Neuroscience

A new treatment for drug-resistant epilepsy with the potential to suppress seizures ‘on demand’ with a pill, similar to how you might take painkillers when you feel a headache coming on, has been developed by UCL researchers funded by the Wellcome Trust.

The treatment, described in Nature Communications, combines genetic and chemical approaches to suppress seizures without disrupting normal brain function. The technique was demonstrated in rodents but in future we could see people controlling seizures on-demand with a simple pill.

Epilepsy affects around 50 million people worldwide including 600,000 in the UK and around a quarter of cases are resistant to conventional treatments. Many of these cases could be addressed by the new treatment method, which relies on genetic modification of brain cells to make them sensitive to a normally inactive compound.

“First, we inject a modified virus into the area of the brain where seizures arise,” explains Professor Dimitri Kullmann of the UCL Institute of Neurology, senior author of the research. “This virus instructs the brain cells to make a protein that is activated by CNO (clozapine-N-oxide), a compound that can be taken as a pill. The activated protein then suppresses the over-excitable brain cells that trigger seizures, but only in the presence of CNO.

“At the moment, severe seizures are treated with drugs that suppress the excitability of all brain cells, and patients therefore experience side effects. Sometimes the dose required to stop seizures is so high that patients need to be sedated and taken to intensive care. If we can take our new method into the clinic, which we hope to do within the next decade, we could treat patients who are susceptible to severe seizures with a one-off injection of the modified virus, and then use CNO only when needed.

“CNO would be given as a pill in the event that patients could predict when seizures were likely to occur. For example, many people with treatment-resistant epilepsy experience clusters of seizures, where severe seizures are preceded by smaller ones. Seizure risk is also high when people are ill, sleep deprived, or at certain times of the menstrual cycle, so these would all be good times to take the pill as a preventative measure. In urgent situations, the compound could be given as an injection. We could even consider a fully automatic delivery system, where CNO was given by a pump, as is done for insulin in some people with diabetes.”

As CNO has a half-life of about a few hours and only affects the pre-treated epileptic parts of the brain, the new method avoids the need to permanently alter the brain or treat the whole brain with seizure-suppressing drugs. It builds on similar work by Professor Kullmann’s group using gene therapy to ‘calm down’ brain cells, or using light pulses to activate seizure-suppressing receptors in the brain. The new technique works in a similar way but is reversible and avoids the need for invasive devices to deliver light to the brain.

“After the one-off injection into affected areas of the brain, our new technique would require nothing beyond CNO, administered as an injection or a pill, to suppress seizures when required,” says Professor Kullmann. “This makes it more attractive than alternative forms of targeted therapy such as surgery to remove the brain region where seizures arise, or gene therapy that permanently alters the excitability of brain cells.

“Although there is currently no evidence that permanently suppressing excitability in a small area affects brain function, we cannot be sure that it would have no impact long-term. Our new method is completely reversible, so if there were any side-effects then people could simply stop taking the CNO pill.”

Virginia Commonwealth University School of Medicine researchers have uncovered a new mechanism of action of fingolimod, a drug widely used to treat multiple sclerosis: elimination of adverse or traumatic memories.

The findings shed light on how the drug works on the molecular level – something that has not been well understood until now.

Fingolimod, or FTY720, which is the first orally available drug for treatment of multiple sclerosis, works by suppressing the immune system. Fingolimod is a prodrug that is phosphorylated in the body to its active form, FTY720-phosphate.

In a study published by the Nature Neuroscience journal on May 25 as an Advanced Online Publication, researchers used a mouse model to show that fingolimod accumulates in the brain and inhibits histone deacetylases, which are enzymes important to regulate gene expression. The team observed an increased expression of a limited number of genes important for certain memory processes. Fingolimod acted similarly to the natural signaling lipid, sphingosine-1-phosphate, which it closely resembles.

“Our work suggests that some of the beneficial effects of FTY720/fingolimod that are not well understood might be mediated by this new activity that we have discovered,” said first author Sarah Spiegel, Ph.D., an internationally renowned researcher and professor and chair of the Department of Biochemistry and Molecular Biology in the VCU School of Medicine.

“It will be important in the future to determine whether this prodrug can reduce loss of cognitive functions and can erase adverse memories,” she said.

Spiegel added that other histone deacetylase inhibitors have long been used for treatment of psychiatric and neurological disorders, yet the mechanism of their effectiveness is not fully understood.

“FTY720/fingolimod may be a useful adjuvant therapy to help stop aversive memories such as in post-traumatic stress disorder and other anxiety disorders,” Spiegel said.

“The work has not been extended to show effectiveness in humans at this time. We are still working to fully understand the molecular underpinnings of the drug and its link to memory,” she said.

The work is based on previous findings by Spiegel’s group that were published in Science in 2009. They had reported that sphingosine-1-phosphate formed in the nucleus of cells is a natural inhibitor of histone deacetylases and a regulator of gene expression.

Puberty is the defining process of adolescent development, beginning a cascade of changes throughout the body, including the brain. Penn Medicine researchers have discovered that cerebral blood flow (CBF) levels decreased similarly in males and females before puberty, but saw them diverge sharply in puberty, with levels increasing in females while decreasing further in males, which could give hints as to developing differences in behavior in men and women and sex-specific pre-dispositions to certain psychiatric disorders. Their findings are available in Proceedings of the National Academy of Science (PNAS).

"These findings help us understand normal neurodevelopment and could be a step towards creating normal ‘growth charts’ for brain development in kids. These results also show what every parent knows: boys and girls grow differently. This applies to the brain as well," says Theodore D. Satterthwaite, MD, MA, assistant professor in the Department of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania. "Hopefully, one day such growth charts might allow us to identify abnormal brain development much earlier before it leads to major mental illness."

