What is a spinal cord injury?

Perceptions about the human spinal cord have undergone a revolution in recent years. What was once considered hopeless is now showing signs of promise. SSPF-funded scientists are on the cutting edge of spinal cord research and making progress. Advances are being made every day. This tutorial is designed as an introduction for the layperson to spinal cord injury and repair. It includes information on what happens to the spinal cord as a result of traumatic injury and some of the latest developments in the search for effective treatments.

The central nervous system (CNS) controls most functions of the body and mind. It consists of two parts: the brain and the spinal cord. The brain is the center of our thoughts, the interpreter of our external environment, and the origin of control over body movement. Like a central computer, it interprets information from our eyes (sight), ears (sound), nose (smell), tongue (taste) and skin (touch), as well as from internal organs such as the stomach. It controls all voluntary movement, such as speech and walking, and involuntary movement like blinking and breathing. It is the core of our thoughts, perceptions and emotions.

The central nervous system is better protected than any other system or organ in the body. Its main line of defense is the bones of the skull and spinal column, which create a hard physical barrier to injury. Below the bones is a space filled with cerebrospinal fluid that provides shock absorbance. Unfortunately, this protection can be a double-edged sword. When an injury to the CNS occurs, the soft tissue of the brain and cord swells, causing pressure because of the confined space. The swelling makes the injury worse unless it is rapidly relieved. Fractured bones can lead to further damage and the possibility of infection.

The spinal cord is the highway for communication between the body and the brain. When the spinal cord is injured, the exchange of information between the brain and other parts of the body is disrupted.

Many organs and tissues in the body can recover after injury without intervention. Unfortunately, some cells of the central nervous system are so specialized that they cannot divide and create new cells. As a result, recovery from a brain or spinal cord injury is extremely difficult.

The complexity of the central nervous system makes the formation of the right connections between brain and spinal cord cells very difficult. It is a huge challenge for scientists to recreate the central nervous system as it existed before the injury. Cells called neurons connect with one another to send and receive messages into the brain and spinal cord. Many neurons working together are responsible for every decision made, every emotion or sensation felt, and every action taken. As many as 10,000 different subtypes of neurons have been identified, each specialized to send and receive certain types of information.

Each neuron is made up of a cell body, which houses the nucleus. Axons and dendrites form extensions from the cell body.

Glia cells are "nerve-helper" cells that provide structural support, nourishment and protection for neurons.

Astrocytes, a kind of glial cell, are the primary support cells of the brain and spinal cord. They make and secrete proteins called neurotrophic factors, which assist in the maintenance of nerve cells in the central nervous system. They also break down and remove proteins or chemicals that might be harmful to neurons (for example, glutamate, a neurotransmitter that in excess causes cells to become overexcited and die by a process called excitotoxicity).

Astrocytes aren't always beneficial: After injury, they divide to make new cells that surround the injury site, forming a glial scar that is a barrier to regenerating axons.

Microglia are immune cells for the spinal cord. After injury, they migrate to the site of injury to help clear away dead and dying cells. They can also produce small molecules called cytokines that trigger cells of the immune system to respond to the injury site. This clean-up process is likely to play an important role in recovery of function following a spinal injury.

Oligodendrocytes are glial cells that produce a fatty substance called myelin which wraps around axons in layers. Axon fibers insulated by myelin can carry electrical messages (also called action potentials) at a speed of 100 meters per second, while fibers without myelin can only carry messages at a speed of one meter per second. A spinal cord injury can compromise or destroy myelin.

Messages are passed from neuron to neuron through synapses, small gaps between the cells, with the help of chemicals called neurotransmitters. To transmit a message across a synapse, neurotransmitter molecules are released from one neuron (the "pre-synaptic" neuron) and cross the gap to the next neuron (the "post-synaptic" neuron).

The process continues until the message reaches its destination. There are millions and millions of connections between neurons within the spinal cord alone. These connections are made during development, using positive and negative (inhibitory proteins) signals to fine-tune them. Amazingly, a single axon can form synapses with as many as 1,000 other neurons.

