Neuroscience

Wellcome Trust researchers have discovered how the brain assesses confidence in its decisions. The findings explain why some people have better insight into their choices than others.

Throughout life, we’re constantly evaluating our options and making decisions based on the information we have available. How confident we are in those decisions has clear consequences. For example, investment bankers have to be confident that they’re making the right choice when deciding where to put their clients’ money.

Researchers at the Wellcome Trust Centre for Neuroimaging at UCL led by Professor Ray Dolan have pinpointed the specific areas of the brain that interact to compute both the value of the choices we have in front of us and our confidence in those choices, giving us the ability to know what we want.

The team used functional magnetic resonance imaging (fMRI) to measure activity in the brains of twenty hungry volunteers while they made choices between food items that they would later eat. To determine the subjective value of the snack options, the participants were asked to indicate how much they would be willing to pay for each snack. Then after making their choice, they were asked to report how confident they were that they had made the right decision and selected the best snack.

It has previously been shown that a region at the front of the brain, the ventromedial prefrontal cortex, is important for working out the value of decision options. The new findings reveal that the level of activity in this area is also linked to the level of confidence participants placed on choosing the best option. The study also shows that the interaction between this area of the brain and an adjacent area reflects participants’ ability to access and report their level of confidence in their choices.

Dr Steve Fleming, a Sir Henry Wellcome Postdoctoral Fellow now based at New York University, explains: “We found that people’s confidence varied from decision to decision. While we knew where to look for signals of value computation, it was very interesting to also observe neural signals of confidence in the same brain region.”

Dr Benedetto De Martino, a Sir Henry Wellcome Postdoctoral Fellow at UCL, added: “Overall, we think our results provide an initial account both of how people make choices, and also their insight into the decision process.”

The treatment of inflammatory pain can be improved by endogenous opioid peptides acting directly in injured tissue. Scientists at the Charité – Universitätsmedizin Berlin and the Université Paris Descartes showed that pain can be successfully treated by targeting immune and nerve cells outside the brain or spinal cord. The study is published in the current issue of The FASEB Journal.

Inflammatory pain is the most common form of painful diseases. Examples are acute pain after surgery, and chronic pain as in the case of rheumatoid arthritis. However, the treatment of inflammatory pain is often difficult because it rarely responds to conventional therapies. Furthermore, opiates, such as morphine, produce serious side effects including addiction mediated in the brain, while drugs, such as ibuprofen, may cause stomach ulcers, internal bleeding, and cardiovascular complications. The activation of opiate receptors in nerve cells outside the brain or spinal cord can alleviate pain without serious side effects. This can be achieved by synthetic opiates or endogenous opioid peptides, e.g. enkephalins and endorphins. However, these peptides are rapidly inactivated by two major enzymes, aminopeptidase N (APN) and neutral endopeptidase (NEP), which limit their analgesic effects.

The aim of the research group of Prof. Halina Machelska-Stein from the Klinik für Anästhesiologie at Campus Benjamin Franklin was to prevent the breakdown of endogenous opioid peptides directly in the inflamed tissue. In an animal model, the group has shown that inflammatory pain can be alleviated if the two enzymes (APN and NEP), responsible for the inactivation of the opioid peptides, were blocked by the selective inhibitors. In preparations from immune or nerve cells, which express these enzymes, the opioid peptides were quickly broken down. This was prevented by the enzyme inhibitors, bestatin, thiorpan and P8B. As a result, the sensation of pain was either markedly reduced or completely disappeared. “Targeting of endogenous opioid peptides directly in injured tissues might be a promising strategy to treat inflammatory pain without serious side effects,” states Prof. Machelska-Stein, explaining the results of the investigation. Furthermore, blocking pain at the site of its origin may prevent excitatory mechanisms in the nervous system, which lead to the development of chronic pain.

Scientists have until now not fully understood how animals see in color, since visual pigments in eyes contain exactly the same chromophore (light absorbing segment of the molecule) and yet can absorb different wavelengths of light.

The chromophore retinal (Vitamin A aldehyde or retinaldehyde) is used by all animals but, depending on the photoreceptor proteins (opsins) associated with it, the same molecule can absorb a spectrum of colors from blues or even ultraviolet to reds. How a single molecule can do this has until now been uncertain.

Now researchers, led by Prof. Babak Borhan of Michigan State University at East Lansing, set out to try to understand the mechanism by which the opsins change the light absorption spectrum of the chromophore retinal. They concentrated their efforts on a pigment found in human retinal photoreceptor cells, rhodopsin, which consists of opsin and chromophore components.

One of the major theories about how retinal works is that because it is strongly positively charged at one end it could distribute this electrostatic charge across the chromophore molecule, and this would enable it to absorb the longer wavelengths at the red end of the spectrum. Another theory held that a change in shape of the chromophore-opsin complex could alter the absorption capabilities.

