Neuroscience

By exploring parts of the brain that trigger during periods of daydreaming and mind-wandering, neuroscientists from Western University have made a significant breakthrough in understanding what physically happens in the brain to cause vegetative state and other so-called “disorders of consciousness.”
Vegetative state and related disorders such as the minimally conscious state are amongst the least understood conditions in modern medicine because there is no particular type of brain damage that is known to cause them. This lack of knowledge leads to an alarmingly high level of misdiagnosis.

In support of the study titled, “A role for the default mode network in the bases of disorders of consciousness,” Davinia Fernandez-Espejo, a post doctoral fellow at Western’s Brain and Mind Institute, utilized a technique called diffusion tensor imaging tractography to investigate more than 50 patients suffering from varying degrees of brain injury.

This state-of-the-art magnetic resonance imaging (MRI) technique allows researchers to virtually reconstruct the pathways that connect different parts of the brain in the patients while detecting subtle differences in their brain damage.

Specifically, Fernandez-Espejo was able to show that in vegetative state patients, a group of brain regions known as the default mode network that are known to activate during periods of daydreaming and mind-wandering were significantly disconnected, relative to healthy individuals.

"These findings are a first step towards identifying biomarkers that will help us to improve diagnosis and to find possible therapies for these patients" says Fernandez-Espejo. "But they also give us new information about how the healthy brain generates consciousness."

Strokes often cause loss or impairment of vital brain functions – such as speech, movement, vision or attention. Restoration of these functions is often possible, but difficult. One of the factors impeding brain plasticity is inflammation.  A study on rats, carried out at the Nencki Institute in Warsaw, suggests that effectiveness of neurorehabilitation after a stroke can be improved by anti-inflammatory drugs.

Post-stroke inflammation slows down recovery and impairs brain plasticity, reveal the results from the lab of Professor Małgorzata Kossut at the Nencki Institute in Warsaw. The popular anti-inflammatory drug ibuprofen restores the ability of brain cortex to reorganize – a process necessary for recovery of stroke-damaged functions. “Our research was conducted on rats, but we have good reasons to suppose that in future our results will help improve effectiveness of rehabilitation of stroke patients”, says Prof. Kossut.

The Nencki Institute team stresses that so far there are no proofs that the treatment will be effective in humans and that they did not investigate if the ibuprofen therapy prevents strokes, but concentrated on post-stroke recovery.

The most frequent cause of stroke is blocking of brain arteries. Without supply of oxygen, neurons die quckly. In the region of stroke-induced damage pathological changes cause decrease of brain tissue metabolism, impairment of neurotransmission and edema.

Brain control over physiological and voluntary functions may be lost, depending on the localization of the infarct. Impairments of movement, vision, speech and attention are frequent. In most cases these functions return either partially or completely. Sometimes they return spontaneously, more often after neurorehabilitation.

“In both instances recovery is based on neuroplasticity, the ability of the brain to reorganize, that is to change the properties of neurons and to alter the connections between them”, says Dr. Monika Liguz-Lęcznar (Nencki Institute).

After a stroke, neuroplasticity is impaired. Scientists from the Nencki Institute suppose that this may be due to inflammation developing at the site of the stroke. The proof that decreasing inflammation helps neurorehabilitation came from experiments done on rats with experimentally induced stroke. The stroke was localized in a special region of the brain cortex, receiving information from whiskers.

The whiskers are important sensory organs of rodents, allowing the animals to orient themselves in their environment in darkness. Every whisker activates a small, precisely delineated chunk of brain cortex.

In healthy rats neuroplastic changes can be induced by cutting off some of the whiskers, that is by eliminating part of the sensory input to the brain. The brain reacts to that by letting the remaining whiskers take over more cortical space, expand their cortical representation, at the expense of the cut off ones.

“This plastic change does not occur when the site of stroke-induced damage is near the region of cortex ‘belonging’ to the whiskers. We showed that application of ibuprofen decreases inflammation and restores neuroplasticity – the brain cortex reorganizes like in healthy animals”, says Prof. Kossut.

New research suggests that a mother’s high blood pressure during pregnancy may have an effect on her child’s thinking skills all the way into old age. The study is published in the October 3, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“High blood pressure and related conditions such as preeclampsia complicate about 10 percent of all pregnancies and can affect a baby’s environment in the womb,” said study author Katri Räikönen, PhD, with the University of Helsinki in Finland. “Our study suggests that even declines in thinking abilities in old age could have originated during the prenatal period when the majority of the development of brain structure and function occurs.”

