transplantation for MS: A single-center experience. Neurology, 2011; 76 (12): 1066 DOI: 10.1212/WNL.0b013e318211c537

Fear is a natural part of our emotional life and acts as a necessary protection mechanism. However, fears sometimes grow beyond proportions and become difficult to shed. Scientists from Freiburg, Basel and Bordeaux have used computer simulations to understand the processes within the brain during the formation and extinction of fears.

In the current issue of the scientific journal PLoS Computational Biology, Ioannis Vlachos from the Bernstein Center Freiburg and colleagues propose for the first time an explanation for how fears that were seemingly overcome are in reality only hidden.

The reason for the persistency of fears is that, literally, their roots run deep: Far below the cerebral cortex lies the "amygdala," which plays a crucial role in fear processes. Fear is commonly investigated in mice by exposing them simultaneously to a neutral stimulus — a certain sound, for example — and an unpleasant one. This leads to the animals being frightened of the sound as well. Context plays an important role in this case: If the scaring sound is played repeatedly in a new context without anything bad happening, the mice shed their fear again. It returns immediately, however, if the sound is presented in the original, or even a completely novel context. Had the mice not unlearned to be frightened after all?

The fact that fears can be "masked" has been known for some time. Recently, two co-authors of the present study discovered that two groups of nerve cells within the amygdala are involved in this process. By creating a model of the amygdala's neuronal network, Ioannis Vlachos and colleagues were now able to find an explanation for how such a masking of fears is implemented in the brain: One group of cells is responsible for the fear response, the second for its suppression. Activity of the latter inhibits the former and, thus, prevents fear signals to be transmitted to other parts of the brain. Nevertheless, the change in their connections that resulted in an increased activity in the fear-coding neurons in the first place, is still present. As soon as the masking by the fear-suppressing neurons disappears, for example by changing the context, these connections come into action again — the fear returns.

According to the scientists, these insights can be transferred to us humans, helping to treat fears more successfully in the future.

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Journal Reference:

1. Ioannis Vlachos, Cyril Herry, Andreas Lüthi, Ad Aertsen, Arvind Kumar. Context-Dependent Encoding of Fear and Extinction Memories in a Large-Scale Network Model of the Basal Amygdala. PLoS Computational Biology, 2011; 7 (3): e1001104 DOI: 10.1371/journal.pcbi.1001104

 A team of researchers at the Instituto Gulbenkian de Ciência (IGC), Portugal, discovered that pollen, the organ that contains the plant male gametes, communicate with the pistil, their female counterpart, using a mechanism commonly observed in the nervous system of animals. This study not only reveals a new mechanism which underlies reproduction in plants, but also opens an exciting new avenue in the study of how cell-cell communication is conserved between animals and plants.

The research was recently published in Science Express of the journal Science.

For many years biologist have observed regular oscillations in several parameters that control growth of pollen tubes, such as pH (concentration of proton ions) and calcium ions, but the actual molecular channels that control these oscillations and their physiological output have remained elusive. Led by José Feijó, group leader at the IGC and Professor at Lisbon University, this international team have now discovered that the oscillations of calcium ions in the growing pollen tubes of tobacco and the Arabidopsis plant are facilitated by channels called Glutamate receptors-like (GLRs), and that these channels are opened by, amongst other components, a rare aminoacid, D-serine (D-Ser). Both D-Ser and GLRs are key molecular players in cell-cell communication in the animal central nervous systems, at various levels: they play a central role in memory and learning processes in the brain, and have been implicated in a wide range of neurodegenerative diseases such as multiple sclerosis, Alzheimer, Huntington's disease and others. And now, surprisingly, they also have a role in reproduction of plants.

Working in the IGC laboratories, the team used an extensive combination of genetic, pharmacologic and electrophysiological techniques to reveal the role of glutamate receptor-like (GLRs) genes and D-serine in pollen grains, and their physiological impact on plant reproduction. In proving that GLRs are calcium channels, the team also solved two long-standing riddles in plant biology: the molecular nature of calcium channels in the outer membrane of plant cells, a central question in plant physiology elusive for more than 20 years, and what are the functions of GLRs genes in plants, a fact that has puzzled biologists ever since the first genome of the model plant Arabidopsis was sequenced.

