The outlook used to be pretty bleak for those who had lost movement in their limbs due to severe nerve damage, but over the last year or so, some incredible advances have been made that are restoring shattered hope for many.
The amazing breakthroughs include spinal cord stimulation that allowed paralyzed men to regain some voluntary control of their legs, a brain implant that enabled a quadriplegic man to move his fingers, and a system that allowed a paralyzed woman to control a robotic armusing her thoughts. Science has definitely been on a roll, but this winning streak isn’t showing any signs of slowing down. Now, the world’s first “bionic reconstructions” have been performed on three Austrian men to help them regain hand function. This technique enabled the newly amputated patients to control prosthetic hands using their minds, allowing them to perform various tasks that most people take for granted.
The men that underwent the procedure had all suffered serious nerve damage as a result of car or climbing accidents, which left them with severely impaired hand function. The nerves that suffered injury were those within a network of fibers supplying the skin and muscles of the upper limbs, known as the brachial plexus. As lead researcher Professor Oskar Aszmann explains in a news release, traumatic events that sever these nerves are essentially inner amputations, irreversibly separating the limb from neural control. While it is possible to operate, Aszmann says the techniques are crude and do little to improve hand function. However, his newly developed procedure is quite different, and is proving to be a success.
Before the men could be fitted with their prosthetic hands, the researchers had to do some preliminary surgical work in which leg muscle was grafted into their arms in order to improve signal transmission from the remaining nerves. After a few months, the fibers had successfully innervated the transplanted tissue, meaning it was time to start the next stage: brain training.
Using a series of sensors placed onto the arm, the men slowly began to learn how to activate the muscle. Next, they mastered how to use electrical nerve signals to control a virtual hand, before eventually moving on to a hybrid hand that was affixed to their non-functioning hand. After around nine months of cognitive training, all of the men had their hand amputated and replaced with a robotic prosthesis that, via sensors, responds to electrical impulses in the muscles.
A few months later, the men had significantly improved hand movement control, which was highlighted by a test of function known as the Southampton Hand Assessment Procedure. As reported in The Lancet, before the procedure, the men scored an average of 9 out of 100, which soared to 65 using the prosthetic. Furthermore, the men reported less pain and a higher quality of life. For the first time since their injuries, they were able to perform avariety of tasks such as picking up objects, slicing food and undoing buttons with both hands.
“So far, bionic reconstruction has only been done in our center in Vienna,” said Aszmann. “However, there are no technical or surgical limitations that would prevent this procedure from being done in centers with similar expertise and resources.”
The Reticular Formation
It’s a ‘diffuse net’ which is formed by nerve cells and fibers. It extends from the neuroaxis spinal cord through medulla, pons, midbrain, subthalamus, hypothalamus and thalamus (spinal cord is relayed superiorly to the cerebral cortex).
Many afferent and efferent pathways project in and out of the RF from most parts of the CNS. The main pathways through the RF is poorly defined and difficult to trace using silver stains. Reticular formation can be divided into three columns : median, medial and lateral columns.
Functions of the Reticular formation
1. Control of skeletal muscles:
- RF modulates muscle tone and reflex activities (via reticulospinal and reticulo bulbar tracts). It is important in controlling muscles of facial expression when associated with emotions.
2. Control somatic and visceral sensation (influence can be excitatory or inhibitory)
3. Control of autonomic nervous system
4. Control of endocrine nervous system (hypothalamus and the pituitary)
5. Influence on the biological clock (rhythm)
6. The reticular activating system (arousal and level of consciousness are controlled by the RF)
When a person smiles for a joke, the motor control is provided by the RF on both side of the brain. The fibers from RF is separated from corticobulbar pathway (supply for facial muscles). If a patient suffers a stroke that involves corticobulbar fibers, he or she has facial paralysis on the lower part of the face, but is still able to smile symmetrically.
The Limbic System
|Limbic structures||Functions of the limbic system|
||1. Influence the emotional behavior:a. Reaction to fear and angerb. Emotions associated with sexual behavior
2. Hippocampus is involved in converting short term memory to long term memory (If the hippocampus is damaged, patient is unable to store long term memory – Anterograde amnesia)
The Basal Ganglia and their connections
Connections of the Basal Ganglia
Yellow arrow : Pallidofugal fibers
Caudate nucleus and the Putamen: main sites of receiving inputs
Globus pallidus: main site from which output leaves
Afferent and Efferent fibers
|Connections of the caudate nucleus and Putamen||Connections of the Globus pallidus|
|CS: CorticostriateTS: Thalamostriate
BS: Brainstem striatal fibers
SN: Striatonigral fibers
Functions of the Basal Nuclei
Basal Nuclei controls muscular movements by influencing the cerebral cortex (it doesn’t have direct control through descending pathways to the brainstem and spinal cord). It helps to prepare for the movements (enables the trunk and limbs to be placed in appropriate positions before discrete movements of the hands and feet).