There is a logical and physical topographical organization of the anatomy of the central nervous system, which is an elaborate web of closely connected neural pathways. This ordered relationship means that different segmental levels of the cord control different things and injury to a particular part of the cord will impact neighboring parts of the body.

Paralysis occurs when communication between the brain and spinal cord fails. This can result from injury to neurons in the brain (a stroke), or in the spinal cord. Trauma to the spinal cord affects only the areas below the level of injury. On the other hand, poliomyelitis (a viral infection) or Lou Gehrig's disease (ALS, amyotrophic lateral sclerosis) can affect neurons in the entire spinal cord.

The spinal cord contains multiple tracts to transmit different information. Specialized neurons carry messages from the skin, muscles, joints and internal organs to the spinal cord about pain, temperature, touch, vibration, and proprioception (or spatial orientation). These messages are then relayed to the brain along an ascending pathway, for example the spinothalamic tract. These pathways are in different locations in the spinal cord, so an injury might not affect them in the same way or to the same degree.

Each segment of the spinal cord receives sensory input from a particular region of the body. Scientists have mapped these areas and determined the "receptive" fields for each level of the spinal cord.

Neurons in the motor cortex, the region of the brain that controls voluntary movement, send their axons through the corticospinal tract to connect with motor neurons in the spinal cord. The spinal motor neurons project out of the cord to the correct muscles via the ventral root. These connections control conscious movements like writing and running.

Information also flows in the opposite direction, resulting in involuntary movement. Sensory neurons provide feedback to the brain via the dorsal root. Some of the sensory information is conveyed directly to lower motor neurons before it reaches the brain, resulting in involuntary or reflex movements. The remaining sensory information travels back to the cortex.

The spinal cord is divided into five sections: the cervical, thoracic, lumbar, sacral, and coccygeal regions. The level of injury determines the extent of paralysis and/or loss of sensation. No two injuries are alike.

In addition to the control of voluntary movement, the central nervous system contains the sympathetic and parasympathetic pathways that control the "fight or flight" response to danger and regulation of bodily functions. These include hormone release, movement of food through the stomach and intestines, and the sensations from and muscular control to all internal organs.

A common set of biological events take place following spinal cord injury:

1. Cells from the immune system migrate to the injury site, causing additional damage to some neurons that survived the initial trauma, and death to others.

2. The death of oligodendrocytes causes axons to lose their myelin, which greatly impairs the conduction of messages or renders the remaining connections useless. The neuronal information highway is further disrupted because many axons are severed, cutting off the lines of communication between the brain and muscles and between the body's sensory systems and the brain.

3. Within several weeks of the initial injury, the area of tissue damage has been cleared away by microglia, and a fluid-filled cavity surrounded by a glilal scar is left behind. Molecules that inhibit regrowth of severed axons are now produced at or near this site. The cavitation is called a syrinx, which acts as a barrier to the reconnection of the two sides of the damaged spinal cord.

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Although spinal cord injury causes complex damage, a surprising amount of the basic circuitry to control movement and process information can remain intact. This is because the spinal cord is arranged in layers of circuitry. Many of the connections and neuronal cell bodies forming this circuitry above and below the site of injury survive the trauma. An important question to research scientists is how much do these surviving neurons "know"? Can they regenerate and make new, correct connections?

Research points to a multiplicity of possible interventions to promote recovery from a spinal injury. Some would be delivered immediately following the injury; others are less time-specific and involve rebuilding and reconnecting the injured cord. Clearly, both approaches are important: Limiting degeneration will enhance the probability of greater recovery, while stimulating regeneration will build upon the remaining system to restore lost connectivity, and perhaps to prevent further degeneration.

To cure the paralysis and loss of function that spinal cord injuries cause, doctors will need a carefully orchestrated series of interventions. Treatments will begin in the emergency room and continue for months. Even new forms of rehabilitation will be part of the therapeutic package. To speed the day when this regimen is available, the Sam Schmidt Paralysis Foundation supports research on a variety of fronts. Individual grants encourage a multi-disciplinary approach to solving the complex medical problems that result from spinal cord injuries, in both the acute and chronic stage.

