Innovative neurology text includes patient videos

Practical Neurology Visual Review, a powerful educational tool for mastering the clinical practice of neurologic diagnosis, is now available in a fully revised and updated Second Editon.

Co-authors are neurologists Jose Biller, MD, of Loyola University Chicago Stritch School of Medicine and Alberto J. Espay, MD, of the University of Cincinnati.

The book previously was known as Practical Neurology DVD Review. It includes online videos of 131 real-world scenarios, and more than 370 multiple-choice questions. QR codes in the book allow easy access to videos via smart phone scanning.

Neurological problems are increasing due to the growing elderly population. But current assessment formats for the education of resident doctors, fellows and medical students underemphasize bedside teaching, Biller and Espay write in the introduction. “Faculty members strained by the pressures of many competing demands may not be in a position to oversee trainees performing physical examinations during their training.”

Practical Neurology Visual Review provides new venues for teaching and learning the essentials of neurology. The videos show patients with both common and unusual neurological problems, ranging from very easy to extremely challenging. The videos are used to teach five fundamental principles of bedside neurology: description and localization of findings, differential diagnosis, evaluation, management and counseling. Each clinical vignette is accompanied by a succinct written discussion.

"This audiovisual electronic teaching format may be somewhat unorthodox," Biller and Espay write. "However, it is actually more effective in its approach because the technology lends itself to displaying the skills necessary for a physician to form a patient’s neurological diagnosis."

Human brain research made easier by database

Researchers will be able to access samples from more than 7,000 donated human brains to help study major brain diseases, thanks to a new on-line database, launched by the Medical Research Council (MRC) today.

The UK Brain Banks Network database speeds up access to donated brain samples held across 10 brain banks in the UK and allows researchers studying Multiple Sclerosis, Alzheimer’s, Parkinson’s and a range of other neurodegenerative and developmental diseases to track down human tissue samples for their work.

Thanks to a unique collaboration between the MRC and five leading charities, the database will help scientists from academia and industry investigate the underlying causes of major brain diseases and understand how they take hold in our bodies.

Although scientists can model diseases in the lab, to fully understand dementia and other brain-related disorders they need to study human brain tissue. A lot of research relies on donated brain tissue stored in brain banks across the UK. Until today, researchers had to apply to each brain bank in turn to find out if they held the samples they needed and find the ‘control’ samples (donated brains free from disease) for comparison – a long and drawn out process. Now samples can be found with the click of a button from one source.

Professor James Ironside, Director of the MRC UK Brain Banks Network, said:

“The database is the result of four years of painstaking planning and data analysis by very dedicated people. It will enable quick and easy access for researchers who are already working on neurological or psychiatric disease (perhaps in animal models or cells) and would like to translate their findings into human tissue and is very useful for those who are planning a grant application. The brain banks have already been given ethical approval, cutting out the need for researchers to go through a separate ethics application.

We must remember that vital research would not be possible without the generosity of those individuals who donate their brains to medical research. We’re working hard to make sure that the access for researchers studying brain samples is much easier. The next step is to improve the systems for those wishing to donate their brain to medical research.”

Five leading charities helped to supply data for the database; the MS Society, Parkinson’s UK, Alzheimer’s Society, Alzheimer’s Research UK and Autistica.

For more information about the database visit: http://www.mrc.ac.uk/brainbanksnetwork

Reward linked to image is enough to activate brain’s visual cortex

Once rhesus monkeys learn to associate a picture with a reward, the reward by itself becomes enough to alter the activity in the monkeys’ visual cortex. This finding was made by neurophysiologists Wim Vanduffel and John Arsenault (KU Leuven and Harvard Medical School) and American colleagues using functional brain scans and was published recently in the leading journal Neuron.

Our visual perception is not determined solely by retinal activity. Other factors also influence the processing of visual signals in the brain. “Selective attention is one such factor,” says Professor Wim Vanduffel. “The more attention you pay to a stimulus, the better your visual perception is and the more effective your visual cortex is at processing that stimulus. Another factor is the reward value of a stimulus: when a visual signal becomes associated with a reward, it affects our processing of that visual signal. In this study, we wanted to investigate how a reward influences activity in the visual cortex.”

Pavlov inverted

To do this, the researchers used a variant of Pavlov’s well-known conditioning experiment: “Think of Pavlov giving a dog a treat after ringing a bell. The bell is the stimulus and the food is the reward. Eventually the dogs learned to associate the bell with the food and salivated at the sound of the bell alone. Essentially, Pavlov removed the reward but kept the stimulus. In this study, we removed the stimulus but kept the reward.”