Studies on structural brain development have shown that puberty is an important source of sex differences. Previous work has shown that CBF declines throughout childhood, but the effects of puberty on properties of brain physiology such as CBF, also known as cerebral perfusion, are not well known. “We know that adult women have higher blood flow than men, but it was not clear when that difference began, so we hypothesized that the gap between women and men would begin in adolescence and coincide with puberty,” Satterthwaite says.

The Penn team imaged the brains of 922 youth ages 8 through 22 using arterial spin labeled (ASL) MRI. The youth were all members of the Philadelphia Neurodevelopmental Cohort, a National Institute of Mental Health-funded collaboration between the University of Pennsylvania Brain Behavior Laboratory and the Center for Applied Genomics at the Children’s Hospital of Philadelphia.

They found support for their hypothesis.

Age related differences were observed in the amount and location of blood flow in males versus females, with blood flow declining at a similar rate before puberty and diverging markedly in mid-puberty. At around age 16, while male CBF values continue to decline with advanced age, females CBF values actually increased. This resulted in females having notably higher CBF than males by the end of adolescence. The difference between males and females was most notable in parts of the brain that are critical for social behaviors and emotion regulation such as the orbitofrontal cortex. The researchers speculate that such differences could be related to females’ well-established superior performance on social cognition tasks. Potentially, these effects could also be related to the higher risk in women for depression and anxiety disorders, and higher risk of flat affect and schizophrenia in men.

Researchers reveal that neurons can utilize a supremely localized internal store of calcium to initiate the secretion of neuropeptides, one class of signaling molecules through which neurons communicate with each other and with other cells. The study appears in The Journal of General Physiology.

(Image caption: Localization of ryanodine receptors (red) in an isolated nerve terminal from the posterior pituitary gland. Image credit: McNally et al., 2014)

Neuropeptides are released from neurons through a process that—like other secretory events—is triggered primarily by the influx of calcium into the neuron through voltage-gated channels. Although neuropeptides are stored in large dense core vesicles (LDCVs) that also contain large amounts of calcium, it has been unclear whether these locally based calcium supplies can also be used to modulate secretion.

A team of researchers led by José Lemos from the University of Massachusetts Medical School examined the mechanisms at play during secretion of vasopressin from nerve terminals in the posterior pituitary gland, which releases the neuropeptide into the blood so that it can make its way to the kidney and regulate water retention. The researchers found that certain intracellular calcium channels known as ryanodine receptors are likely responsible for mobilizing calcium from LDCVs to facilitate vasopressin release. The findings indicate that neurons have a greater capacity than previously appreciated to fine-tune the release of neuropeptides and thereby their communications with other cells.

Research presented by Dr. Lynn Raymond, from the University of British Columbia, shows that blocking a specific class of glutamate receptors, called extrasynaptic NMDA receptors, can improve motor learning and coordination, and prevent cell death in animal models of Huntington disease. As Huntington disease is an inherited condition that can be detected decades before any clinical symptoms are seen in humans, a better understanding of the earliest changes in brain cell (neuronal) function, and the molecular pathways underlying those changes, could lead to preventive treatments that delay the onset of symptoms and neurodegeneration. “After more than a decade of research on the pre-symptomatic phase of Huntington disease, markers are being developed to facilitate assessment of interventional therapy in individuals carrying the genetic mutation for Huntington disease, before they become ill. This will make it possible to delay onset of disease,” says Dr. Raymond. These results were presented at the 2014 Canadian Neuroscience Meeting, the 8th annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN), held in Montreal, May 25-28.

The neurotransmitter glutamate has long been known to promote cell death, and its toxic effects occur through the action of a family of receptors known as the NMDARs (N-methyl-D-Aspartate ionotropic glutamate receptors). Unfortunately, treating disorders of the nervous system by blocking NMDARs has not been successful because such treatments have numerous side effects. A recent hypothesis based on work from many scientists suggests that NMDARs located in different regions at the surface of neurons may have opposite effects, which would explain why blocking all NMDARs is not a good treatment option. A synapse is a structure that allows one neuron to connect to another neuron and pass an electrical or chemical signal between them. Many receptors for neurotransmitters are located in synapses, as these are the main area where these chemical signals are transmitted. However, receptors can also be found outside the synapse, and in this case are called extra-synaptic receptors. Many recent studies have revealed that NMDARs located at synapses act to increase survival signaling and promote learning and memory, whereas extra-synaptic NMDARs shut off survival signaling, interfere with learning mechanisms, and increase cell death pathways.

Dr. Raymond and her team were able, by using a drug that selectively blocks extra-synaptic NMDARs early, before the appearance of any symptoms, to delay the onset of Huntington-like symptoms in a mouse model of the disease. These promising results could lead to new treatment avenues for Huntington patients, and delay the appearance of symptoms. “The drug we used, memantine, is currently being used to treat moderate-stage Alzheimer disease patients. Our results suggest that clinical studies of memantine and similarly-acting drugs in Huntington disease, particularly in the pre-symptomatic stage, are warranted,”says Dr. Raymond.

Extra-synaptic NMDARs have also been shown to be involved in other neurodegenerative diseases, such as Alzheimer disease, and in damage caused by traumatic brain injury and some forms of stroke. These results therefore suggest novel treatment avenues for many conditions in which neurons degenerate and die, a new way to protect neurons before the appearance of symptoms of neurodegeneration.

‘Seeing is believing’, so the idiom goes, but new research suggests vision also involves a bit of hearing.

Scientists studying brain process involved in sight have found the visual cortex also uses information gleaned from the ears as well as the eyes when viewing the world.

They suggest this auditory input enables the visual system to predict incoming information and could confer a survival advantage.

Professor Lars Muckli, of the Institute of Neuroscience and Psychology at the University of Glasgow, who led the research, said: “Sounds create visual imagery, mental images, and automatic projections.

