How chronic pain disrupts short term memory

A group of Portuguese researchers from IBMC and FMUP at the University of Porto has found the reason why patients with chronic pain often suffer from impaired short –term memory. The study, to be published in the Journal of Neuroscience, shows how persistent pain disrupts the flow of information between two brain regions crucial to retain temporary memories.

Chronic pain suffers often complain of short term memory’s problems. The neural mechanisms why this occurs are however not understood. Recent studies in animals showed that pain can disturb several cognitive processes as well as change the brain pathways for how we think and feel. Of the many cognitive disturbances observed the most important include problems in spatial memory, recognition memory, attention and even emotional and non-emotional decisions.

In the new article the team of researchers from the University of Porto led by Vasco Gallardo describes in a rat model of neuropathic pain how a neuronal circuit crucial for the processing of short-term memory is affected by pain. The circuit, established between the prefrontal cortex and the hippocampus, is essential for encoding and retaining temporary memories on spatial information. The researchers used multi-electrodes implanted in the brain to record neuronal activity during a behaviour dependent of spatial memory - the animals were trained in a maze where they had to choose between two alternative paths and then asked to recall their chosen path.

The results show that after a painful injury there is a significant reduction in the amount of information that passes through the circuit. This could mean a loss of ability to process information on spatial localization memory, or that those regions critical to memory are now “overwhelmed” by the painful stimuli disrupting the flow of information for memory.

According to Vasco Gallardo, the team ” has already demonstrated that peripheral nerve injury induces an instability in the spatial coding capacity of hippocampus neurons “, where is seen “a clear reduction in their capacity to encode information on the location of the animal.”

So to the author “this new work contributes to the demonstration that chronic pain induces alterations in the function of brain circuits that are not directly connected to tactile or painful processes”. So as a result of chronic pain it is seen that “are also affected neuronal circuits linked to the processing of memories and emotions, what might mean a need for larger and more integrative strategies in the treatment of painful pathologies”, says the researcher.

Translation error tracked in the brain of dementia patients

In certain dementias silent areas of the genetic code are translated into highly unusual proteins by mistake. An international team of scientists including researchers from the German Center for Neurodegenerative Diseases (DZNE) in Munich and the Ludwig-Maximilians-Universität (LMU) present this finding in the online edition of “Science”. The proteins that have now been identified shouldn’t actually exist. Nevertheless, they build the core of cellular aggregates whose identity has been enigmatic until now. These aggregates are typically associated with hereditary neurodegenerative diseases including variants of frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). They are likely to be damaging and might be a target for therapy.

FTD and ALS are part of a group of neurodegenerative diseases that show a broad and overlapping variety of symptoms: Patients often suffer from dementia, personality changes and may also be affected by language abnormalities and movement disorders. The problems often arise before the age of 65 without a clear cause. However, about 30 percent of cases are linked to a genetic cause. In Europe approximately 10 percent of patients show a common genetic feature: In their DNA (the carrier of the genetic code) a particular short sequence appears in numerous copies one after another. Furthermore, proteins of unknown identity accumulate inside the brain of these patients. As it turns out both findings are directly related – that is what the team of researchers including molecular biologists Dieter Edbauer and Christian Haass has now been able to show.

“We have found that the proteins are linked to a genetic peculiarity which many patients have in common. At a certain location inside the gene C9orf72 there are several hundred repeats of the sequence GGGGCC, while healthy people display less than 20 such copies,” explains Prof. Edbauer, who researches at the DZNE and the LMU. “But it is surprising that these proteins are actually made, because these repeats fall into a region of the DNA that should not be translated into proteins.”

An area of DNA assumed to be silent

The DNA holds the blueprints for building proteins. In general, the beginning of such a blueprint is indicated by a certain molecular start signal, but the usual signal is missing in this case. The region of DNA comprising the numerous repeats should therefore not be translated into proteins. It seems that the process of protein synthesis is initiated in a non-textbook way. “Although quite rare there are two known alternatives to the common mechanism. Which procedure applies here, we don’t know yet,” says Prof. Haass, Site Speaker of the DZNE in Munich and chair of Metabolic Biochemistry at LMU.

Nevertheless, in cell culture experiments the researchers were able to show that long repeats of the sequence GGGGCC may in fact lead to the production of proteins, even though the usual start signal is missing. Furthermore, they identified the same proteins in the particles that typically accumulate in the brain of patients. The scientist could also identify their composition: They turned out to be dipeptid-repeat proteins, which comprise a very large number of identical building blocks.

“These are very extraordinary proteins that usually don’t show-up in the organism,” Edbauer notes. “As far as we know, they are completely useless and scarcely soluble. Therefore, they tend to aggregate and seem to damage the nerve cells. We haven’t formally proven toxicity, but there is ample evidence.” Because of their peculiarity these proteins might be an interesting target for new therapies. “As the mechanism of their production is so unusual, we may find ways to inhibit their synthesis without interfering with the formation of other proteins. One could also try to block their aggregation and accelerate their decomposition.”