In the study, the rhesus monkeys first encountered images projected on a screen followed by a juice reward (classical conditioning). Later, the monkeys received juice rewards while viewing a blank screen. fMRI brain scans taken during this experiment showed that the visual cortex of the monkeys was activated by being rewarded in the absence of any image.

Importantly, these activations were not spread throughout the whole visual system but were instead confined to the specific brain regions responsible for processing the exact stimulus used earlier during conditioning. This result shows that information about rewards is being sent to the visual cortex to indicate which stimuli have been associated with rewards.

Equally surprising, these reward-only trials were found to strengthen the cue-reward associations. This is more or less the equivalent to giving Pavlov’s dog an extra treat after a conditioning session and noticing the next day that he salivates twice as much as before. More generally, this result suggests that rewards can be associated with stimuli over longer time scales than previously thought.

Dopamine

Why does the visual cortex react selectively in the absence of a visual stimulus on the retina? One potential explanation is dopamine. “Dopamine is a signalling chemical (neurotransmitter) in nerve cells and plays an important role in processing rewards, motivation, and motor functions. Dopamine’s role in reward signalling is the reason some Parkinson’s patients fall into gambling addiction after taking dopamine-increasing drugs. Aware of dopamine’s role in reward, we re-ran our experiments after giving the monkeys a small dose of a drug that blocks dopamine signalling. We found that the activations in the visual cortex were reduced by the dopamine blocker. What’s likely happening here is that a reward signal is being sent to the visual cortex via dopamine,” says Professor Vanduffel.

The study used fMRI (functional Magnetic Resonance Imaging) scans to visualise brain activity. fMRI scans map functional activity in the brain by detecting changes in blood flow. The oxygen content and the amount of blood in a given brain area vary according to the brain activity associated with a given task. In this way, task-specific activity can be tracked.

Multiple Sclerosis research: the thalamus moves into the spotlight

A growing body of research by multiple sclerosis (MS) investigators at the University at Buffalo and international partners is providing powerful new evidence that the brain’s gray matter reflects important changes in the disease that could allow clinicians to diagnose earlier and to better monitor and predict how the disease will progress.

Over the past three years, the UB researchers and their partners around the world, supported by an active fellowship program at UB’s Buffalo Neuroimaging Analysis Center (BNAC), have published journal papers and given presentations demonstrating that the thalamus region, in particular, is key to a host of issues involving MS.

“The thalamus is providing us with a new window on MS,” says Robert Zivadinov, MD, PhD, UB professor of neurology, BNAC director and leader of the research team. “In our recent studies, we have used large datasets to investigate the evolution of atrophy of the thalamus and its association with clinical impairment in MS, starting with the earliest stages of the disease. The location of the thalamus in the brain, its unique function and its vulnerability to changes wrought by the disease make the thalamus a critical barometer of the damage that MS causes to the brain.”

Zivadinov and UB professor of neurology Ralph Benedict discuss the new research in a video.

At the annual meeting of the American Academy of Neurology today, Zivadinov will discuss a study he performed in collaboration with colleagues from Charles University in Prague. The study found that atrophy of the thalamus, determined with MRI, can help identify which patients with clinically isolated syndrome (CIS), a patient’s first episode of MS, are at risk for developing clinically definite MS. Such a tool would be immensely helpful to clinicians, Zivadinov notes.

“This study, which included more than 200 patients, shows that thalamic atrophy is one of the most important predictors of clinically definite MS,” says Dana Horakova, MD, PhD, the principal investigator at Charles University.

“Therefore, based on these findings, we think MRI should be used to determine which patients are at highest risk for a second attack,” explains Zivadinov.

The neuroscience of finding your lost keys

Ever find yourself racking your brain on a Monday morning to remember where you put your car keys?

When you do find those keys, you can thank the hippocampus, a brain region responsible for storing and retrieving memories of different environments-such as that room where your keys were hiding in an unusual spot.

Now, scientists have helped explain how the brain keeps track of the incredibly rich and complex environments people navigate on a daily basis. They discovered how the dentate gyrus, a subregion of the hippocampus, helps keep memories of similar events and environments separate, a finding they reported March 20 in eLife. The findings, which clarify how the brain stores and distinguishes between memories, may also help identify how neurodegenerative diseases, such as Alzheimer’s disease, rob people of these abilities.

