(Image caption: Example axial sections of a three-dimensional MPF map (A) obtained from a 63-year old woman with SPMS disease course and results of brain tissue segmentation (B-D). Segmentation masks corresponding to white matter (WM) (B), gray matter (GM) (C), and lesi)

MRI Shows Gray Matter Myelin Loss Strongly Related to MS Disability

People with multiple sclerosis (MS) lose myelin in the gray matter of their brains and the loss is closely correlated with the severity of the disease, according to a new magnetic resonance imaging (MRI) study. Researchers said the findings could have important applications in clinical trials and treatment monitoring. The study appears online in the journal Radiology.

Loss of myelin, the fatty protective sheath around nerve fibers, is a characteristic of MS, an inflammatory disease of the central nervous system that can lead to a variety of serious neurological symptoms and disability. MS is typically considered a disease of the brain’s signal-conducting white matter, where myelin is most abundant, but myelin is also present in smaller amounts in gray matter, the brain’s information processing center that is made up primarily of nerve cell bodies. Though the myelin content in gray matter is small, it is still extremely important to proper function, as it enables protection of thin nerve fibers connecting neighboring areas of the brain cortex, according to Vasily L. Yarnykh, Ph.D., associate professor in the Department of Radiology at University of Washington in Seattle.

“The fact that MS patients lose myelin not only in white but also in gray matter has been proven by earlier post-mortem pathological studies,” he said. “However, the clinical significance of the myelin loss, or demyelination, in gray matter has not been established because of the absence of appropriate imaging methods.”

To learn more about associations between MS and demyelination in both white and gray matter, Dr. Yarnykh and colleagues used a refined MRI technique that provides information on the content of biological macromolecules – molecules present in tissues and composed of a large number of atoms, such as proteins, lipids and carbohydrates. The new method, known as macromolecular proton fraction (MPF) mapping, has been hampered in the past because of the length of time required for data collection, but improvements now allow much faster generation of whole-brain maps that reflect the macromolecular content in tissues.

“The method utilizes a standard MRI scanner and doesn’t require any special hardware—only some software modifications,” Dr. Yarnykh said. “MPF mapping allows quantitative assessment of microscopic demyelination in brain tissues that look normal on clinical images, and is the only existing method able to evaluate the myelin content in gray matter.”

The researchers looked at 30 MS patients, including 18 with relapsing-remitting MS (RRMS), the most common type of MS initially diagnosed, and 12 with the more advanced type of disease known as secondary progressive MS (SPMS). Fourteen healthy control participants were also included in the study. Each participant underwent MRI on a 3-Tesla imager, and the researchers reconstructed 3-D whole-brain MPF maps to look at normal-appearing white matter, gray matter and MS lesions. The researchers further compared the results of their imaging technique with clinical tests characterizing neurological dysfunction in MS patients.

The results showed that MPF was significantly lower in both white and gray matter in RRMS patients compared with healthy controls, and was also significantly reduced in both normal-appearing brain tissues and lesions of SPMS patients compared to RRMS patients with the largest relative decrease in gray matter. MPF in brain tissues of MS patients significantly correlated with clinical disability and the strongest associations were found for gray matter.

“The major finding of the study is that the loss of myelin in gray matter caused by MS in its relative amount is comparable to or even larger than that in white matter,” said Dr. Yarnykh. “Furthermore, gray matter demyelination is much more advanced in patients with secondary-progressive MS, and it is very strongly related to patients’ disability. As such, we believe that information about gray matter myelin damage in MS is of primary clinical relevance.”

The improved technique has potentially important applications for MS treatments targeted to protect and restore myelin.

“First, this method may provide an objective measure of the disease progression and treatment success in clinical trials,” Dr. Yarnykh said. “And second, assessment of both gray and white matter damage with this method may become an individual patient management tool in the future.”

Dr. Yarnykh and colleagues are currently conducting additional research on the new method with the support of the National Multiple Sclerosis Society and the National Institutes of Health.