“So, for example, if you are in a street and you hear the sound of an approaching motorbike, you expect to see a motorbike coming around the corner. If it turned out to be a horse, you’d be very surprised.”

The study, published in the journal Current Biology, involved conducting five different experiments using functional Magnetic Resonance Imaging (fMRI) to examine the activity in the early visual cortex in 10 volunteer subjects.

In one experiment they asked the blindfolded volunteers to listen to three different sounds – birdsong, traffic noise and a talking crowd.

Using a special algorithm that can identify unique patterns in brain activity, the researchers were able to discriminate between the different sounds being processed in early visual cortex activity.

A second experiment revealed even imagined images, in the absence of both sight and sound, evoked activity in the early visual cortex.

Lars Muckli said: “This research enhances our basic understanding of how interconnected different regions of the brain are. The early visual cortex hasn’t previously been known to process auditory information, and while there is some anatomical evidence of interconnectedness in monkeys, our study is the first to clearly show a relationship in humans.

“In future we will test how this auditory information supports visual processing, but the assumption is it provides predictions to help the visual system to focus on surprising events which would confer a survival advantage.

“This might provide insights into mental health conditions such as schizophrenia or autism and help us understand how sensory perceptions differ in these individuals.”

Children with profound deafness who receive a cochlear implant had as much as five times the risk of having delays in areas of working memory, controlled attention, planning and conceptual learning as children with normal hearing, according to Indiana University research published May 22 in the Journal of the American Medical Association Otolaryngology—Head and Neck Surgery.

The authors evaluated 73 children implanted before age 7 and 78 children with normal hearing to determine the risk of deficits in executive functioning behaviors in everyday life.

Executive functioning, a set of mental processes involved in regulating and directing thinking and behavior, is important for focusing and attaining goals in daily life. All children in the study had average to above-average IQ scores. The results, reported in “Neurocognitive Risk in Children With Cochlear Implants,” are the first from a large-scale study to compare real-world executive functioning behavior in children with cochlear implants and those with normal hearing.

A cochlear implant device consists of an external component that processes sound into electrical signals that are sent to an internal receiver and electrodes that stimulate the auditory nerve. Although the device restores the ability to perceive many sounds to children who are born deaf, some details and nuances of hearing are lost in the process.

First author William Kronenberger, Ph.D., professor of clinical psychology in psychiatry at the IU School of Medicine and a specialist in neurocognitive and executive function testing, said that delays in executive functioning have been commonly reported by parents and others who work with children with cochlear implants. Based on these observations, his group sought to evaluate whether elevated risks of delays in executive functioning in children with cochlear implants exist, and what components of executive functioning were affected.

"In this study, about one-third to one-half of children with cochlear implants were found to be at-risk for delays in areas of parent-rated executive functioning such as concept formation, memory, controlled attention and planning. This rate was 2 to 5 times greater than that seen in normal-hearing children," reported Dr. Kronenberger, who also is co-chief of the ADHD-Disruptive Behavior Disorders Clinic and directs the psychology testing clinic at Riley Hospital for Children at IU Health.

"This is really innovative work," said co-author David B. Pisoni, Ph.D., director of the Speech Research Laboratory in the IU Department of Psychological and Brain Sciences. "Almost no one has looked at these issues in these children. Most audiologists, neuro-otologists, surgeons and speech-language pathologists — the people who work in this field — focus on the hearing deficit as a medical condition and have been less focused on the important discoveries in developmental science and cognitive neuroscience." Dr. Pisoni also is a Chancellors’ Professor of Psychological and Brain Sciences at IU Bloomington.

Richard Miyamoto, M.D., chair of the IU School of Medicine Department of Otolaryngology-Head and Neck Surgery and a pioneer in the field of cochlear implantation in children and adults, said this finding augments other research on interventions to help children with cochlear implants perform at a level similar to children without hearing deficits.

"The ultimate goal of our department’s research with cochlear implants has always been to influence higher-level neurocognitive functioning," Dr. Miyamoto said. "Much of the success we have seen to date clearly relates to the brain’s ability to process an incomplete signal. The current research will further assist in identifying gaps in our knowledge."

One possible answer may lie in earlier implantation, Dr. Miyamoto said. The age at which children are implanted has been steadily decreasing, which has produced significant improvement in spoken language outcomes. Research shows the early implantation is related to better outcomes in speech and understanding, and it is reasonable to believe that there may be less of a deficit in executive functioning with earlier implantation, said Dr. Miyamoto, who is the Arilla Spence DeVault Professor of Otolaryngology-Head and Neck Surgery and medical director of audiology and speech language pathology at the IU School of Medicine.

Preschoolers in the IU study were implanted at an average age of 18 months, and they had fewer executive function delays than school-age children who were implanted 10 months later, at an average age of 28 months. 

Children in the study were divided into two age groups: preschool (3 to 5 years) and school-age (7 to17 years). Using an established rating scale, parents rated executive function in everyday life for children with cochlear implants and for the control group with normal hearing.

"We compared parent ratings and looked at the percentage of children in each group who scored above a cut-off value that indicates at least a mild delay in executive functioning," Dr. Kronenberger said. "In the critical areas of controlled attention, working memory, planning and solving new problems, about 30 to 45 percent of the children with cochlear implants scored above the cut-off value, compared to about 15 percent or less of the children in the normal-hearing sample."

Dr. Kronenberger said the research also shows that many children develop average or better executive functioning skills after cochlear implantation.

"These results show that half or more of our group with cochlear implants did not have significant delays in executive functioning," Dr. Kronenberger said. "Cochlear implants produce remarkable gains in spoken language and other neurocognitive skills, but there is a certain amount of learning and catch-up that needs to take place with children who have experienced a hearing loss prior to cochlear implantation. So far, most of the interventions to help with this learning have focused on speech and language. Our findings show a need to identify and help some children in certain domains of executive functioning as well."