"Everyday, we have to remember subtle differences between how things are today, versus how they were yesterday - from where we parked our car to where we left our cellphone," says Fred H. Gage, senior author on the paper and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease at Salk. "We found how the brain makes these distinctions, by storing separate ‘recordings’ of each environment in the dentate gyrus."

The process of taking complex memories and converting them into representations that are less easily confused is known as pattern separation. Computational models of brain function suggest that the dentate gyrus helps us perform pattern separation of memories by activating different groups of neurons when an animal is in different environments.

However, previous laboratory studies found that in fact the same populations of neurons in the dentate gyrus are active in different environments, and that the way the cells distinguished new surroundings was by changing the rate at which they sent electrical impulses. This discrepancy between theoretical predictions and laboratory findings has perplexed neuroscientists and obscured our understanding of memory formation and retrieval.

To explore this mystery more deeply, the Salk scientists compared the functioning of the mouse dentate gyrus and another region of the hippocampus, known as CA1, using laboratory techniques for tracking the activity of neurons at multiple time points.

First, the researchers took mice from their original chamber and placed them in a novel chamber to learn about a new environment (episode 1). Meanwhile, they recorded which hippocampal neurons were active as the animals responded to their new surroundings. Subsequently, the mice were either returned to that same novel chamber to measure memory recall or to a slightly modified chamber to measure discrimination (episode 2). The active neurons in episode 2 were also labeled in order to determine if the neurons activated in episode 1 were used in the same way for recall and for discrimination of small differences between environments.

When the researchers compared the neural activity during the two episodes, they found that the dentate gyrus and CA1 sub-regions functioned differently. In CA1, the same neurons that were active during the initial learning episode were also active when the mice retrieved the memories. In the dentate gyrus, however, distinct groups of cells were active during the learning episodes and retrieval. Also, exposing the mice to two subtly different environments activated two distinct groups of cells in the dentate gyrus.

"This finding supported the predictions of theoretical models that different groups of cells are activated during exposure to similar, but distinct, environments," says Wei Deng, a Salk postdoctoral research and first author on the paper. "This contrasts with the findings of previous laboratory studies, possibly because they looked at different sub-populations of neurons in the dentate gyrus."

The Salk researchers’ findings suggest that recalling a memory-such as the location of missing keys-does not always involve reactivation of the same neurons that were active during encoding. More importantly, the results indicate that the dentate gyrus performs pattern separation by using distinct populations of cells to represent similar but non-identical memories.

The findings help clarify the mechanisms that underpin memory formation and shed light on systems that are disrupted by injuries and diseases of the nervous system.

How Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication

A team including scientists from The Scripps Research Institute (TSRI), the University of North Carolina at Chapel Hill and the Chinese Academy of Sciences has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor. The new findings help explain why some drugs that interact with these receptors have had unexpectedly complex and sometimes harmful effects.

“Understanding the structure-function of these receptors allows us to discover new biology of serotonin signaling and also gives us better ideas about what biological questions to probe in a more intelligent manner,” said TSRI Professor Raymond Stevens, who was a senior investigator for the new research. The studies were published in two papers on March 21, 2013 in Science Express [1 , 2], the advance online version of the journal Science.

Pioneering Important Molecular Structures

Stevens’s laboratory at TSRI has pioneered the development of techniques for determining the 3D atomic structures of cellular receptors—particularly the large receptor class known as G protein-coupled receptors (GPCRs). GPCRs sit in the cell membrane and sense various molecules outside cells. When certain molecules bind to them, the receptor’s respond in a way to transmit a signal inside the cell.

“Because G protein-coupled receptors are the targets of nearly 50 percent of medicines, they are the focus of several major National Institutes of Health (NIH) initiatives,” said Jean Chin of the NIH’s National Institute of General Medical Sciences, which partly funded the work through the Protein Structure Initiative. “These detailed molecular structures of two serotonin receptor subfamilies bound to antimigraines, antipsychotics, antidepressants or appetite suppressants will help us understand how normal cellular signaling is affected by these drugs and will offer a valuable framework for designing safer and more effective medicines.”

In the past several years, using X-ray crystallography, the Stevens laboratory has determined the high-resolution structures of 10 of the most important GPCRs for human health—including the β2 adrenergic receptor, the A2a adenosine receptor (the target of caffeine), HIV related CXCR4 receptor, the pain-mediating nociceptin receptor, S1P1 receptor important for inflammatory diseases, H1 histamine receptor (antihistamine medications) and the D3 dopamine receptor which is involved in mood, motivation and addiction.