Plant reproduction is a complex and highly coordinated process. Pollen grains, which contain the plants' male gametes (sperm cells), are carried from the male organ of the flower (the stamen) to the female organ (the pistil). Here the pollen germinates and grows a pollen tube, which extends and is guided to the ovary, where it releases the sperm. The sperm fuse with the egg cells, giving rise to an embryo, part of the seed.

In this study, the researchers showed that impairing the GLR functions in male gametes leads to partial male sterility: fewer seeds are produced by the plant, and the pollen tubes are abnormal. Furthermore, D-serine activates the GLRs on the tips of pollen tubes, allowing calcium ions to flow into the tube. They took their research a step further demonstrating that D-serine is indeed produced in the female sexual organs, and that absence of D-serine in these organs also leads to deformed pollen tubes. Together, these findings strongly suggest that D-serine, produced in the female sexual organs may have a role in guiding pollen tubes to their final target.

José Feijó says, "Pollen tubes are a model system for cellular tip-growth, a process common to fission yeast, filamentous fungi, the root hairs of plants and nerve cells. Our findings, implicating analogous genes in growth processes in both plants and animals, underscores how evolution re-uses successful mechanisms, over and over again. We feel that our research, performed in Arabidopsis and tobacco, now opens doors for the study of conserved cell-cell communication processes, across plant and animals species."

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Journal Reference:

1. Erwan Michard, Pedro T. Lima, Filipe Borges, Ana Catarina Silva, Maria Teresa Portes, João E. Carvalho, Matthew Gilliham, Lai-Hua Liu, Gerhard Obermeyer and José a Feijó. Glutamate Receptor–Like Genes Form Ca2 Channels in Pollen Tubes and Are Regulated by Pistil D-Serine. Science, 17 March 2011 DOI: 10.1126/science.1201101

A dendritic cell vaccine personalized for each individual based on the patient's own tumor may increase median survival time in those with a deadly form of brain cancer called glioblastoma, an early phase study at UCLA's Jonsson Comprehensive Cancer Center has found.

Published in the peer-reviewed journal Clinical Cancer Research, the study also identified a subset of patients more likely to respond to the vaccine, those with a subtype of glioblastoma known as mesenchymal, which accounts for about one-third of all cases. This is the first time in brain cancer that a subset of patients more likely to respond to an immunotherapy has been identified, said Dr. Linda Liau, a Jonsson Cancer Center researcher, professor of neurosurgery and senior author of the study.

The study found that the vaccine, administered after the conventional treatments of surgery and radio-chemotherapy, was associated with a median survival of 31.4 months, double the 15 months of historical controls in the published literature. In all, 23 patients were enrolled in the Phase I study that was launched in 2003. Of those, about one third of participants are still alive, some more than eight years after their diagnosis.

The study also found that the vaccine was safe and that side effects were minimal, limited mostly to flu-like symptoms and rashes near the vaccine injection site.

"This is quite an encouraging result, especially in an early phase study like this," Liau said. "It's promising to see patients with this type of brain cancer experience such long survivals."

However, Liau cautioned that the findings need to be confirmed in larger, randomized studies. She currently is leading a Phase II, randomized study at UCLA testing the vaccine in newly diagnosed glioblastoma patients. The patients will receive either the standard of care (surgery, radiation and chemotherapy) or the standard of care plus the vaccine. The study is a multi-center trial, and UCLA is the only site offering it in California.

It has recently been discovered that there are at least three subtypes of glioblastoma: proneural, proliferative and mesenchymal. During the course of her study, Liau and her colleagues saw that one group of patients seemed to be responding very well to the vaccine and examined their tumors using a microarray analysis of their DNA. They found that those with a gene expression profile identifying their cancers as mesenchymal responded better to the vaccine.

The finding was surprising, Liau said, because patients with the mesenchymal subtype generally have more aggressive disease and shorter survival than those with the other subtypes. In patients with this type of glioblastoma, several genes that modulate the immune system are dysregulated, meaning they don't work properly. Liau speculates that the vaccine helped replenish the immune system, allowing that subset of patients to more easily fight the brain cancer.