“This study was done on the participants at a single point in time,” he said. “Now we want to compare MS patients with control participants to see how myelin content will evolve over time. We further plan to extend our method to the spinal cord imaging and test whether the combined assessment of demyelination in the brain and spinal cord could better explain disability progression as compared to brain demyelination alone.”

A simple eye test for multiple sclerosis

As you step outdoors into the bright sunshine, your pupils automatically contract. Scientists from the Australian Centre of Excellence in Vision Science (ACEVS) based at The Australian National University (ANU) are making use of how this ‘pupil reflex’ is connected to the brain as a potential new way of testing the severity of multiple sclerosis (MS).

Dr Eman Ali and her ACEVS colleagues have used an instrument they are developing to accurately measure the pupil responses of MS patients and have found that the pupils of MS sufferers respond appreciably slower. The finding opens the door to a simple and quick way of tracking the severity of MS over time: the slower the response, the worse the MS.

“Our instrument uses special patterns of flashing lights that the patient looks at for four minutes,” says Professor Ted Maddess, a vision scientist at ANU who is head of the ACEVS team.

“We use infrared cameras to measure light-induced changes in the diameters of both pupils, and with computer tracking we can measure the diameter to within a micrometre 30 times a second.

“We have just published the results of our study of 85 MS patients, and we find that in MS patients the pupil response is about 25 milliseconds slower than in our control group. Although the study is preliminary, we believe the test has good potential in individual patients because it can precisely measure the speed of their response to within a millisecond.

“So instead of an expensive MRI to track the condition, the new method gives an accurate readout after just a few minutes. That quick and easy test might, in the future, allow MS patients to be assessed on the spot and have their medication adjusted accordingly,” he says.

MS is a potentially devastating neurological condition affecting the myelin sheath of nerve fibres, leading to sensory disturbances and muscle weakness. Vision, speech, and walking are most often affected, and pain can occur. Puzzlingly, MS affects different people in different ways, but the condition inexorably gets worse with age and there is currently no cure. Some patients experience acute, inflammatory attacks while others don’t.

“MS is the most common neurological disability in adults, with about 12,000 sufferers in Australia,” says Professor Maddess. “Although it seems to be some sort of immune disorder, its cause is still obscure.

“There are many puzzling aspects to MS, and there are many theories,” he says. “But our main aim in this work was just to find a way of accurately monitoring the progression of the disease, a single measure that relates to the degree of disability. MRI is good for giving insight into the inflammation associated with episodic attacks, but it’s not so good at monitoring the chronic decline that’s always going on.

“If we can use our pupil measurements to monitor the decline, we might be in a better position to adjust medications, which often have unpleasant side-effects.”

The instrument to measure the pupil responses is the same one which has also been shown to be helpful in diagnosing vision loss in glaucoma, diabetes, and age-related macular degeneration. The device was developed by Professor Maddess together with Associate Professor Andrew James and other ACEVS team members. Under the name TrueField, it is being commercially developed by an Australian company, Seeing Machines, which plans to sell it as a multipurpose medical diagnostic instrument.

TrueField has already received American FDA clearance, and Professor Maddess is hopeful it might, after some more research, also find a role in monitoring MS. He believes it has good prospects of reducing the high treatment costs associated with the disease.

The paper by Dr Ali and colleagues, “Pupillary response to sparse multifocal stimuli in multiple sclerosis patients”, is available online in the Multiple Sclerosis Journal.

Pulse propagation and signal transduction in the hydraulic brain

When Descartes turned his critical eye to the nervous system, he reasoned that the nerves must transduce hydraulic power to control the musculature. In the circulatory system, blood is pushed comparatively slowly through the aorta, perhaps around 0.3 meters per second. Superimposed on that flow, however, is an arterial pulse wave which propagates much faster, both through the blood and the walls of the vessel. For compliant and healthy vessels that speed might be around 10 meters per second, while for more hardened arteries, it could be 15 or higher. Modern day electrophysiologists have since replaced the hydraulic model with the idea that nerves really only transmit information—electrical information no less. Yet when looking at the power supply to the leg, for example, it is still hard to ignore the fact that the main femoral artery, at a diameter scarcely a half of an inch, looks rather meager next to the “information-supplying” sciatic nerve, which may actually be more like three-quarters of an inch. A conflux of ideas from a variety of disciplines has recently led to a critical re-emergence of the more mechanical side of the nervous system. To that point, two German scientists have just published a paper in the journal, Medical Hypotheses, where they suggest that the pulse wave is the main event in nervous conduction, while the electrical show is mere epiphenomenon.