Serotonin receptors are no less important. “Nearly all psychiatric drugs affect serotonin receptors to some extent, and these receptors also mediate a host of effects outside the brain, for example on blood coagulation, smooth muscle contraction and heart valve growth,” said Bryan Roth, a collaborator on both studies who is professor of pharmacology at the University of North Carolina (UNC).

Untangling Two Serotonin Receptors

Roth’s laboratory teamed up with Stevens’s as part of the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative. For this project the two labs also worked with the laboratories of Professors Eric Xu and Hualiang Jiang at the Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences. “By collaborating with the Chinese teams we were able to complete a much more thorough study and get the most out of our fundamental structural results,” said Stevens.

In the first of the new studies, co-lead author Chong Wang, a graduate student in the Stevens laboratory, and his colleagues determined the structure of the serotonin receptor subtype 5-HT_1B, the principal target of several drug classes. (5-HT, or 5-hydroxytryptamine, is a technical term for serotonin.) The team produced the 5-HT_1B receptor while it was bound by either ergotamine or dihydroergotamine—two old-line anti-migraine drugs that work in part by activating 5-HT_1B receptors.

With the help of the special fusion protein, nicknamed BRIL (apocytochrome b562RIL), Wang and colleagues were able to stabilize these structures and coax them to line up in a regular ordering known as a crystal. X-ray crystallography revealed, at high resolution, an atomic structure of 5-HT_1B with a main binding pocket and a separate, extended binding pocket.

Harmful Off-Target Effects

In the second study, TSRI graduate student and lead author Daniel Wacker and colleagues used similar techniques to determine the structure of the 5-HT_2B receptor bound to ergotamine. The 5-HT_2B receptor was chiefly of interest because drug developers want to avoid activating it.

“Drugs that are meant to target other serotonin receptors in the brain can have harmful off-target effects on 5-HT_2B receptors, which are found abundantly on heart valves, for example,” said Roth. The weight-loss drug fenfluramine and closely related dexfenfluramine were withdrawn from the US market in 1997 after being linked to heart valve disease. Roth’s laboratory later showed that this side effect was mediated by heart valve 5-HT_2B receptors.

Analyses of the 5-HT_1B and 5-HT_2B receptor structures revealed a subtle difference between them. “Although their main binding pockets look very similar, their extended binding pockets are not as similar—the one for 5-HT_2B is narrower and in a slightly different position,” said Wang.

With the two receptor structures in hand, the Xu and Jiang team simulated the bindings of various drugs. They showed, for example, that anti-migraine drugs called triptans should bind well to 5-HT_1B receptors but poorly to 5-HT_2B receptor structures, in which the extended binding pocket is less accessible. Similarly, the team’s calculations confirmed that fenfluramine’s active metabolite should bind very tightly to the 5-HT_2B receptor.

Delving Deeper

In the second study, the researchers used the 5-HT_2B and 5-HT_1B structural data to better understand a recently discovered GPCR signaling pathway.

When a neurotransmitter such as serotonin binds to its GPCR receptor and triggers the primary, G protein-mediated activation signal, it also usually triggers another signal, often mediated by a protein called β-arrestin. This second signaling cascade may simply have the effect of “arresting” or inhibiting the primary, G protein-mediated signaling. But it can also have other effects on the cell, and although most molecules bind to their target GPCRs in a way that activates these primary and secondary signals equally, others preferentially activate one or the other. “Such functional selectivity, as we call it, adds another layer of complexity to drug effects on GPCRs,” said Roth, a co-senior author of the study.

Roth’s laboratory produced several 5-HT receptor subtypes in test cells, and compared the strength of G-protein and β-arrestin signaling when these receptors were bound by ergotamine or various other drugs, including the ergotamine-derived hallucinogen LSD (lysergic acid diethylamide). Most of the tested drugs showed no bias. However, ergotamine, LSD and some of their relatives turned out to be clearly biased in favor of β-arrestin signaling at the 5-HT_2B receptor. Comparison of the ergotamine-bound 5-HT_2B structure with the ergotamine-bound 5-HT_1B structure revealed the likely reason. “We could see that when ergotamine is bound to the 5-HT_2B receptor it stabilizes the receptor structure in a conformation that interferes with G protein signaling,” said Wacker.

The findings allow scientists to start probing this arrestin-mediated signaling pathway and its downstream effects in a more targeted manner. “These structural data are teaching us to ask better questions about receptor biology,” said Stevens.