"Glioblastoma remains one of the diseases for which there is no curative therapy … and the prognosis for patients with primary malignant brain tumors remains dismal," the study states. "Our results suggest that the mesenchymal gene expression profile may identify an immunogenic sub-group of glioblastoma that may be more responsive to immune-based therapies."

Brad Silver, 41, who grew up in Southern California and now lives in a Cleveland suburb, was diagnosed with glioblastoma in 2003 and was told that he had, at best, two months to live. He was stunned.

"I was 33 years and my wife was seven months pregnant with my son," said Silver, a college water polo instructor. 'I didn't think I was going to live to see my son born, let alone grow up."

Silver sought a second opinion at UCLA and the golf-ball sized tumor in his left lateral lobe was removed. He underwent radiation and chemotherapy and enrolled in the vaccine clinical trial. Today, eight years later, he remains cancer free. His son, named Brad Silver II and a miniature version of his dad, will celebrate his eighth birthday in April.

"If I had listened to that first doctor, I would not be here today. If not for Dr. Liau, I would not be here today," Silver said. "I'm 100 percent back to being me because of this vaccine and that clinical trial. It's almost unbelievable."

The vaccine preparation is personalized for each individual. After the tumor is removed, Liau and her team extract the proteins, which provide the antigens for the vaccine to target. After radiation and chemotherapy, the white blood cells are taken from the patient and grown into dendritic cells, a type of white blood cell that is an antigen-presenting cell. The vaccine preparation from this point takes about two weeks, as the dendritic cells are grown together with the patient's own tumor antigens. The tumor-pulsed dendritic cells are then injected back in to the body, prompting the T cells to go after the tumor proteins and fight the malignant cells.

"The body may have trouble fighting cancer because the immune system doesn't recognize it as a foreign invader," Liau said. "The dendritic cells activate the patient's T cells to attack the tumor, basically teaching the immune system to respond to the tumor."

The individualized vaccine is injected into the patient in three shots given every two weeks for a total of six weeks. Booster shots are given once every three months until the cancer recurs. Patients are scanned every two months to monitor for disease recurrence, Liau said.

This study was funded in part by the National Institutes of Health, the Philip R. and Kenneth A. Jonsson Foundation, the Neidorf Family Foundation, STOP Cancer, the Ben & Catherine Ivy Foundation and Northwest Biotherapeutics, Inc.

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Journal Reference:

1. R. M. Prins, H. Soto, V. Konkankit, S. K. Odesa, A. Eskin, W. H. Yong, S. F. Nelson, L. M. Liau. Gene Expression Profile Correlates with T-Cell Infiltration and Relative Survival in Glioblastoma Patients Vaccinated with Dendritic Cell Immunotherapy. Clinical Cancer Research, 2010; 17 (6): 1603 DOI: 10.1158/1078-0432.CCR-10-2563

A gene therapy called NLX-P101 dramatically reduces movement impairment in Parkinson's patients, according to results of a Phase 2 study published today in the journal Lancet Neurology. The approach introduces a gene into the brain to normalize chemical signaling.

The study is the first successful randomized, double-blind clinical trial of a gene therapy for Parkinson's or any neurologic disorder, and it represents the culmination of 20 years of research by study co-authors Dr. Michael Kaplitt, vice chairman for research in the Department of Neurological Surgery at Weill Cornell Medical College and a neurosurgeon at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and Dr. Matthew During, originally at Yale University and now professor of molecular virology, immunology and medical genetics, neuroscience and neurological surgery at the Ohio State University.

"Patients who received NLX-P101 showed a significant reduction in the motor symptoms of Parkinson's, including tremor, rigidity and difficulty initiating movement," says Dr. Kaplitt, who pioneered the approach and helped design the clinical trial. "This not only confirms the results of our Phase 1 trial performed at NewYork-Presbyterian/Weill Cornell but also represents a major milestone in the development of gene therapy for a wide range of neurological diseases."

