Neanderthals may have had a lower threshold for pain

Depiction of early humans, photo concept

Pain is mediated through specialized nerve cells that are activated when potentially harmful things affect various parts of our bodies. These nerve cells have a special ion channel that has a key role in starting the electrical impulse that signals pain and is sent to the brain. According to a new study, people who inherited the Neanderthal variant of this ion channel experience more pain.

As several Neanderthal genomes of high quality are now available researchers can identify genetic changes that were present in many or all Neanderthals, investigate their physiological effects and look into their consequences when they occur in people today. Looking into one gene that carries such changes, Hugo Zeberg, Svante Pääbo and colleagues found that some people, especially from central and south America but also in Europe, have inherited a Neanderthal variant of a gene that encodes an ion channel that initiates the sensation of pain.

By using data from a huge population study in the UK, the authors show that people in the UK who carry the Neanderthal variant of the ion channel experience more pain. "The biggest factor for how much pain people report is their age. But carrying the Neanderthal variant of the ion channel makes you experience more pain similar to if you were eight years older," says lead author Hugo Zeberg, a researcher at the Max Planck Institute for Evolutionary Anthropology and Karolinska Institutet. "The Neanderthal variant of the ion channel carries three amino acid differences to the common, 'modern' variant," explains Zeberg. "While single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying three amino acid substitutions leads to heightened pain sensitivity in present-day people."

On a molecular level, the Neanderthal ion channel is more easily activated which may explain why people who inherited it have a lowered pain threshold. "Whether Neanderthals experienced more pain is difficult to say because pain is also modulated both in the spinal cord and in the brain," says Pääbo. "But this work shows that their threshold for initiating pain impulses was lower than in most present-day humans."

From Science Daily

Scientists regenerate neurons in mice with spinal cord injury and optic nerve damage

Neuron illustration

Like power lines in an electrical grid, long wiry projections that grow outward from neurons -- structures known as axons -- form interconnected communication networks that run from the brain to all parts of the body. But unlike an outage in a power line, which can be fixed, a break in an axon is permanent. Each year thousands of patients confront this reality, facing life-long losses in sensation and motor function from spinal cord injury and related conditions in which axons are badly damaged or severed.

New research by scientists at the Lewis Katz School of Medicine Temple University (LKSOM) shows, however, that gains in functional recovery from these injuries may be possible, thanks to a molecule known as Lin28, which regulates cell growth. In a study published online in the journal Molecular Therapy, the Temple researchers describe the ability of Lin28 -- when expressed above its usual levels -- to fuel axon regrowth in mice with spinal cord injury or optic nerve injury, enabling repair of the body's communication grid.

"Our findings show that Lin28 is a major regulator of axon regeneration and a promising therapeutic target for central nervous system injuries," explained Shuxin Li, MD, PhD, Professor of Anatomy and Cell Biology and in the Shriners Hospitals Pediatric Research Center at the Lewis Katz School of Medicine at Temple University and senior investigator on the new study. The research is the first to demonstrate the regenerative ability of Lin28 upregulation in the injured spinal cord of animals.

"We became interested in Lin28 as a target for neuron regeneration because it acts as a gatekeeper of stem cell activity," said Dr. Li. "It controls the switch that maintains stem cells or allows them to differentiate and potentially contribute to activities such as axon regeneration."

To explore the effects of Lin28 on axon regrowth, Dr. Li and colleagues developed a mouse model in which animals expressed extra Lin28 in some of their tissues. When full-grown, the animals were divided into groups that sustained spinal cord injury or injury to the optic nerve tracts that connect to the retina in the eye.

Another set of adult mice, with normal Lin28 expression and similar injuries, were given injections of a viral vector (a type of carrier) for Lin28 to examine the molecule's direct effects on tissue repair.