"We are now looking for early markers in children who are at risk before they get implants," Dr. Pisoni said. "It will be beneficial to identify as early as possible which children might be at risk for poor outcomes, and we need to understand the variability in the outcome and what can be done about it."

Approximately one third of all brain aneurysms rupture during a patient’s lifetime, resulting in a brain haemorrhage. A recent Finnish study demonstrates that, unlike what was previously assumed, the size of the aneurysm does not significantly impact the risk of rupture.

(Image credit: Miikka Korja)

The new Finnish study established that approximately one third of all aneurysms and up to one fourth of small aneurysms will rupture during a patient’s lifetime. The lifetime risk for rupture of a brain aneurysm depends heavily on the patient’s overall load of risk factors.

The risk of rupture is particularly high for female smokers with brain aneurysms of seven millimetres or more in diameter.

What surprised the researchers most was that the size of an aneurysm had little impact on its risk for rupture, particularly for men, despite a previously presumed correlation. In addition, the risk of rupture among non-smoking men was exceptionally low.

This is not to say that aneurysms in non-smoking men never rupture, but that the risk is much lower than we previously thought. This means treating every unruptured aneurysm may be unnecessary if one is discovered in a non-smoking man with low blood pressure, says Docent Seppo Juvela, University of Helsinki.

The study, published in Stroke 22nd May, is unique in that it monitored aneurysm patients over their entire lifetimes, whereas typical follow-up studies last only between one and five years in duration. The study is also exceptionally broad in scope.

It is unlikely that another similar, non-selected lifetime follow-up study on aneurysm patients will ever be conducted again, Juvela states.

Current care practices are based largely on the results of previous, shorter studies. Such studies have shown that the size of the aneurysm is the most significant factor predicting its risk for rupture. Consequently, small aneurysms have often been left untreated.

It is difficult to conduct reliable epidemiological research in brain aneurysms. The past 10–15 years have seen a distortion in the field due to a very limited group of researchers determining the direction for research. Now the situation is clearly changing, and clinically reasonable, population-based studies using non-selected data are on the rise again, states Docent Miikka Korja of the HUCS neurosurgery clinic.

Blocking a pain receptor in mice not only extends their lifespan, it also gives them a more youthful metabolism, including an improved insulin response that allows them to deal better with high blood sugar.

"We think that blocking this pain receptor and pathway could be very, very useful not only for relieving pain, but for improving lifespan and metabolic health, and in particular for treating diabetes and obesity in humans," said Andrew Dillin, a professor of molecular and cell biology at the University of California, Berkeley, and senior author of a new paper describing these results. "As humans age they report a higher incidence of pain, suggesting that pain might drive the aging process."

The “hot” compound in chili peppers, capsaicin, is already known to activate this pain receptor, called TRPV1 (transient receptor potential cation channel subfamily V member 1). In fact, TRPV1 is often called the capsaicin receptor. Constant activation of the receptor on a nerve cell results in death of the neuron, mimicking loss of TRPV1, which could explain why diets rich in capsaicin have been linked to a lower incidence of diabetes and metabolic problems in humans.

More relevant therapeutically, however, is an anti-migraine drug already on the market that inhibits a protein called CGRP that is triggered by TRPV1, producing an effect similar to that caused by blocking TRPV1. Dillin showed that giving this drug to older mice restored their metabolic health to that of younger mice.

"Our findings suggest that pharmacological manipulation of TRPV1 and CGRP may improve metabolic health and longevity," said Dillin, who is a Howard Hughes Medical Institute investigator and the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research. "Alternatively, chronic ingestion of compounds that affect TRPV1 might help prevent metabolic decline with age and lead to increased longevity in humans."

Dillin and his colleagues at UC Berkeley and The Salk Institute for Biological Studies in La Jolla, Calif., will publish their results in the May 22 issue of the journal Cell.

Pain and obesity

TRPV1 is a receptor found in the skin, nerves and joints that reacts to extremely high temperatures and other painful stimuli. The receptor is also found in nerve fibers that contact the pancreas, where it stimulates the release of substances that cause inflammation or, like CGRP (calcitonin gene-related peptide), prevent insulin release. Insulin promotes the uptake of sugar from the blood and storage in the body’s tissue, including fat.

Past research has shown that mice lacking TRPV1 are protected against diet-induced obesity, suggesting that this receptor plays a role in metabolism. Disrupting sensory perception also increases longevity in worms and flies. But until now, it was not known whether sensory perception also affects aging in mammals.

Dillin and his team have now found that mice genetically manipulated to lack TRPV1 receptors lived, on average, nearly four months – or about 14 percent – longer than normal mice. The TRPV1-deficient mice also showed signs of a youthful metabolism late in life, due to low levels of CGRP — a molecule that blocks insulin release resulting in increased blood glucose levels and thus could contribute to the development of type 2 diabetes. Throughout aging, these mice showed improved ability to quickly clear sugar from the blood as well as signs that they could burn more calories without increasing exercise levels.

Moreover, old mice treated with the anti-migraine drug, which inhibits the activity of CGRP receptors, showed a more youthful metabolic profile than untreated old mice.

UC Berkeley and The Salk Institute filed a patent May 16 on the technology described in the Cell paper. Dillin plans to continue his studies of the effects of TRPV1 and CGRP blockers on mice and, if possible, humans.

Learning can only occur if certain neuronal “brakes” are released. As the group led by Andreas Lüthi at the Friedrich Miescher Institute for Biomedical Research has now discovered, learning processes in the brain are dynamically regulated by various types of interneurons. The new connections essential for learning can only be established if inhibitory inputs from interneurons are reduced at the right moment. These findings have now been published in Nature.

Image caption: Example of a dendrite of a principal neuron (white) and synaptic contacts (yellow arrowheads) from SOM1 interneurons.