"This is great news for the 1.5 million Americans living with Parkinson's disease," adds Dr. During, who is the co-inventor, with Dr. Kaplitt, of the gene therapy procedure. "Since this is also the first gene therapy study for a neurological disease to achieve success in a rigorous randomized, double-blind design compared with a sham group, this is also a crucial step forward toward finally bringing gene therapy into clinical practice for patients with debilitating brain disorders."

Although medical therapy is usually effective for most symptoms of Parkinson's early in the disease, over time many patients become resistant to treatment or develop disabling side effects. An alternative treatment is electrical deep brain stimulation, which requires the implantation of permanent medical devices in the brain.

In the current study, 45 patients with moderate to advanced Parkinson's disease who were not adequately controlled with current therapies were enrolled in the double-blind trial, with half randomized to receive the gene therapy and the other half to a "sham surgery" — a mock procedure designed to make patients think they could have received the experimental approach.

The results were significant. Half of patients receiving gene therapy achieved dramatic symptom improvements, compared with just 14 percent in the control group. Overall, patients receiving gene therapy had a 23.1 percent improvement in motor score, compared to a 12.7 percent improvement in the control group. This greater improvement in the gene therapy patients compared with the sham patients was statistically significant over the entire six-month blinded study period. (Dr. Kaplitt explains that the improvements in the control group were likely a chimera, the result of placebo effect or a similar phenomenon called regression to the mean.)

"Improved motor control was seen at one month and continued virtually unchanged throughout the six-month study period," says Dr. Kaplitt, who also serves as associate professor of neurological surgery and director of the Laboratory of Molecular Neurosurgery at Weill Cornell Medical College. "Patients also reported better control of their medication and no worsening of non-motor symptoms."

How NLX-P101 Gene Therapy Works

Gene therapy is the use of a gene to change the function of cells or organs to improve or prevent disease. To transfer genes into cells, an inert virus is used to deliver the gene into a target cell. In this case, the glutamic acid decarboxylase (GAD) gene was used because GAD makes a chemical called GABA, a major inhibitory neurotransmitter in the brain that helps "quiet" excessive neuronal firing related to Parkinson's disease.

"In Parkinson's disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement," explains Dr. During.

In the Phase 2 study, each patient in the experimental group received an infusion of the genetic material directly into their subthalamic nucleus, a key brain region involved in motor function. The GAD gene instructed cells in that area to begin making GABA neurotransmitters in order to re-establish the normal chemical balance which becomes dysfunctional within circuits that control movement.

While patients in the Phase 1 study only received the therapy on one side of their brain, patients in the Phase 2 were infused on both sides. And while the infusion happened entirely in the operating room in the previous phase, the current study made use of a novel delivery system conceived by Drs. Kaplitt and During that allowed for the infusion to take place outside of the OR — at the hospital bedside — something Dr. Kaplitt says makes for a more comfortable patient experience.

Drs. Kaplitt and During also designed the sham surgery, one of the most complex of its kind. The challenge was especially great because patients were required to remain awake to enable surgeons to locate the targeted brain area. In the sham procedure, a small indentation was drilled partway into their skull. Pre-recorded audio of a subthalamic nucleus mapping procedure was played while patients were asked to move various body parts, leading them to believe that an actual brain procedure was being performed. Lastly patients were attached to an infusion system that appeared identical to the system used in the gene therapy group but were subcutaneously injected with saline solution instead of the gene therapy.

The NLX-P101 gene therapy was pioneered by Neurologix Inc. scientific founders Drs. Kaplitt and During. The two researchers have been at the forefront of gene therapy research since 1989. They were the first to demonstrate that the viral vector AAV could be an effective gene therapy agent in the brain, which they reported in a landmark Nature Genetics paper in 1994. Drs. During, Kaplitt and colleagues subsequently published additional research demonstrating the beneficial effects of AAV-GAD gene therapy for Parkinson's in the journal Science in 2002. The Phase 1 clinical trial, performed at NewYork-Presbyterian/Weill Cornell, was the first ever clinical gene therapy trial for Parkinson's or any other adult neurological disorder. Results of that study appeared in 2007 as a cover article in The Lancet and in a second article in the Proceedings of the National Academy of Sciences.