AREAS OF RESEARCH

Axon Guidance, Synapse Formation and Neurotransmission
Spinal cord researchers have had increasing success coaxing nerve cells, or neurons, to regenerate their damaged axons following a spinal cord injury. However, to rebuild nerve circuitry and restore lost function, those new axons must travel distances up to several feet, recognize their target neurons, and forge working connections, or synapses, with them. Neurotransmitters, chemicals that facilitate neuron-to-neuron communication, must also be replaced. So too must a host of receptors, the molecular sentinels that intercept the external signals that control the behavior of a neuron. A growing number of researchers are studying developing organisms to see how their brains and spinal cords assemble their complex wiring in the first place. If this process could be restarted in the adult, then doctors would have a valuable tool for repairing the injured spinal cord.

Cellular Replacement, Stem Cells and Artificial Substrate
One approach to spinal cord repair involves replacing the neurons and the cells that support them, which are destroyed or damaged by an injury and its aftermath. Toward that end, some scientists are trying to generate dependable lines of primitive spinal cells that, when transplanted, would evolve into the cell types needed to fix the injured cord. Others are investigating transplant techniques, including one that includes transplanting both cells and tiny bridges or tunnels that direct and support replacement axons as they grow across a breach in the spinal cord. Still other researchers hope to restart the mechanisms that first created the nervous system.

Concomitant Function
In addition to paralysis, spinal cord injuries cause a range of complications, some life threatening. The problems include infection, pneumonia, spasticity, chronic pain, and blood pressure and temperature irregularities. Scientists are increasingly turning their attention to these difficult-to-treat conditions that affect both the health and the quality of life of the spinal cord injured.

Growth Inhibition
Unlike cells in the peripheral nervous system, cells in the central nervous system do not regrow after an injury. Spinal neurons might replace their damaged axons, however, were it not for the body's complicated responses to a trauma. These complex responses transform the area around the lesion into hostile territory for axon regeneration. Scientists have identified a number of so-called growth inhibitors. If treatments could be developed to stymie these inhibitors or prevent them from congregating at the spinal lesion, then the body might repair lost nerve circuitry.

Neuroprotection
For weeks and possibly months after a spinal cord injury the cellular casualty count rises. The body's immune response and toxic chemicals released by dying cells attack cells that survived the initial injury. Other cells just seem to know that something in their neighborhood is terribly wrong, and they self-destruct, a process called apoptosis. This mayhem amplifies the lesion and the loss of function. If this biological ripple effect could be prevented the injury might wreak less havoc.

Promotion of Axon Growth and Remyelination
Although spinal cord injuries destroy axons, the cell bodies to which they belonged often survive. But unlike nerve cells in the peripheral nervous system, neurons in the spinal cord and brain cannot repair their damaged axons or grow new ones. One approach, then, to treating spinal cord injuries is to reprogram neurons so that they can spout new axons that would recreate the nerve circuits an injury destroys. However, for new axons to work properly they need to be enwrapped in myelin, a fatty substance that insulates and protects them. A spinal cord injury also can cause demyelination, in which axons that survive the initial trauma then lose their myelin in a process similar to what occurs in multiple sclerosis. Researchers are pursuing strategies to trigger axon regeneration or myelination following an injury.

Rehabilitation
Rehabilitation therapy helps to maintain bone and muscle mass and is vital for maintaining the general health of people with spinal cord injuries. Yet evidence is mounting that certain forms of rehabilitation also may lead to beneficial changes in the spinal cord itself. For example, nerve circuits above and below an injury retain their ability to reshape themselves to become more efficient and even to assume new roles, a quality known as plasticity. Some of these adaptations can be initiated or enhanced by vigorous exercise. For example, a training routine that involves assisted stepping on a moving treadmill spurs plasticity and improves walking and standing in animals and people with certain types of spinal cord injuries. Known as locomotor training, this approach also may improve function by promoting axon regeneration and improving communication between nerve cells.

Glossary

Actin - A filamentous protein that is a key component of the framework of the cell.

Allodynia - A disorder in which sensations that normally do not hurt become painful.

Analgesic - A class of drugs that relieves pain without causing loss of consciousness.