For some years, most neurobiologists studying learning processes have assumed that the new connections required for learning can only be established and ultimately reinforced if certain neuronal “brakes” are released – a process known as disinhibition. It has also been supposed for some time that various types of interneurons could be involved in disinhibition. Interneurons are nerve cells that surround and – via their connections – inhibit the activity of principal neurons. It has not been clear, however, whether these cell types actually play a role in disinhibition and how they control learning.

Andreas Lüthi and his group at the Friedrich Miescher Institute for Biomedical Research have now demonstrated for the first time how a learning process is dynamically regulated by specific types of interneurons.

In Lüthi’s experiments, mice were trained to associate a sound with an unpleasant stimulus, so that the animals subsequently knew what would happen when they heard the auditory cue. The researchers showed that, during the learning process, the sound stimulus released a brake in some of the principal neurons. More precisely, it induced the activation of parvalbumin-positive (PV+) interneurons, leading indirectly – via somatostatin-positive (SOM+) interneurons – to disinhibition of the principal neurons. The latter thus became receptive to further sensory inputs. If this was immediately followed by the unpleasant stimulus, then another brake was released. Once again, PV+ interneurons were involved, but this time the principal neurons were directly disinhibited. Steffen Wolff, a postdoc in Lüthi’s group and first author of the publication, explains: “The principal neurons temporarily reached a level of activation enabling neuronal connections to be reinforced in such a way that the animal could learn the association between the sound and the unpleasant stimulus.”

Lüthi comments: “This is the first time we’ve been able to identify so clearly the function of defined interneurons in a learning process, and to show how successive disinhibition can enable this process. We assume that interneurons disinhibit the principal neurons in a highly dynamic manner. They integrate, as it were, the state of numerous different neural networks, activated for example by sensory input, earlier experiences or emotional states, and thus permit or prevent learning. I think these findings are also of interest in the context of conditions where learning processes are impaired or dysfunctional, as in the case of anxiety disorders.”

Duke University researchers have found an antibody that simultaneously blocks the sensations of pain and itching in studies with mice.

The new antibody works by targeting the voltage-sensitive sodium channels in the cell membrane of neurons. The results appear online on May 22 in Cell.

Voltage-sensitive sodium channels control the flow of sodium ions through the neuron’s membrane. These channels open and close by responding to the electric current or action potential of the cells. One particular type of sodium channel, called the Nav1.7 subtype, is responsible for sensing pain.

Mutations in the human gene encoding the Nav1.7 sodium channel can lead to either the inability to sense pain or pain hypersensitivity. Interestingly, these mutations do not affect other sensations such as touch or temperature. Hence, the Nav1.7 sodium channel might be a very specific target for treating pain disorders without perturbing the patients’ ability to feel other sensations.

"Originally, I was interested in isolating these sodium channels from cells to study their structure," said Seok-Yong Lee, assistant professor of biochemistry in the Duke University Medical School and principal investigator of the study. He designed antibodies that would capture the sodium channels so that he could study them. "But then I thought, what if I could make an antibody that interferes with the channel function?"

The team first tested the antibody in cultured cells engineered to express the Nav1.7 sodium channel. They found that the antibody can bind to the channel and stabilize its closed state.

"The channel is off when it is closed," Lee explained. "Since the antibody stabilizes the closed state, the channel becomes less sensitive to pain." If this held true in live animals, then the animals would also be less sensitive to pain.

To test this idea, Lee sought the help of Ru-Rong Ji, professor of anesthesiology and neurobiology, who is an expert in the study of pain and itch sensation. Using laboratory mouse models of inflammatory and neuropathic pain, they showed that the antibody can target the Nav1.7 channel and reduce the pain sensation in these mice. More importantly, mice receiving the treatment did not show signs of physical dependence or enhanced tolerance toward the antibody.

"Pain and itch are distinct sensations, and pain is often known to suppress itch", said Ji.
The team found that the antibody can also relieve acute and chronic itch in mouse models, making them the first to discover the role of Nav1.7 in transmitting the itch sensation.

"Now we have a compound that can potentially treat both pain and itch at the same time," said Lee. Both of these symptoms are common in allergic contact dermatitis, which affects more than 10 million patients a year in the United States alone.

The team is pursuing a patent for the antibody.

"We hope our discovery will garner interest from pharmaceutical companies that can help us expand our studies into clinical trials," Lee said. Their goal is to develop a safer treatment for pain and itch as an alternative to opioids, which often cause addiction and other detrimental side effects.

Vivid hallucinations experienced by people with sight loss last far longer and have more serious consequences than previously thought, according to new research from King’s College London and the Macular Society. 

The study is the largest survey of the phenomenon, known as Charles Bonnet Syndrome, and documented the experiences of 492 visually impaired people who had experienced visual hallucinations. The findings, published in the British Journal of Ophthalmology, show there is a serious discrepancy between medical opinion and the realities of the condition.

Charles Bonnet Syndrome is widely considered by the medical profession to be benign and short-lived. However, the new research shows that 80% of respondents had hallucinations for five years or more and 32% found them predominantly unpleasant, distressing and negative. 

The study described this group of people as having “negative outcome Charles Bonnet Syndrome”. The group was more likely to have frequent, fear inducing, longer duration hallucinations, which affected daily activities. They were more likely to attribute hallucinations to serious mental illness and were less likely to have been warned about the possibility of hallucinations before they started. 

Of respondents, 38% regarded their hallucinations as startling, terrifying or frightening when they first occurred and 46% said hallucinations had an effect on their ability to complete daily tasks. 36% of people who discussed the issue with a medical professional said the professional was “unsure or did not know” about the diagnosis.

Dr Dominic ffytche, who led the research at the Institute of Psychiatry at King’s, says:  “Charles Bonnet Syndrome has been traditionally thought of as benign. Indeed, it has been questioned whether it should even be considered a medical condition given it does not cause problems and goes away by itself. The results of our survey paint a very different picture.