The Phase 2 study was funded by Neurologix Inc., of Fort Lee, N.J., which is developing the adeno-associated virus-borne GAD (AAV-GAD) agent and has licensed intellectual property rights to NLX-P101 gene therapy. Drs. Kaplitt and During are co-founders of the company and remain paid consultants. Additionally, Dr. Kaplitt's father, Dr. Martin Kaplitt, is chairman of the board of Neurologix, and as such has stock ownership and receives salary.

Leading the study were neurologists Dr. Andrew Feigin of the North Shore — LIJ Health System in Manhasset, N.Y., and Dr. Peter A. LeWitt of the Henry Ford Health System in West Bloomfield, Mich.

Additional co-authors include Jason M. Schwalb from the Henry Ford Health System, West Bloomfield Charter Township, Mich; Ali R. Rezai, Sandra K. Kostyk, Karen Thomas and Atom Sarkar from the Ohio State University College of Medicine, Columbus, Ohio; Maureen A. Leehey and Steven G. Ojemann from the University of Colorado School of Medicine, Aurora, Colo.; Alice W. Flaherty and Emad N. Eskandar from the Massachusetts General Hospital, Boston; Mustafa S. Siddiqui and Stephen B. Tatter from the Wake Forest University School of Medicine, Winston-Salem, N.C.; Kathleen L. Poston and Jaimie M. Henderson from the Stanford University School of Medicine, Stanford, Calif.; Roger M. Kurlan and Irene H. Richard from the University of Rochester School of Medicine, Rochester, N.Y.; Lori Van Meter from PharmaNet Development Group, Princeton, N.J.; and Christine V. Sapan from Neurologix Inc., Fort Lee, N.J.

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Journal Reference:

1. Peter A LeWitt et al. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. The Lancet Neurology, 17 March 2011 DOI: 10.1016/S1474-4422(11)70039-4

 Imaging techniques have become an integral part of the neurosciences. Methods that enable us to look through the human skull and right into the active brain have become an important tool for research and medical diagnosis alike. However, the underlying data have to be processed in elaborate ways before a colourful image informs us about brain activity.

Scientists from Freiburg and colleagues were now able to demonstrate how the use of different filters may influence the resulting images and lead to contradicting conclusions.

In the current issue of Human Brain Mapping, Tonio Ball of the Bernstein Center Freiburg and colleagues from the universities of Oldenburg, Basel and Magdeburg demonstrate how variable the results of imaging techniques like functional Magnetic Resonance Imaging (fMRI) can be — depending on the way how the original data are filtered. The use of filtering algorithms is indispensable in order to separate meaningful information from inherent noise that is part of every data set. These filters have different "mesh sizes" or widths, and are indispensable in the first place to reveal activity patterns that span different scale sizes. In most cases, only a filter of one specific width, which differs from study to study, is employed.

Tonio Ball and colleagues systematically investigated the influence of the mesh size of these filters on the resulting imagery of brain activity. They conducted an experiment during which test persons had to rate music by pressing a button while lying in an fMRI scanner. During this task, brain regions responsible for hearing, vision, and arm movements were active. The scientists treated the gained data with filters of different widths and found surprising results: The filters had a marked influence on the outcome of the brain scan analyses, showing increased brain activity in one region in one case, and in a different region — in the other. Even smallest changes in filter width led to areas of the brain appearing to be either active or inactive. This effect can ultimately lead to widely disparate interpretations of such a scan.

Tonio Ball and his colleagues therefore stress the importance of taking into account the effect of filtering in future interpretations of fMRI studies. This way, scientists won't run the risk of inadvertently skewing our view of the brain.

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Journal Reference:

1. Tonio Ball, Thomas P.K. Breckel, Isabella Mutschler, Ad Aertsen, Andreas Schulze-Bonhage, Jürgen Hennig, Oliver Speck. Variability of fMRI-response patterns at different spatial observation scales. Human Brain Mapping, 2011; DOI: 10.1002/hbm.21274