The problem with testing the theories, Borhan said, is that the visual pigments have proved difficult to work with. So instead, Borhan and colleagues used human cellular retinol binding protein II, (hCRBPII), a gut protein that binds retinol, which is closely related to retinal but which tolerates mutations more readily.

The team first created a mutation of hCRPBII that could bind retinal. They then changed the distribution of the electrostatic charge on the retinal molecule by replacing amino acids at the binding site retinal uses on hCRPBII in various ways, and in so doing created a range of pigment proteins.

The team then used spectrophotometry to compare the light entering and leaving the proteins to determine which wavelengths were being absorbed. Using this approach they were able to prove the charge distribution theory was correct and that no change in shape was necessary.

A by-product of the new research is the production of the 11 new artificial pigments, which could be used in tracking proteins or cell types being studied, as well as other possible applications such as in food dyes. One of the new pigments could absorb a red wavelength of 644 nanometers (nm), which is above the theoretical maximum wavelength retinal can absorb (560 nm) and is close to infrared (750 nm +).

The paper was published in the journal Science.

Humans may be endowed with the ability to perform complex forms of learning, attention and function but the evolutionary process that led to this has put us at risk of mental illness.

Data from new research, published today in the journal Nature Neuroscience, was analysed by Dr Richard Emes, a bioinformatics expert from the School of Veterinary Medicine and Science at The University of Nottingham. The results showed that disease-causing mutations occur in the genes that evolved to make us smarter than our fellow animals.

Dr Emes, Director of The University of Nottingham’s Advanced Data Analysis Centre, conducted an analysis of the evolutionary history of the Discs Large homolog (Dlg) family of genes which make some of the essential building blocks of the synapse — the connection between nerve cells in the brain. He said: “This study highlights the importance of the synapse proteome — the proteins involved in the brains signalling processes — in the understanding of cognition and the power of comparative studies to investigate human disease.”

The study involved scientists from The University of Edinburgh, The Wellcome Trust Sanger Institute, the University of Aberdeen, The University of Nottingham and the University of Cambridge.

This cross-disciplinary team of experts carried out what they believe to be the first genetic dissection of the vertebrate’s ability to perform complex forms of learning, attention and function. They focussed on Dlg — a family of genes that humans shared with the ancestor of all backboned animals some 550 million years ago. Gene families like the Dlgs arose by duplication of DNA, changed by mutation over millions of years and now contribute to the complex cognitive processes we have today. However, this redundancy and subsequent accumulation of changes in the DNA may have led to increased susceptibility to some diseases.

Components of the human cognitive repertoire are routinely assessed by using computerised touch-screen methods. By using the same technique with mice researchers were able to probe the cognitive mechanisms conserved since humans and mice shared a common ancestor — around 100 million years ago. By comparing the effect of DNA changes on behavioural test outcomes this research showed a common cause of mutation and effect of learning changes in both mice and humans.

Dr Emes said: “This research shows the importance of discerning information from data and how the power of computational research combined with behavioural and cognitive studies can provide such novel insight into the basis of clinical disorders. This research provides continued support that discovery occurs at the boundary of disciplines by the integration of data.”

(Image Credit: Stanford University)

A team of brain cancer researchers at Barrow Neurological Institute at St. Joseph’s Hospital and Medical Center has effectively treated brain tumor cells using a unique combination of diet and radiation therapy. The study, “The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma,” was published in PLOS ONE.

Led by Adrienne C. Scheck, PhD, Principal Investigator in Neuro-Oncology and Neurosurgery Research at Barrow, the groundbreaking research studied the effects of the ketogenic diet in conjunction with radiation therapy for the treatment of malignant gliomas, an aggressive and deadly type of brain tumor. The ketogenic diet is a high-fat, low-carbohydrate diet that alters metabolism and is used in the treatment of pediatric epilepsy that does not respond to conventional therapies. The diet’s affects on brain homeostasis have potential for the treatment of other neurological diseases, as well.

In the study, mice with high-level malignant gliomas were maintained on either a standard or a ketogenic diet. Both groups received radiation therapy. Dr. Scheck’s team discovered that animals fed a ketogenic diet had an increased median survival of approximately five days relative to animals maintained on a standard diet. Of the mice that were fed a ketogenic diet and received radiation, nine of 11 survived with no signs of tumor recurrence, even after being switched back to standard food, for over 200 days. None on the standard diet survived more than 33 days.

One theory behind the success of the treatment is that the ketogenic diet may reduce growth factor stimulation, inhibiting tumor growth. Barrow scientists also believe that it may reduce inflammation and edema surrounding the tumors. This is believed to be the first study of its kind to look at the effects of the ketogenic diet with radiation.

Dr. Scheck believes that the study has promising implications in the treatment of human malignant gliomas. “We found that the ketogenic diet significantly enhances the anti-tumor effect of radiation, which suggests that it may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas,” she says.

Dr. Scheck adds that the ketogenic diet could quickly and easily be added into current brain tumor treatment plans as an adjuvant therapy without the need for FDA approval. She is currently exploring options for clinical trials.