Apoptosis - Programmed cell death, or cell suicide, which is part of the natural life cycle of a cell. Apoptosis can be triggered by age, injury, or unknown factors. When the cell senses that it's not healthy, it goes through a series of changes, finally chopping its DNA and proteins into small packets that are cleaned up by microglia.

Astrocytes - Cells that nourish and support spinal neurons.

Autonomic dysreflexia - A potentially fatal complication of spinal cord injuries that involves episodes of extreme hypertension and sometimes leads to intracranial hemorrhage or stroke. It occurs in 90% of people with cervical or high thoracic cord injuries.

Axon - The long tail of a neuron that transmits electrical impulses from the cell body.

Axonal Transport - The mechanism that enables neurons to send proteins and chemical messages back and forth along axons.

Catecholamines - Chemicals produced by organs that are controlled by the sympathetic nervous system. These substances are involved in the fight-or-flight response to stress.

Cell Adhesion Molecules (CAMs) - Proteins that adhere to the surface of an elogating axon and direct it to its final address in the brain or spinal cord.

Central Nervous System - The brain and spinal cord.

Central Pattern Generator (CPG) - A network of spinal neurons that, when stimulated by neurotransmitters, cause the muscles of the legs to move in rhythmic stepping motions.

Cervical - The high-level nervous structure of the spinal cord responsible for controlling the neck muscles, diaphragm, shoulders, wrists, triceps and fingers.

Chondroitin Sulfate Proteoglycans - Molecules that are a major component of the scar that forms at the site of a spinal cord injury and inhibit axon regeneration. They may act on their own or, because of their large size and negative charge, may attract other growth inhibitors to the lesion - or both.

Cortocospinal Tract - A nerve circuit pathway that originates in the brain's cerebral cortex and extends to lower levels of the cord, where descending axons send electrical impulses to the spinal motor neurons that, in turn, control the muscles.

Cytokines - Messenger molecules that enable immune cells to "talk" to one another and to other cells. Cytokines regulate the strength and duration of an immune response. Neurons also use certain cytokines to communicate with each other. Common cytokines include interferon, interlukin and lymphokines.

Cytoskeleton - A self-renewing support structure that enables cells, including neuron, to move and maintain their proper shape and size.

Demyelination - A cellular response to trauma that destroys myelin, the fatty substance that insulates and protects axons to improve their transmission of electrical impulses. Demyelination impedes or halts that transmission, resulting in a loss of function.

Dorsal Root Ganglion (DRG) neurons - Neurons just outside the spinal cord that receive sensory information from the periphery of the body and transmit it to the brain. These cells readily regenerate their axons after an injury.

Dorsal Horns (also called posterior horns) - A pair of projections that form the back "wings" of the butterfly-shaped gray matter in the spinal cord.

Drosophila melanogaster - A fruit fly often used in genetic studies.

Embryonic Stem Cells - Very primitive cells that develop within days of ova fertilization with the potential to develop into all of the body's cell types.

Excitotoxicity - An abnormal stimulation or activation of neurons in the brain and spinal cord that result in cell death. This stimulation is attributed to excess amounts of the neurotransmitter, glutamate.

Intracellular Matrix - The filamentous material surrounding cells. It contains nourishment for cells as well as molecules that tell them what to do, including some that guide growing axons.

Free Radicals - Highly unstable molecules, released by a spinal cord injury, which can quickly attack healthy cells. These molecules overwhelm the body's antioxidants, which normally neutralize them, creating a damaging condition known as oxidative stress.

Gait - The manner in which a human or animal walks.

Gangliosides - Proteins that give the surface of a cell a negative charge and are thought to be involved in many different cell functions.

Gene Expression - A term used to describe which genes are active in, or influence, a biologic process.

Glia (also neuroglia) - Nerve-helper cells that provide structural support, nourishment and protection for neurons. Members of the glia family are oligodendrocytes (oligodendria), astroglia cells (astrocytes), ependymal cells and microglia cells. Glia form scar tissue at the site of a spinal cord injury and pose both a physical and - because they produce several types of growth inhibiting molecules - a chemical barrier to regenerating axons.

Glial Scar - Non-viable nerve tissue composed of glial cells that form a barrier to nerve regrowth after spinal cord trauma has occurred.