Extra Lin28 stimulated long-distance axon regeneration in all instances, though the most dramatic effects were observed following post-injury injection of Lin28. In mice with spinal cord injury, Lin28 injection resulted in the growth of axons to more than three millimeters beyond the area of axon damage, while in animals with optic nerve injury, axons regrew the entire length of the optic nerve tract. Evaluation of walking and sensory abilities after Lin28 treatment revealed significant improvements in coordination and sensation.

"We observed a lot of axon regrowth, which could be very significant clinically, since there currently are no regenerative treatments for spinal cord injury or optic nerve injury," Dr. Li explained.

One of his goals in the near-term is to identify a safe and effective means of getting Lin28 to injured tissues in human patients. To do so, his team of researchers will need to develop a vector, or carrier system for Lin28, that can be injected systemically and then hone in on injured axons to deliver the therapy directly to multiple populations of damaged neurons.

Dr. Li further wants to decipher the molecular details of the Lin28 signaling pathway. "Lin28 associates closely with other growth signaling molecules, and we suspect it uses multiple pathways to regulate cell growth," he explained. These other molecules could potentially be packaged along with Lin28 to aid neuron repair.

Read more at Science Daily

Researchers regrow damaged nerves with polymer and protein

University of Pittsburgh School of Medicine researchers have created a biodegradable nerve guide -- a polymer tube -- filled with growth-promoting protein that can regenerate long sections of damaged nerves, without the need for transplanting stem cells or a donor nerve.

So far, the technology has been tested in monkeys, and the results of those experiments appeared today in Science Translational Medicine.

"We're the first to show a nerve guide without any cells was able to bridge a large, 2-inch gap between the nerve stump and its target muscle," said senior author Kacey Marra, Ph.D., professor of plastic surgery at Pitt and core faculty at the McGowan Institute for Regenerative Medicine. "Our guide was comparable to, and in some ways better than, a nerve graft."

Half of wounded American soldiers return home with injuries to their arms and legs, which aren't well protected by body armor, often resulting in damaged nerves and disability. Among civilians, car crashes, machinery accidents, cancer treatment, diabetes and even birth trauma can cause significant nerve damage, affecting more than 20 million Americans.

Peripheral nerves can regrow up to a third of an inch on their own, but if the damaged section is longer than that, the nerve can't find its target. Often, the disoriented nerve gets knotted into a painful ball called a neuroma.

The most common treatment for longer segments of nerve damage is to remove a skinny sensory nerve at the back of the leg -- which causes numbness in the leg and other complications, but has the least chance of being missed -- chop it into thirds, bundle the pieces together and then sew them to the end of the damaged motor nerve, usually in the arm. But only about 40 to 60% of the motor function typically returns.

"It's like you're replacing a piece of linguini with a bundle of angel hair pasta," Marra said. "It just doesn't work as well."

Marra's nerve guide returned about 80% of fine motor control in the thumbs of four monkeys, each with a 2-inch nerve gap in the forearm.

The guide is made of the same material as dissolvable sutures and peppered with a growth-promoting protein -- the same one delivered to the brain in a recent Parkinson's trial -- which releases slowly over the course of months.

The experiment had two controls: an empty polymer tube and a nerve graft. Since monkeys' legs are relatively short, the usual clinical procedure of removing and dicing a leg nerve wouldn't work. So, the scientists removed a 2-inch segment of nerve from the forearm, flipped it around and sewed it into place, replacing linguini with linguini, and setting a high bar for the nerve guide to match.

Functional recovery was just as good with Marra's guide as it was with this best-case-scenario graft, and the guide outperformed the graft when it came to restoring nerve conduction and replenishing Schwann cells -- the insulating layer around nerves that boosts electrical signals and supports regeneration. In both scenarios, it took a year for the nerve to regrow. The empty guide performed significantly worse all around.

With these promising results in monkeys, Marra wants to bring her nerve guide to human patients. She's working with the Food and Drug Administration (FDA) on a first-in-human clinical trial and spinning out a startup company, AxoMax Technologies Inc.