The scientists have applied for a patent and are pursuing a major goal. “At the DZNE in Munich it is our dream to develop a therapy against these devastating diseases,“ Haass and Edbauer conclude.

Researchers identify potential target for age-related cognitive decline

Cognitive decline in old age is linked to decreasing production of new neurons. Scientists from the German Cancer Research Center have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals.

The hippocampus – a structure of the brain whose shape resembles that of a seahorse – is also called the “gateway” to memory. This is where information is stored and retrieved. Its performance relies on new neurons being continually formed in the hippocampus over the entire lifetime. “However, in old age, production of new neurons dramatically decreases. This is considered to be among the causes of declining memory and learning ability”, Prof. Dr. Ana Martin-Villalba, a neuroscientist, explains.

Martin-Villalba, who heads a research department at the German Cancer Research Center (DKFZ), and her team are trying to find the molecular causes for this decrease in new neuron production (neurogenesis). Neural stem cells in the hippocampus are responsible for continuous supply of new neurons. Specific molecules in the immediate environment of these stem cells determine their fate: They may remain dormant, renew themselves, or differentiate into one of two types of specialized brain cells, astrocytes or neurons. One of these factors is the Wnt signaling molecule, which promotes the formation of young neurons. However, its molecular counterpart, called Dickkopf-1, can prevent this.

"We find considerably more Dickkopf-1 protein in the brains of older mice than in those of young animals. We therefore suspected this signaling molecule to be responsible for the fact that hardly any young neurons are generated any more in old age." The scientists tested their assumption in mice whose Dickkopf-1 gene is permanently silenced. Professor Christof Niehrs had developed these animals at DKFZ. The term "Dickkopf" (from German "dick" = thick, "Kopf" = head) also goes back to Niehrs, who had found in 1998 that this signaling molecule regulates head development during embryogenesis.

Study Seeks Biomarkers for Invisible War Scars

Over the past decade, about half a million veterans have received diagnoses of post-traumatic stress disorder or traumatic brain injury. Thousands have received both. Yet underlying the growing numbers lies a disconcerting question: How many of those diagnoses are definitive? And how many more have been missed?

Read more

Finding challenges accepted view of MS: Unexpectedly, damaged nerve fibers survive

Multiple sclerosis, a brain disease that affects over 400,000 Americans, causes movement difficulties and many neurologic symptoms. MS has two key elements: The nerves that direct muscular movement lose their electrical insulation (the myelin sheath) and cannot transmit signals as effectively. And many of the long nerve fibers, called axons, degenerate.

Many scientists believe that axons are doomed once they lose the insulation, but a new study by graduate student Chelsey Smith and former undergraduate Elizabeth Cooksey in the Journal of Neuroscience shows axons can survive for long periods in rats even after losing myelin.

"This was the first study to demonstrate long-term axon survival after myelin deterioration," says senior author Ian Duncan, a professor in the School of Veterinary Medicine at the University of Wisconsin-Madison.

The mutant rats in the experiment have substantial myelin at first, but by eight weeks the essential myelin insulation is lost. “It was surprising,” says Duncan, an expert in MS pathology. “Nine months is a relatively long period in a rat’s lifetime, and there wasn’t a loss of axons, so the assumption that axons must automatically die without myelin seems incorrect.”

One in Three Children with Multiple Sclerosis has Cognitive Impairment

Data from the largest multicenter study accessing cognitive functioning in children with multiple sclerosis (MS) reveals that one-third of these patients have cognitive impairment, according to a research paper published in the Journal of Child Neurology. Led by Lauren B. Krupp, MD, Director of the Lourie Center for Pediatric Multiple Sclerosis at Stony Brook Long Island Children’s Hospital, the study indicates that patients experience a range of problems related to cognition.

In “Cognitive Impairment Occurs in Children and Adolescents with Multiple Sclerosis: Results from a United States Network,” Dr. Krupp and colleagues from Stony Brook and five other national Pediatric MS Centers of Excellence measured the cognitive functioning of 187 children and adolescents with MS, and 44 who experienced their first neurologic episode (clinically isolated syndrome) indicative of MS. They found that 35 percent of the patients with MS and 18 percent of those with clinically isolated syndrome met criteria for cognitive impairment. All patients were under age 18 with an average disease duration of about two years. 

“This study is important because it represents the largest study to date to apply a comprehensive neuropsychological battery of tests to evaluate the cognitive functioning of children with MS, and the results clearly show us that cognitive issues are widespread and can occur early on in the disease course of these patients,” said Dr. Krupp, also a Professor of Neurology at Stony Brook University School of Medicine. “These are critically important findings that emphasize the need for prompt recognition of our patients’ cognitive problems and for neurologists and other MS specialists to discover ways to intervene and help improve the cognitive abilities of these children while they are in school and beyond.”

Can Nerve Stimulation Help Prevent Migraine?