Researchers looked at medical records for the mother’s blood pressure in pregnancy for 398 men who were born between 1934 and 1944. The men’s thinking abilities were tested at age 20 and then again at an average age of 69. Tests measured language skills, math reasoning and visual and spatial relationships.

The study found that men whose mothers had high blood pressure while pregnant scored 4.36 points lower on thinking ability tests at age 69 compared to men whose mothers did not have high blood pressure. The group also scored lower at the age of 20 and had a greater decline in their scores over the decades than those whose mothers did not have problems with blood pressure. The finding was strongest for math-related reasoning.

The researchers also looked at whether premature birth affected these findings and found no change. Whether the baby’s father was a manual laborer or an office worker also did not change the results.

Efforts to treat disorders like Lou Gehrig’s disease, Paget’s disease, inclusion body myopathy and dementiawill receive a considerable boost from a new research model created by UC Irvine scientists.

The team, led by pediatrician Dr. Virginia Kimonis, has developed a genetically modified mouse that exhibits many of the clinical features of human diseases largely triggered by mutations in the valosin-containing protein.

The mouse model will let researchers study how these now-incurable, degenerative disorders progress in vivo and will provide a platform for translational studies that could lead to lifesaving treatments.

“Currently, there are no effective therapies for VCP-associated diseases and related neurodegenerative disorders,” said Kimonis, a professor of pediatrics who specializes in genetics and metabolism. “This model will significantly spark new approaches to research directed toward the creation of novel treatment strategies.”

She and her team reported their discovery Sept. 28 online in PLOS ONE, a peer-reviewed, open-access journal.

The UCI researchers – from pediatrics, neurology, pathology and radiological sciences – specifically bred the first-ever “knock-in” mouse in which the normal VCP gene was substituted with one containing the common R155H mutation seen in humans with VCP-linked diseases. Subsequently, these mice exhibited the same muscle, brain and spinal cord pathology and bone abnormalities as these patients.

VCP is part of a system that maintains cell health by breaking down and clearing away old and damaged proteins that are no longer necessary. Mutations in the VCP gene disrupt the demolition process, and, as a result, excess and abnormal proteins may build up in muscle, bone and brain cells. These proteins form clumps that interfere with the cells’ normal functions and can lead to a range of disorders.

Another study carried out by members of this group – and published in August in the journal Cell Death & Disease – made use of these genetically altered mice to examine the development of Lou Gehrig’s disease, or ALS. The researchers, led by Dr. Hong Yin and Dr. John Weiss in UCI’s Department of Neurology, documented slow, extensive pathological changes in the spinal cord remarkably similar to changes observed in other animal models of ALS as well as in human patients. ALS research is currently limited by a paucity of animal models in which disease processes can be studied.

Genetically modified mice have become important research models in the effort to cure human ailments. Mice bred to exhibit the brain pathology of Alzheimer’s disease, for example, have dramatically sped up the race to advance new treatments – one such model was developed at UCI. And many cancer therapies were created and tested using genetically altered mice.

Parents should not worry that proposed changes to the medical criteria redefining a diagnosis of autism will leave their children excluded and deemed ineligible for psychiatric and medical care, says a team of researchers led by psychologists at Weill Cornell Medical College.

Their new study, published in the October 1 issue of the American Journal of Psychiatry, is the largest to date that has tried to unpack the differences between the diagnostic criteria for autism spectrum disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the proposed revision in the fifth edition (DSM-5), which is expected to be published in May 2013. These manuals provide diagnostic criteria for people seeking mental-health-related medical services.

"I know that parents worry, but I don’t believe there is any substantial reason to fear that children who need to be diagnosed with autism spectrum disorders, and provided with vital services, will not be included in the new criteria in this updated manual," says the study’s senior investigator, Dr. Catherine Lord, director of the Center for Autism and the Developing Brain at NewYork-Presbyterian Hospital’s Westchester campus, along with its affiliated medical schools Weill Cornell Medical College and Columbia University College of Physicians and Surgeons.

At issue is whether DSM-5 will “capture” the same individuals diagnosed with different forms of autism by the DSM-IV. The DSM-5 proposal redefines autism as a single category — autism spectrum disorder (ASD) — whereas DSM-IV had multiple categories and included Autistic Disorder, Asperger’s Disorder, and Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS).

Critics have particularly worried that among the excluded will be children now diagnosed with PPD-NOS and Asperger’s disorder. That isn’t the case, says Dr. Lord, who is also a DeWitt Wallace Senior Scholar at Weill Cornell and an attending psychologist at NewYork-Presbyterian Hospital. The study, the largest to date and arguably, the most rigorous, finds that when relying on parent report, 91 percent of the 4,453 children in the sample currently diagnosed with a DSM-IV autism spectrum disorder would be diagnosed with ASD using DSM-V.