Read more at Science Daily

Nerve transfer surgery restores hand function and elbow extension in 13 young adults with complete paralysis

13 young adults with tetraplegia are able to feed themselves, hold a drink, brush their teeth, and write as a result of a novel surgical technique which connects functioning nerves with injured nerves to restore power in paralysed muscles Nerve transfer surgery has enabled 13 young adults with complete paralysis to regain movement and function in their elbows and hands, according to the largest case series of this technique in people with tetraplegia (paralysis of both the upper and lower limbs), published in The Lancet.

During the surgery, Australian surgeons attached functioning nerves above the spinal injury to paralysed nerves below the injury. Two years after surgery, and following intensive physical therapy, participants were able to reach their arm out in front of them and open their hand to pick up and manipulate objects. Restoring elbow extension improved their ability to propel their wheelchair and to transfer into bed or a car.

They can now perform everyday tasks independently such as feeding themselves, brushing teeth and hair, putting on make-up, writing, handling money and credit cards, and using tools and electronic devices.

The findings suggest that nerve transfers can achieve similar functional improvements to traditional tendon transfers, with the benefit of smaller incisions and shorter immobilisation times after surgery.

In 10 participants, nerve transfers were uniquely combined with tendon transfers allowing different styles of reconstruction to be performed in each hand, and enabling participants to benefit from the innate strengths of both tendon and nerve transfers. Nerve transfers restored more natural movement and finer motor control in one hand, and tendon transfers restored more power and heavy lifting ability in the other hand.

While only a small study, researchers say that nerve transfers are a major advance in the restoration of hand and arm function, and offer another safe, reliable surgical option for people living with tetraplegia.

Nevertheless, four nerve transfers failed in three participants and the authors conclude that more research will be needed to determine which people are the best candidates to select for nerve transfer surgery to minimise the incidence of failure.

"For people with tetraplegia, improvement in hand function is the single most important goal. We believe that nerve transfer surgery offers an exciting new option, offering individuals with paralysis the possibility of regaining arm and hand functions to perform everyday tasks, and giving them greater independence and the ability to participate more easily in family and work life," says Dr Natasha van Zyl from Austin Health in Melbourne, Australia who led the research.

"What's more, we have shown that nerve transfers can be successfully combined with traditional tendon transfer techniques to maximise benefits. When grasp and pinch was restored using nerve transfers in one hand and tendon transfers in the other, participants consistently reporting that they liked both hands for different reasons and would not choose to have two hands reconstructed in the same way."

Traditionally, upper limb function has been reconstructed using tendon transfer surgery, during which muscles that still work, but are designed for another function, are surgically re-sited to do the work of muscles that are paralysed. In contrast, nerve transfers allow the direct reanimation of the paralysed muscle itself. Additionally, nerve transfers can re-animate more than one muscle at a time, have a shorter period of immobilisation after surgery (10 days in a sling vs 6-12 weeks in a brace for a nerve transfer for elbow extension), and avoid the technical problems associated with of tendon transfer surgery including tendon tensioning during surgery and mechanical failure (stretch or rupture) after surgery.

Previous single case reports and small retrospective studies have shown nerve transfer surgery to be feasible and safe in people with tetraplegia. But this is the first prospective study to use standardised functional outcome measures and combinations of multiple nerve and tendon transfer surgeries.

In total the study recruited 16 young adults (average age 27 years) with traumatic, early (less than 18 months post injury) spinal cord injury to the neck (C5-C7), who were referred to Austin Health in Melbourne for restoration of function in the upper limb. Most were the result of motor vehicle accidents or sports injuries.

Participants underwent single or multiple nerve transfers in one or both upper limbs to restore elbow extension, grasp, pinch, and hand opening. This involved taking working nerves to expendable muscles innervated above the spinal injury and attaching them to the nerves of paralysed muscles innervated below the injury to restore voluntary control and reanimate the paralysed muscle.