We recently discussed the increasingly popular idea that action potentials may actually be soliton waves which propagate in the membranes of axons as phase transitions with minimal loss in energy. Convincing biologists that these subtle creatures could exist in the chaotic and varied conditions inside neurons has been a challenge. However, it is harder to argue against the fact that any kind of electrochemical spike based on the rapid influx of ions will be accompanied by a significant pressure pulse. The idea that the German researchers have supported, is that these as the pressure pulses naturally decay in the viscoelastic medium of the nerve, they are refreshed by ionic input at the nodes between myelinated axon segments, or continuously in unmyelinated axons.

If you have ever been absent-minded enough to grab a live wire, or even brush up strongly against one, the sensation is unforgettable. It is not such a stretch to acknowledge that when you slam your funny bone, or more precisely the Ulnar nerve (largest unprotected nerve in your body), the resultant vibe and decay feels almost identical to a real electrical assault. Similarly, the so-called “stingers” that run down the limbs after a sharp blow to the head are familiar to most footballers, and can give one quite a shock. Unfortunately these (albeit very simplistic) macroscopic intuitions don’t hold up so well when extended to the microscopic domain. Granted, when the electrochemical mechanisms that are assumed to underlie nervous conduction are looked at in detail, it becomes more difficult to disentangle the mechanical from the electric. However, as the authors observe, at some point, an attentive electrophysiologist must ask his or herself, “why are so many ion channels mechanosensitive” ?

One unexpected finding of the patch clamp recording technique was that the dilation of the membrane caused by local tension leads to considerable increase in transmembrane ion flow. Impulse waves causing short extensions in the membrane can directly induce opening and closing of both voltage and ligand gated channels. The idea that the pore in these channels is a rigid tube isolated from larger membrane events is difficult to support in this context. According to the authors, it is quite likely that common mechanoreceptor devices, like the pressure- or vibration-sensitive Vater-Pacinian corpuscles of the skin, conduct signals to initiate high-speed polysynaptic muscle reflex circuits without any classical intermediary electrical conversion.

The exact conduction velocity of mechanical impulses in nerve fibers remains unknown. It is estimated that under physiologic conditions, an unamplified axoplasmic pressure pulse would decay over roughly 1 mm due to viscosity, depending on the distensibility of the axon wall. When compared to the theoretical case of an absolutely rigid wall, a typical myelin sheath may be rigid enough to support pulse speeds up to one-fifth of the estimated maximum. That speed is not to shabby when compared with some rough estimates from previous authors, which put the maximum pulse velocity under an indistensible membrane somewhere upwards of 1500 meters per second. Suddenly, the quicker than life eyeblink response, or speed of the tenderfoot stepping on a sharp shard, become a little more comprehensible.

The theory as it stands is incomplete and needs to be adapted for specific cases with real biology in mind. In different animals, and in different regions of their brains, conduction in neurons goes by different names. For example, in the cerebellum, the unmyelinated parallel fibers pack to extreme densities in a regular crystalline lattice whose reason to be defies physiologic explanation to this day. Just as we currently have no good explanation for how signals could be properly isolated in nerve bundles where seemingly random nodes of Ranvier overlap in extent and influence, it is hard to imagine parallel fibers could maintain their electrochemical, or even mechanical, autonomy within this geometry.

The pressure wave theory wields considerable predictive power when it comes to explaining some of the unique synaptic specializations found throughout the brain. When considered only from an electrochemical point of view, the huge structural synaptic investments, like those found at the neuromuscular junction (NMJ), can hardly be imagined to be driven by local, and weak, current or field effects. One might need look no further than simple-to-recreate Chaldni patterns set up in two dimensions on the surface of a taunt drum, to make the imaginative leap to a three dimensional system, with multiple vibrating players, where more extreme patterns might easily be set up to provide authorship to repeatable complex structure. For the NMJ in particular, the case has been made that at the end-plate, the comparatively enormous efflux of acetylcholine to the deeply-guttered cleft, and propagation of excitation through the transverse tubule system, are all components of a continuous mechanical amplifier.