“With no specific treatments for Charles Bonnet Syndrome, the survey highlights the importance of raising awareness to reduce the distress it causes, particularly before symptoms start. All people with Charles Bonnet Syndrome are relieved or reassured to find out about the cause of their hallucinations and our evidence shows the knowledge may help reduce negative outcome.”

People with macular disease are particularly prone to Charles Bonnet hallucinations. They are thought to be a reaction of the brain to the loss of visual stimulation. More than half of people with severe sight loss experience them but many do not tell others for fear they will be thought to have a serious mental illness. 

Age-related macular (AMD) degeneration affects the central vision and is the most common cause of sight loss in the UK. Nearly 600,000 people have late-stage AMD today and more people will become affected as our population ages. Around half will have hallucinations at some stage. 

Tony Rucinski, Chief Executive, the Macular Society, said: “It is essential that people affected by sight loss are given information about Charles Bonnet Syndrome at diagnosis or as soon after as possible. 

“Losing your sight is bad enough without the fear that you have something like dementia as well. We need medical professionals to recognise the seriousness of Charles Bonnet Syndrome and ensure that people don’t suffer unnecessarily. More research is also needed to investigate Charles Bonnet Syndrome and possible ways of reducing its impact.”

Dr ffytche is also leading a large NIHR funded research programme on visual hallucinations to develop a much-needed evidence base to inform NHS practice in managing and treating the symptoms. 

Most schools across the United States provide simple vision tests to their students—not to prescribe glasses, but to identify potential problems and recommend a trip to the optometrist. Researchers are now on the cusp of providing the same kind of service for autism.

Researchers at Duke University have developed software that tracks and records infants’ activity during videotaped autism screening tests. Their results show that the program is as good at spotting behavioral markers of autism as experts giving the test themselves, and better than non-expert medical clinicians and students in training.

The results appear online in the journal Autism Research and Treatment.

“We’re not trying to replace the experts,” said Jordan Hashemi, a graduate student in computer and electrical engineering at Duke. “We’re trying to transfer the knowledge of the relatively few autism experts available into classrooms and homes across the country. We want to give people tools they don’t currently have, because research has shown that early intervention can greatly impact the severity of the symptoms common in autism spectrum disorders.”

The study focused on three behavioral tests that can help identify autism in very young children.

In one test, an infant’s attention is drawn to a toy being shaken on the left side and then redirected to a toy being shaken on the right side. Clinicians count how long it takes for the child’s attention to shift in response to the changing stimulus. The second test passes a toy across the infant’s field of view and looks for any delay in the child tracking its motion. In the last test, a clinician rolls a ball to a child and looks for eye contact afterward—a sign of the child’s engagement with their play partner.

In all of the tests, the person administering them isn’t just controlling the stimulus, he or she is also counting how long it takes for the child to react—an imprecise science at best. The new program allows testers to forget about taking measurements while also providing more accuracy, recording reaction times down to tenths of a second.

“The great benefit of the video and software is for general practitioners who do not have the trained eye to look for subtle early warning signs of autism,” said Amy Esler, an assistant professor of pediatrics and autism researcher at the University of Minnesota, who participated in some of the trials highlighted in the paper.

“The software has the potential to automatically analyze a child’s eye gaze, walking patterns or motor behaviors for signs that are distinct from typical development,” Esler said. “These signs would signal to doctors that they need to refer a family to a specialist for a more detailed evaluation.”

According to Hashemi and his adviser, Guillermo Sapiro, professor of electrical and computer engineering and biomedical engineering at Duke, because the program is non-invasive, it could be useful immediately in homes and clinics. Neither, however, expects it to become widely used—not because clinicians, teachers and parents aren’t willing, but because the researchers are working on an even more practical solution.

Later this year, the Duke team (which includes students and faculty from engineering and psychiatry) plans to test a new tablet application that could do away with the need for a person to administer any tests at all. The program would watch for physical and facial responses to visual cues played on the screen, analyze the data and automatically report any potential red flags. Any parent, teacher or clinician would simply need to download the app and sit their child down in front of it for a few minutes.

The efforts are part of the Information Initiative at Duke, which connects researchers from disparate fields to experts in computer programming to help analyze large data sets.

“We’re currently working with autism experts at Duke Medicine to determine what sorts of easy tests could be used on just a computer or tablet screen to spot any potential concerns,” said Sapiro. “The goal is to mimic the same sorts of social interactions that the tests with the toys and balls measure, but without the toys and balls. The research has shown that the earlier autism can be spotted, the more beneficial intervention can be. And we want to provide everyone in the world with the ability to spot those signs as early as possible.”

A type of retina cell plays a more critical role in vision than previously known, a team led by Johns Hopkins University researchers has discovered.

Working with mice, the scientists found that the ipRGCs – an atypical type of photoreceptor in the retina – help detect contrast between light and dark, a crucial element in the formation of visual images. The key to the discovery is the fact that the cells express melanopsin, a type of photopigment that undergoes a chemical change when it absorbs light.

“We are quite excited that melanopsin signaling contributes to vision even in the presence of functional rods and cones,” postdoctoral fellow Tiffany M. Schmidt said.

Schmidt is lead author of a recently published study in the journal Neuron. The senior author is Samer Hattar, associate professor of biology in the university’s Krieger School of Arts and Sciences. Their findings have implications for future studies of blindness or impaired vision.

Rods and cones are the most well-known photoreceptors in the retina, activating in different light environments. Rods, of which there are about 120 million in the human eye, are highly sensitive to light and turn on in dim or low-light environments. Meanwhile the 6 million to 7 million cones in the eye are less sensitive to light; they drive vision in brighter light conditions and are essential for color detection.