For example, the surgeons selected the nerve supplying the teres minor muscle in the shoulder as a donor nerve and attached it to the nerve supplying the triceps that activates the muscles that extend (straighten) the elbow. To restore grasp and pinch the nerve to a spare wrist extensor muscle was transferred to the anterior interosseous nerve.

In total, 59 nerve transfers were completed in 16 participants (13 men and three women; 27 limbs). In 10 participants (12 limbs), nerve transfers were combined with tendon transfers to improve hand function.

Participants completed assessments on their level of independence related to activities of daily living (e.g., self-care, toilet, upper limb function, muscle power, grasp and pinch strength, and hand opening ability) before surgery, one year after surgery, and again two years later. Two participants were lost to follow up, and there was one death (unrelated to the surgery).

At 24 months, significant improvements were noted in the hands ability to pick up and release several objects within a specified time frame and independence. Prior to surgery, none of the participants were able to score on the grasp or pinch strength tests, but 2 years later pinch and grasp strength were high enough to perform most activities of daily living.

Three participants had four failed nerve transfers -- two had a permanent decrease in sensation, and two had a temporary decrease in wrist strength that resolved by 1 year after surgery. Overall, surgery was well tolerated. Five serious adverse events were recorded (including a fall from a wheelchair with femur fracture), but none were related to the surgery.

Despite these achievements, nerve transfer surgery still has some limitations. For the best results nerve transfers should ideally be performed within 6-12 months of injury. Additionally, it can take months after nerve transfer for nerve regrowth into the paralysed muscle to occur and for new movement to be seen, and years until full strength is achieved. However, the authors note that one of the benefits of nerve transfers is that most movements not successfully restored by nerve transfers can still be restored using tendon transfers.

Read more at Science Daily

Pain signaling in humans more rapid than previously known

Pain signals can travel as fast as touch signals, according to a new study from researchers at Linköping University in Sweden, Liverpool John Moores University in the UK, and the National Institutes of Health (NIH) in the US. The discovery of a rapid pain-signalling system challenges our current understanding of pain. The study is published in the scientific journal Science Advances.

It has until now been believed that nerve signals for pain are always conducted more slowly than those for touch. The latter signals, which allow us to determine where we are being touched, are conducted by nerves that have a fatty sheath of myelin that insulates the nerve. Nerves with a thick layer of myelin conduct signals more rapidly than unmyelinated nerves. In contrast, the signalling of pain in humans has been thought to be considerably slower and carried out by nerves that have only a thin layer of myelin, or none at all.

In monkeys and many other mammals, on the other hand, part of the pain-signalling system can conduct nerve signals just as fast as the system that signals touch. The scientists speculated whether such a system is also present in humans.

"The ability to feel pain is vital to our survival, so why should our pain-signalling system be so much slower than the system used for touch, and so much slower than it could be?" asks Saad Nagi, principal research engineer of the Department of Clinical and Experimental Medicine and the Center for Social and Affective Neuroscience (CSAN) at Linköping University.

To answer this, the scientists used a technique that allowed them to detect the signals in the nerve fibres from a single nerve cell. They examined 100 healthy volunteers and looked for nerve cells that conducted signals as rapidly as the nerve cells that detect touch, but that had the properties of pain receptors, otherwise known as nociceptors. Pain receptors are characterised by the ability to detect noxious stimuli, such as pinching and abrasion of the skin, while not reacting to light touch. The researchers found that 12% of thickly myelinated nerve cells had the same properties as pain receptors, and in these nerve cells the conduction speed was as high as in touch-sensitive nerve cells.

The next step of the scientists' research was to determine the function of these ultrafast pain receptors. By applying short electrical pulses through the measurement electrodes, they could stimulate individual nerve cells. The volunteers described that they experienced sharp or pinprick pain.