Many of the remaining nine percent would likely be reincluded once a clinician can offer input, says Dr. Lord, who is also a member of the American Psychiatric Association’s DSM-5 Neurodevelopmental Disorders Work Group.

The study researchers also concluded that DSM-5 has higher specificity than DSM-IV—in their study, DSM-5 criteria resulted in fewer misclassifications.

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In a study published in Nature Neuroscience, neurobiologists from the Friedrich Miescher Institute for Biomedical Research have been linking synapse formation in the hippocampus to distinct learning steps. They show how different regions of the hippocampus have specific and sequential functions in the mastery of a complex task.

The setup is natural. The mouse finds herself in the water and is looking for a dry place. But how does she solve this task? And what happens if she finds herself in the same situation again? Here is what the scientists observed: At the beginning, the mouse swims all around the little pool, randomly searching for the platform. After two days, there is a change in search approach: The mouse has learned where about the platform is and will start to search right away in the area of the platform. Finally, after another five days, the mouse knows exactly where the platform is and swims directly for it. What is astonishing is that every mouse behaves same way and all the mice learn to find the platform in about the same time, through the same trial and error search strategy stages.

Pico Caroni, senior group leader at the Friedrich Miescher Institute for Biomedical Research, and his team not only described for the first time how mice learn to master such a complex task step by step, but they have also been able to show how one region of the brain, the hippocampus, is engaged in these learning processes. The hippocampus is the region of the brain that is the relay station for a lot of sensory information. In this function, the hippocampus is extremely important for learning and the consolidation of memory. The hippocampus can be divided into three areas termed ventral (vH), intermediate (iH) and dorsal hippocampus (dH). Even though the composition of the neuronal networks in each area is comparable, they differ in gene expression, connectivity, tuning and function.

Caroni and his team could now show that this difference has functional implications in learning. It has been known that during learning new synapses are formed in the hippocampus by so called mossy fibers. In their study published in Nature Neuroscience the scientists show that each search strategy, each level of learning, is associated with a different region of the hippocampus. First, mossy fiber synapses are formed in vH. With the first change in search strategy, mossy fiber formation moves to iH. The mice now have a clear understanding of the relative position of the platform, e.g. distance from the pool wall. Finally, synapse formation moves to dH. By now the mouse has a clear map of the pool, the platform and her position in these surroundings. From now on the mouse will always know where the platform is and will directly head for it.

"We believe that many complex learning tasks are achieved through sub-tasks and that the three areas of the hippocampus are involved in similar ways," comments Caroni. "Our experiments indicate further that this approach is innate, which indicates that similar processes may play as we learn to bike or become proficient in playing tennis."

Diseases that progressively destroy nerve cells in the brain or spinal cord, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are devastating conditions with no cures.

Now, a team that includes a University of Iowa researcher has identified a new class of small molecules, called the P7C3 series, which block cell death in animal models of these forms of neurodegenerative disease. The P7C3 series could be a starting point for developing drugs that might help treat patients with these diseases. These findings are reported in two new studies published the week of Oct. 1 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).

“We believe that our strategy for identifying and testing these molecules in animal models of disease gives us a rational way to develop a new class of neuroprotective drugs, for which there is a great, unmet need,” says Andrew Pieper, M.D., Ph.D., associate professor of psychiatry at the UI Carver College of Medicine, and senior author of the two studies.

About six years ago, Pieper, then at the University of Texas Southwestern Medical Center, and his colleagues screened thousands of compounds in living mice in search of small, drug-like molecules that could boost production of neurons in a region of the brain called the hippocampus. They found one compound that appeared to be particularly successful and called it P7C3.

“We were interested in the hippocampus because new neurons are born there every day. But, this neurogenesis is dampened by certain diseases and also by normal aging,” Pieper explains. “We were looking for small drug-like molecules that might enhance production of new neurons and help maintain proper functioning in the hippocampus.”

However, when the researchers looked more closely at P7C3, they found that it worked by protecting the newborn neurons from cell death. That finding prompted them to ask whether P7C3 might also protect existing, mature neurons in other regions of the nervous system from dying as well, as occurs in neurodegenerative disease.

Using mouse and worm models of PD and a mouse model of ALS, the research team has now shown that P7C3 and a related, more active compound, P7C3A20, do in fact potently protect the neurons that normally are destroyed by these diseases. Their studies also showed that protection of the neurons correlates with improvement of some disease symptoms, including maintaining normal movement in PD worms, and coordination and strength in ALS mice.

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