Rods and cones were thought to be the only light-sensing photoreceptors in the retina until about a decade ago when scientists discovered a third type of retinal photoreceptor – the ipRGC, or intrinsically photosensitive retinal ganglion cell – that contains melanopsin. Those cells were thought to be needed exclusively for detecting light for non-image-dependent functions, for example, to control synchronization of our internal biological clocks to daytime and the constriction of our pupils in response to light.

“Rods and cones were thought to mediate vision and ipRGCs were thought to mediate these simple light-detecting functions that happen outside of conscious perception,” Schmidt said. “But our experiments revealed that ipRGCs influence a greater diversity of behaviors than was previously known and actually contribute to an important aspect of image-forming vision, namely contrast detection.”

The Johns Hopkins team along with other scientists conducted several experiments with mice and found that when melanopin was present in the retinal ganglion cells, the mice were better able to see contrast in a Y-shaped maze, known as the visual water task test. In the test, mice are trained to associate a pattern with a hidden platform that allows them to escape the water. Mice that had the melanopsin gene intact had higher contrast sensitivity than mice that lack the gene.

“Melanopsin signaling is essential for full contrast sensitivity in mouse visual functions,” said Hattar. “The ipRGCs and melanopsin determine the threshold for detecting edges in the visual scene, which means that visual functions that were thought to be solely mediated by rods and cones are now influenced by this system. The next step is to determine if melanopsin plays a similar role in the human retina for image-forming visual functions.”

A precise rhythm of electrical impulses transmitted from cells in the inner ear coaches the brain how to hear, according to a new study led by researchers at the University of Pittsburgh School of Medicine. They report the first evidence of this developmental process today in the online version of Neuron.

The ear generates spontaneous electrical activity to trigger a response in the brain before hearing actually begins, said senior investigator Karl Kandler, Ph.D., professor of otolaryngology and neurobiology, Pitt School of Medicine. These patterned bursts start at inner hair cells in the cochlea, which is part of the inner ear, and travel along the auditory nerve to the brain.

"It’s long been speculated that these impulses are intended to ‘wire’ the brain auditory centers," he said. "Until now, however, no one has been able to provide experimental evidence to support this concept."

To map neural connectivity, Dr. Kandler’s team prepared sections of a mouse brain containing the auditory pathways in a chemical that is inert until UV light hits it. Then, they pulsed laser light at a neuron, making the chemical active, which excites the nerve cells to generate an electrical impulse. They then tracked the spread of the impulse to adjacent cells, allowing them to map the network a neuron at a time.

All mice are born unable to hear, a sense that develops around two weeks after birth. But even before hearing starts, the ear produces rhythmic bursts of electrical activity which causes a broad reaction in the brain’s auditory processing centers. As the beat goes on, the brain organizes itself, pruning unneeded connections and strengthening others. To investigate whether the beat is indeed important for this reorganization, the team used genetically engineered mice that lack a key receptor on the inner hair cells which causes them to change their beat.

"In normal mice, the wiring diagram of the brain gets sharper and more efficient over time and they begin to hear," Dr. Kandler said. "But this doesn’t happen when the inner ear beats in a different rhythm, which means the brain isn’t getting the instructions it needs to wire itself correctly. We have evidence that these mice can detect sound, but they have problems perceiving the pitch of sounds."

In humans, such subtle hearing deficits are associated with Central Auditory-Processing Disorders (CAPD), difficulty processing the meaning of sound. About 2 to 3 percent of children are affected with CAPD and these children often have speech and language disorders or delays, and learning disabilities such as dyslexia. In contrast to causes of hearing impairments due to ear deficits, the causes underlying CAPD have remained obscure.

"Our findings suggest that an abnormal rhythm of electrical impulses early in life may be an important contributing factor in the development of CAPD. More research is needed to find out whether this also holds true for humans, but our results point to a new direction that is worth following up," Dr. Kandler said.

How does a DJ mix two songs to make the beat seem common to both tracks? A successful DJ makes the transition between tracks appear seamless while a bad mix is instantly noticeable and results in a ‘galloping horses’ effect that disrupts the dancing of the crowd. How accurate does beat mixing need to be to enhance, rather than disrupt perceived rhythm?

In a study published today (Wednesday 21 May 2014) in the journal Proceedings of the Royal Society B, scientists from the Universities of Birmingham and Cambridge present a new model that predicts whether or not two tracks will seem to share a common beat. This model also promises to help us understand how groups of people often start moving in synchrony, for example, football fans bouncing up and down at a stadium, or crowds falling into step when walking over a bridge.

‘We found that the time window in which two beat lines are heard as one isn’t fixed - it changes according to the statistical properties of each beat line, including how consistent or predictable they are,’ said Dr Mark Elliott, lead researcher on the study from the University of Birmingham’s School of Psychology. ‘For example, with two very consistent beat lines we only allow a very small time difference between them before we consider them to be separate. By analogy, given that DJs tend to play songs with a strong bass beat, they need to be very accurate in aligning the beats of the two songs if they are to be heard as one so as not to disrupt the flow of dancing. Our model and experiments reveal the timing properties of separate beat lines that determine whether they will be heard as one or two.’

Dr Elliott and his colleagues tested their model using a laboratory task that involved people tapping their fingers in time with two similar beat lines played simultaneously, one defined by high pitched tones, the other low pitched tones. The concurrency of the lines was varied such that the high and low pitched tones were played close together in time or far apart. Furthermore, the separation between the high-low tones was either consistent or randomly varied across the experiment. The researchers determined when people change from tapping along to a single beat formed from the two tones or targeted one of the tones while ignoring the other. They found that the time separation between tones that was required for people to judge them as distinct beats varied according to the consistency of the timings between the tones. Subsequently, these judgments influenced the timing of their movements.

Dr Elliott added, ‘People develop an expectation of when in time the next beat will occur. In defining the beat, they use the separation and consistency of the beat lines to determine whether the two tones should be combined together or whether just one tone should be attended to and the other ignored. Our model was able to predict the timing of participants’ movements based on the timing statistics of the tones we presented. Therefore, it not only allows us to calculate whether two beats will be heard as one, but also means we can predict the subtle effects the perception of an underlying rhythm can have on the movements people make to keep in synchrony with more complex beats.’