"When we activated an individual nerve cell, it caused a perception of pain, so we conclude that these nerve cells are connected to pain centres in the brain," says Saad Nagi.

The research team also investigated patients with various rare neurological conditions. One group of people had, as adults, acquired nerve damage that led to the thickly myelinated nerve fibres being destroyed, while the small fibres were spared. These patients cannot detect light touch. The scientists predicted that the loss of myelinated nerve fibres should also affect the rapidly conducting pain system they had identified. It turned out that these people had an impaired ability to experience mechanical pain. Examination of patients with two other rare neurological conditions gave similar results. These results may be highly significant for pain research, and for the diagnosis and care of patients with pain.

Read more at Science Daily

Rerouting nerves during amputation reduces phantom limb pain before it starts

Robert Haas experienced debilitating pain following the amputation of his left leg that prevented him from using his prosthetic and required medication to manage. However, a surgery that reconnects severed nerves eliminated his pain and allowed him to adjust to life with an artificial limb.

Doctors at The Ohio State University Wexner Medical Center and College of Medicine are pioneering the use of primary targeted muscle reinnervation (TMR) to prevent or reduce debilitating phantom limb and stump pain in amputees.

Losing a limb due to trauma, cancer, or poor circulation can result in phantom limb and stump pain in upwards of 75 percent of amputees in the United States. Primary TMR - the rerouting of nerves cut during amputation into surrounding muscle - greatly reduces phantom limb and residual limb pain, as reported in recent publications by Dr. Ian Valerio, division chief of Burn, Wound and Trauma in Ohio State's Department of Plastic and Reconstructive Surgery, and Dr. J. Byers Bowen, a former resident who is now in private practice. Their latest work featured in the January 2019 issue of Plastic and Reconstructive Surgery describes how to perform this technique in below-the-knee amputations.

TMR was first developed to allow amputees better control of upper limb prosthetics. Traditionally doctors perform the surgery months or years after the initial amputation. When surgeons discovered the procedure also improves certain causes of pain, they started using it to treat disorganized nerve endings called symptomatic neuromas and/or phantom limb pain.

In this paper, Valerio and Bowen provide a detailed description of TMR in below-the-knee amputees and document the benefits of primary TMR for preventing pain.

"This paper provides a blueprint for improving patient outcomes and quality of life following amputation," said Dr. K. Craig Kent, dean of The Ohio State University College of Medicine.

Over the course of three years, the surgeons performed 22 TMR surgeries on below-the-knee amputees, 18 primary and four secondary. None of the patients have developed symptomatic neuromas and only 13 percent of patients who received primary TMR reported having pain six months later.

"A significant amount of pain in amputees is caused by disorganized nerve endings, i.e. symptomatic neuromas, in the residual limb. They form when nerves are severed and not addressed, thus they have nowhere to go," Valerio said. "Attaching those cut nerve endings to motor nerves in a nearby muscle allows the body to re-establish its neural circuitry. This alleviates phantom and residual limb pain by giving those severed nerves somewhere to go and something to do."

Valerio said patients who've had TMR significantly reduce or sometimes stop using narcotics and other nerve pain related medications, which can greatly improve their quality of life.

"TMR has been shown to reduce pain scores and multiple types of pain via a variety of validated pain surveys. These findings are the first to show that surgery can greatly reduce phantom and other types of limb pain directly," Valerio said.

Bowen added that upper extremity amputees are better able to use and control their prosthetics in addition to their improved pain outcomes. He said, "TMR allows for more individual muscle unit firings through the patient's thoughts. It provides for better intuitive control resulting in more refined functional movements and more degrees of motion by an advanced prosthetic."

The researchers believe primary TMR is a reliable technique to prevent the development of disorganized nerve endings and to reduce phantom and other limb pain in all types of amputations. When done at the time of initial amputation, there is minimal health risk and recovery is similar to that of traditional amputation surgery.

Read more at Science Daily