The apparent ease with which evolving organisms manage to cobble together all manner of sensitive hearing devices becomes infinitely more explicable once we see that nature has apparently been doing this kind of thing all alone inside of neurons. The amplification and transduction through liquid channels, of barely noticeable vibrations against a background of thermal noise much greater in magnitude, is in this light, no evolutionary stumble-upon, but rather the bread and butter of neural systems, and perhaps many aspects of life in general.

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

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

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

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

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

Glial cells assist in the repair of injured nerves

Unlike the brain and spinal cord, the peripheral nervous system has an astonishing capacity for regeneration following injury. Researchers at the Max Planck Institute of Experimental Medicine in Göttingen have discovered that, following nerve damage, peripheral glial cells produce the growth factor neuregulin1, which makes an important contribution to the regeneration of damaged nerves.

From their cell bodies to their terminals in muscle or skin, neuronal extensions or axons in the peripheral nervous system are surrounded along their entire length by glial cells. These cells, which are known as Schwann cells, envelop the axons with an insulating sheath called myelin, which enables the rapid transmission of electrical impulses. Following injury to a peripheral nerve, the damaged axons degenerate. After a few weeks, however, they regenerate and are then recovered with myelin by the Schwann cells. For thus far unexplained reasons, however, the Schwann cells do not manage to regenerate the myelin sheaths completely. Thus the function of damaged nerves often remains permanently impaired and certain muscles remain paralysed in affected patients.

In a current research study, the scientists have succeeded in showing that the growth factor neuregulin1 supports nerve repair and the redevelopment of the myelin layer. This protein is usually produced by neurons and is localised on axons where it acts as an important signal for the maturation of Schwann cells and myelin formation. Because the axons rapidly degenerate after injury, the remaining Schwann cells lose their contact with the axons. They thus lack the neuregulin1 signal of the nervous fibres. “In the phase following nerve damage, in which the axons are missing, the Schwann cells must carry out many tasks without the help of axonal signals. If the Schwann cells cannot overcome this first major obstacle in the aftermath of nerve injury, the nerve cannot be adequately repaired,” explains Ruth Stassart, one of the study authors.

To prevent this, the Schwann cells themselves take over the production of the actual neuronal signal molecule. After nerve damage, they synthesise the neuregulin1 protein until the axons have grown again. With the help of genetically modified mice, the researchers working on this study were able to show that the neuregulin1 produced in Schwann cells is necessary for the new maturation of the Schwann cells and the regeneration of the myelin sheath after injury. “In mice that lack the neuregulin1 gene in their Schwann cells, the already incomplete nerve regeneration process is extensively impaired,” explains co-author Robert Fledrich.

The researchers would now like to examine in greater detail how the Schwann cells contribute to the complete repair of myelinated axons after nerve damage, so that this information can also be used for therapeutic purposes.

MRI research sheds new light on nerve fibres in the brain

World-leading experts in Magnetic Resonance Imaging from The University of Nottingham’s Sir Peter Mansfield Magnetic Resonance Centre have made a key discovery which could give the medical world a new tool for the improved diagnosis and monitoring of neuro-degenerative diseases like multiple sclerosis.

The new study, published in the Proceedings of the National Academy of Science, reveals why images of the brain produced using the latest MRI techniques are so sensitive to the direction in which nerve fibres run.

The white matter of the brain is made up of billions of microscopic nerve fibres that pass information in the form of tiny electrical signals. To increase the speed at which these signals travel, each nerve fibre is encased by a sheath formed from a fatty substance, called myelin. Previous studies have shown that the appearance of white matter in magnetic resonance images depends on the angle between the nerve fibres and the direction of the very strong magnetic field used in an MRI scanner.