Wearing a nerve stimulator for 20 minutes a day may be a new option for migraine sufferers, according to new research published in the February 6, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The stimulator is placed on the forehead, and it delivers electrical stimulation to the supraorbital nerve.

For the study, 67 people who had an average of four migraine attacks per month were followed for one month with no treatment. Then they received either the stimulation 20 minutes a day for three months or sham stimulation, where they wore the device but the stimulation given was at levels too low to have any effect.

Those who received the stimulation had fewer days with migraine in the third month of treatment compared to the first month with no treatment. The number of days with migraine decreased from 6.9 days to 4.8 days per month. The number did not change for those who received the sham treatment.

The study also looked at the number of people who had 50 percent or higher reduction in the number of days with migraine in a month. That number was 38 percent for those who had the stimulation compared to 12 percent of those who received the sham treatment.

There were no side effects from the stimulation.

“These results are exciting, because the results were similar to those of drugs that are used to prevent migraine, but often those drugs have many side effects for people, and frequently the side effects are bad enough that people decide to quit taking the drug,” said study author Jean Schoenen, MD, PhD, of Liège University in Belgium and a member of the American Academy of Neurology. The study was supported by the Walloon Region, Department of Economy, Employment and Research in Belgium.

The brain circuit that makes it hard for obese people to lose weight

Imagine you are driving a car, and the harder you press on the accelerator, the harder an invisible foot presses on the brake. That’s what happens when obese people diet – the less food they eat, the less energy they burn, and the less weight they lose.

While this phenomenon is known, scientists at Sydney’s Garvan Institute of Medical Research and the University of NSW have pinpointed the exact brain circuitry behind it and have published their findings in the prestigious international journal Cell Metabolism, now online.

Dr Shu Lin, Dr Yanchuan Shi and Professor Herbert Herzog and his team have been studying the complex processes behind energy balance using various mouse models. They have shown that the neurotransmitter Neuropeptide Y (NPY), known for stimulating appetite, also plays a major role in controlling whether the body burns or conserves energy.

The researchers found that NPY produced in a particular region of the brain – the arcuate nucleus (Arc) of the hypothalamus – inhibits the activation of ‘brown fat’, one of the primary tissues where the body generates heat.

“This study is the first to identify the neurotransmitters and neural pathways that carry signals generated by NPY in the brain to brown fat cells in the body. It is also the first to show a direct connection between Arc NPY, the sympathetic nervous system and the control of energy expenditure.” said Professor Herzog.

“We know that NPY also influences other aspects of the sympathetic nervous system – such as heart rate and gut function – but its control of heat generation through brown fat seems to be the most critical factor in the control of energy expenditure.”

“When you don’t eat, or dramatically curtail your calorie intake, levels of NPY rise sharply. High levels of NPY signal to the body that it is in ‘starvation mode’ and should try to replenish and conserve as much energy as possible. As a result, the body reduces processes that are not absolutely necessary for survival.”

“Evolution has provided us with these mechanisms to help us survive famine, and they are strictly controlled. When people had to survive by finding food or hunting game, they could not afford to run out of energy and die of exhaustion, so their bodies evolved to cope.”

“Until the twentieth century, there were no fast food chains and people did not have ready access to high fat, high sugar, foods. So in evolutionary terms, it was unlikely that people were going to get very fat and mechanisms were only put in place to prevent you losing weight.”

“Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight – and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs.”

Brain research provides clues to what makes people think and behave differently

Differences in the physical connections of the brain are at the root of what make people think and behave differently from one another. Researchers reporting in the February 6 issue of the Cell Press journal Neuron shed new light on the details of this phenomenon, mapping the exact brain regions where individual differences occur. Their findings reveal that individuals’ brain connectivity varies more in areas that relate to integrating information than in areas for initial perception of the world.

"Understanding the normal range of individual variability in the human brain will help us identify and potentially treat regions likely to form abnormal circuitry, as manifested in neuropsychiatric disorders," says senior author Dr. Hesheng Liu, of the Massachusetts General Hospital.

Dr. Liu and his colleagues used an imaging technique called resting-state functional magnetic resonance imaging to examine person-to-person variability of brain connectivity in 23 healthy individuals five times over the course of six months.

The researchers discovered that the brain regions devoted to control and attention displayed a greater difference in connectivity across individuals than the regions dedicated to our senses like touch and sight. When they looked at other published studies, the investigators found that brain regions previously shown to relate to individual differences in cognition and behavior overlap with the regions identified in this study to have high variability among individuals. The researchers were therefore able to pinpoint the areas of the brain where variable connectivity causes people to think and behave differently from one another.

Higher rates of variability across individuals were also displayed in regions of the brain that have undergone greater expansion during evolution. “Our findings have potential implications for understanding brain evolution and development,” says Dr. Liu. “This study provides a possible linkage between the diversity of human abilities and evolutionary expansion of specific brain regions,” he adds.