Dr Elliott is currently involved in a study, in collaboration with the University of Leeds, investigating the timing accuracy of movements in professional DJs compared to classical musicians and non-musicians. In addition, the findings of the current research are being applied to other areas: ‘We are currently investigating how spontaneous synchronisation of movements occurs within crowds. For example, in football stadiums the crowd sometimes starts to bounce up and down together. When the crowd moves together like this, it can create problems with structural vibration. Working with vibration engineers from the Universities of Sheffield and Exeter, we are applying our models to understand how such crowd dynamics might arise from the way each person adjusts their timing in relation to timing information from the people around them.’

In surprise findings, scientists at The Scripps Research Institute (TSRI) have discovered that a protein with a propensity to form harmful aggregates in the body when produced in the liver protects against Alzheimer’s disease aggregates when it is produced in the brain. The results suggest that drugs that can boost the protein’s production specifically in neurons could one day help ward off Alzheimer’s disease.

“This result was completely unexpected when we started this research,” said TSRI Professor Joel N. Buxbaum, MD. “But now we realize that it could indicate a new approach for Alzheimer’s prevention and therapy.”

Buxbaum and members of his laboratory report their latest finding in the May 21, 2014 issue of the Journal of Neuroscience.

First Hints

The study centers on transthyretin (TTR), a protein that is known to function as a transporter, carrying the thyroid hormone thyroxine and vitamin A through the bloodstream and cerebrospinal fluid. To do this job, it must come together in a four subunit structure called a tetramer. Certain factors such as old age and TTR gene mutations can make these tetramers prone to fall apart and misfold into tough aggregates called amyloids. TTR amyloids accumulate in the heart, kidneys, peripheral nerves and other tissues and cause life-shortening diseases including familial amyloid polyneuropathy and senile systemic (cardiac) amyloidosis.

Starting in the mid 1990s, however, reports from several laboratories hinted that TTR in the brain might protect against other amyloids—particularly the Alzheimer’s-associated protein amyloid beta. In test tube experiments, TTR seemed able to grab hold of amyloid beta and prevent it from aggregating. In transgenic “Alzheimer’s mice,” which overproduce amyloid beta, TTR expression was increased in affected brain tissue, compared to control mice, as one would expect from a protective response.

“I didn’t really believe those reports at the time,” Buxbaum said.

But he was working on TTR amyloidoses and had the tools needed to investigate the issue genetically. He and his colleagues at TSRI did those experiments, and found, to their surprise, that overproducing TTR in “Alzheimer’s mice” did indeed protect the animals: it reduced their memory deficits as well as the accumulations of amyloid beta aggregates in their brains. Since that 2008 study, Buxbaum and colleagues have gone on to publish additional experiments examining the mechanism of the protection including two last year, in collaboration with the Wright and Kelly laboratories at TSRI and Roberta Cascella in Florence, that showed how TTR tetramers can bind to amyloid beta and inhibit the latter from forming the more harmful types of aggregate.

Context Is Everything

In the latest study, Buxbaum and his team, including lead authors Xin Wang and Francesca Cattaneo, at the time both postdoctoral fellows in the Buxbaum laboratory, found another key piece of evidence for TTR’s protective role.

TTR is known to be produced principally in the liver and in the parts of the brain where cerebrospinal fluid is made. Prior studies in the Buxbaum group found evidence that TTR can also be produced in neurons, albeit at low levels. Still, it has remained unclear how TTR production, in neurons or in other cells, would be increased in response to amyloid beta accumulation.

To start, the team analyzed a segment of DNA near the TTR gene called the promoter region, where, in principle, special DNA-binding proteins called transcription factors could increase TTR gene activity. The analysis suggested that Heat Shock Factor 1 (HSF1), known as a master switch for a broad protective response against certain types of cellular stress, could bind to the TTR gene’s promoter.

Further experiments showed that HSF1 does indeed bind to this region and that two known stimulators of HSF1—heat and a compound called celastrol—also boost HSF1 binding to the TTR promoter, in addition to boosting TTR production. Remarkably, though, the researchers found that HSF1’s dialing-up of TTR production seemed to occur only in neuronal-type cells, not in liver cells where most TTR is produced.

In fact, the researchers found that in liver cells the HSF1 response somehow brought about a modest decrease in TTR production. That result may seem puzzling, but it is consistent with the idea that liver-cell TTR, which is produced at 15 to 20 times the levels of neuronal TTR, is more likely to be hazardous than protective.

Using genetic techniques to force cells to overproduce HSF1, the researchers again saw jumps in TTR gene activity and protein production, but only in neuronal cells. In liver cells TTR activity rose when HSF1 was blocked, suggesting that HSF1 normally helps keep a lid on liver TTR production.

“It’s becoming more and more evident in biology that the same molecule can do very different things in different contexts,” Buxbaum said.

To underscore the relevance to Alzheimer’s, his team examined neurons from the hippocampus brain region in ordinary lab mice and in amyloid-beta-overproducing Alzheimer’s mice. Again consistent with the concept of TTR as protective in neurons, they found that the frequency of HSF1 binding to the TTR gene promoter, and the numbers of resulting TTR gene transcripts, were both doubled in the Alzheimer’s mice compared to the ordinary lab mice.

Buxbaum and his colleagues plan to do further research on this apparent TTR-mediated stress response in neurons to determine, among other things, precisely how Alzheimer’s-associated amyloid beta switches it on. But they have already begun to think about developing a small molecule compound, suitable for delivery in a pill, that at least modestly boosts HSF1 activity and/or TTR production in neurons—and thus might prevent or delay Alzheimer’s dementia.