Functional connections of the Basal Nuclei and how they influence muscle activities
1. Ben Greenstein, Ph.D, Adam Greenstein, BSc (Hons) Mb, ChB Color Atlas of Neuroscience
2. Allan Siegel Ph.D, Hreday N. Sapru Ph.D Essential Neuroscience, 1st Edition
3. Stanley Jacobson, Elliot M. Marcus Neuroanatomy for the Neuroscientist
4. Patrick f. Chinnery Neuroscience for Neurologists
5. Dale Purves Neuroscience, 3rd Edition
6. Suzan Standring Gray’s Anatomy
7. Keith L. Moore, Arthur F. Dalley, Anne M. R. Agur Clinically Oriented Anatomy
8. Frank H. Netter Atlas of Human Anatomy
9. Walter J. Hendelman, M.D., C.M. Atlas of Functional Neuroanatomy
10. Mark F. Bear, Barry W. Connors, Michael A. Paradiso Neuroscience Exploring the Brain
11. Dale Purves et al. Principles of Cognitive Neuroscience
12. Eric R. Kandel et al. Principles of Neural Science
Every year, hundreds of thousands of people suffer from paralyzed limbs as a result of peripheral nerve injury. Recently, implantation of artificial nerve grafts has become the method of choice for repairing damaged peripheral nerves. Grafts can lead to some degree of functional recovery when a short segment of nerve is damaged. But they are of little use when it comes to regenerating nerves over distances greater than a few millimeters, and such injuries therefore often lead to permanent paralysis.
Now though, surgeons from Germany have made what could be a significant advance in nerve tissue engineering. They have developed artificial nerve grafts made from hollowed-out pig veins filled with spider silk fibres and, in a series of animal experiments, showed that the grafts can enhance the regeneration of peripheral nerves over distances of up to 6cm. Their findings have just been published in the open access journal PLoS One.
Peripheral nerves have a greater regenerative capacity than those in the central nervous system, but regenerating them properly is challenging. The individual nerve fibres must not only regrow into the damaged area, but also find their proper targets. Furthermore, the regenerated nerve will not function properly unless it is populated by Schwann cells, which produce myelin. This fatty tissue is essential for full recovery, as it wraps itself around the nerve fibres at regular intervals (a process called myelination), facilitating the conductance of nervous impulses along their length.
Conventionally, damaged peripheral nerves are treated either by suturing or by implantation of nerve grafts. The two ends of a severed nerve can be surgically re-attached to each other, as long as the nerve is not stretched in the process. This is not possible for gaps longer than about 5mm, in which case a short length of nerve from elsewhere in the patient’s body can be grafted into the damaged area. But this often causes causes pain in the donor area, and it can be difficult to find a nerve segment that has the same diameter as the damaged nerve. Nerves can be obtained from another person, but they can be rejected by the recipient’s immune system, so drugs that suppress the immune response are usually administered.
An alternative approach, which has emerged in the past ten years or so, is the use of artificial nerve grafts made from silicon or synthetic polymers such as polyethylene. These form scaffolds which bridge the gap in the damaged nerve and serve as conduits through which the nerve fibres can regrow. Artificial grafts can lead to some degree of functional recovery, but they can become toxic with time, or they can constrict the nerve.
These problems can potentially be overcome by using nerve grafts made from biodegradable materials. Five years ago, Peter Vogt and his colleagues in the Department of Plastic, Hand and Reconstructive Surgery at Hannover Medical School reported that Schwann cells readily ensheath spider silk fibres when grown on them, and that nerve grafts made of de-cellularized veins filled with spider silk can be maintained in culture for periods of up to a week. More recently, they showed that spider silk vein grafts can be used to regenerate 20mm gap in the sciatic nerve of rats, either alone or when supplemented with Schwann cells.
In the new study, Vogt’s group dissected 6cm lengths from the small veins in pigs’ legs, washed them and stripped away most of the endothelial cells from their inner walls. They then harvested dragline silk from the golden silk spider Nephila clavipes and pulled the silk through the de-cellularized veins, until it filled about one quarter of their diameter. Using adult sheep, the researchers removed a 6cm length of the tibial nerve in the leg. In one group of animals, the gap was bridged with the spider silk constructs; in another, the section of nerve that had been removed was replaced in reverse orientation.
Defects in the animals’ gait became apparent immediately after the surgery – the hind limb was partially paralyzed and flexed abnormally. But within three weeks there was a significant improvement, with both groups of animals being able to stand properly. By four months, the animals could stand upright on both hind limbs, the hind limbs moved in co-ordination with one another during walking, and there was no obvious difference in strength between the operated and unoperated limbs.
Ten months after surgery, the sheep were killed and their regenerated nerves examined under the microscope. In both groups of animals, the severed nerve fibres had regrown into the nerve grafts to bridge the 6cm gap; Schwann cells had migrated into the grafts and wrapped themselves around the entire length of the regenerated nerves; and the sodium channels required for generating nerve impulses were distributed irregularly along the fibres. This shows that myelination had occurred properly, with the formation of Nodes of Ranvier, the regular gaps in the myelin sheath at which the sodium channels normally cluster. No trace of residual spider silk was detected in the experimental animals, and there was no sign of inflammation at the repair site, indicating that the silk fibres were absorbed subtly without adverse effects.
These findings could have important applications in reconstructive nerve surgery. This is the first time that a large animal model has been used to study nerve regeneration, and the study is the first in which a defect longer than 2cm in length has been successfully repaired. The spider silk constructs enhanced nerve regeneration at least as effectively as the sheeps’ own nerves, and would be advantageous in the clinic, because transplanting large lengths of a patient’s own nerves is unfeasible.
More work will be needed before the technique can be applied to humans. Meanwhile, the regeneration reported here could be further enhanced in a number of ways. The spider silk constructs could, for example, be loaded with substances such as Nerve Growth Factor, or they could be grafted together with Schwann cells, to speed up nerve regrowth. But ultimately, engineering fully functional peripheral nerves will probably require a combination of advanced microsurgery, transplantation of both cells and tissues, advances in materials science and, possibly, gene transfer for the effective delivery of growth factors.
Radtke, C. et al. (2011). Spider Silk Constructs Enhance Axonal Regeneration and Remyelination in Long Nerve Defects in Sheep. PLoS ONE, 6 (2) DOI: 10.1371/journal.pone.0016990.