Gliosis - The process of scar formation after a spinal cord injury. Gliosis clears dead tissue and walls off the damaged region to prevent aberrant nerve cell activity, but it also inhibits the survival of neighboring cells. The resultant scar poses both a physical and chemical barrier to nerve cell regeneration.

Growth Cone - The leading tip of a growing axon. It is highly responsive to growth factors and guidance molecules.

Guidance Molecules - Proteins that push and pull the axons of embryonic nerve cells toward their target connections.

Interneurons - The most abundant type of neuron in the central nervous system. They are the "middlemen" of nerve circuitry that connect only to other neurons, not to sensory cells or muscles, and help transmit nerve impulses. Interneurons are crucial determinants of many rhythmic motor behaviors.

Ligands - Messenger molecules that bind to and activate receptors on the surface of cells, which then change the behavior of the cell.

Locomotor Training - A rehabilitation therapy that enables some people with spinal cord injuries to regain limited independent walking. The training involves supporting people over a treadmill while they are helped to make stepping motions.

Lumbar - The low-level nervous structure of the spinal cord responsible for controlling the abdomen, hips, quadriceps, hamstrings, feet and ejaculation.

Methylprednisolone - A powerful steroid administered in the hours immediately after a spinal cord injury to limit harmful inflammation. It is the only approved treatment for acute spinal cord injury.

Microglia - Tiny immune system scavenger cells that remove debris from the brain and spinal cord.

Midline -
1) A line of cells, running from top to bottom, down the center of an embryo.
2) An imaginary line dividing the left and right halves of the body.

Motoneurons - Nerve cells that control the muscles.

Myelin - A fatty substance, produced by cells in the central nervous system known as oligodendrocytes. Myelin forms a protective sleeve around axons that enables them to conduct electrical impulses.

Nerve Sprouting - A condition following spinal cord trauma that results in the axon reconnecting to an inappropriate target. Synaptic conduction is restored but the pathway does not result in restoration of function.

Netrins - Molecules that attract and repel developing axons and appear to govern the direction they travel.

Neural Progenitors - Parent cells that give rise to each of the types of nerve cells.

Neurogenesis - The birth of neurons. Neurons (nerve cells) are the basic unit of the nervous system. Neurons come in assorted shapes and sizes, and each type has a specific role. Chains of neurons transmit electrical impulses throughout the body.

Neurons (nerve cells) - The basic unit of the nervous system. Neurons come in assorted shapes and sizes and each type has a specific role. Chains of neurons transmit electrical impulses throughout the body.

Neuropathic pain - Pain caused by disease in, or injury to, the nervous system.

Neurotransmission - The sending and receiving of electrical impulses through chains of neurons.

Neurotransmitters - The chemical messengers of the nervous system. They are released at the synapse (connection between nerve cells) and influence cell behavior. Common neurotransmitters include glutamate, serotonin, acetylcholine and norepinephrine.

Neurotrophins - Molecules that are important in the development and maintenance of the nervous system. Neurotrophins, which promote axon regeneration almost like a nerve-cell fertilizer, include nerve-growth factor (NGF), NT-3, BDNF, and NT 4/5.

Neutrophils - A type of white blood cell and one of the first immune cells to arrive during the acute inflammatory response to a spinal cord injury. Neutrophils manufacture enzymes, which help kill bacteria; but in the brain and spinal cord they are lethal to nerve cells.

Nogo - A powerful protein that occurs naturally in the spinal cord and prevents nerve cells from regenerating axons.

Olfactory Ensheathing Glia (OEG) - Cells that support the sensory neurons lining the nasal cavity. When transplanted into the spinal cord, these cells may remyelinate damaged axons.

Oligodendrocytes - Cells that enwrap an axon with their flattened membranes to create an insulating layer of myelin.

Peripheral Nervous System - The network of nerves outside the brain and spinal cord. Unlike nerves in the central nervous system, peripheral nerves can regrow after an injury.

Plasticity - The ability of nerve circuitry to remodel itself.

Precursor Cells - Cells that have the ability to divide for indefinite periods in culture and differentiate into multiple specialized cell types.

Progenitor Cell - Any type of cell that spawns other cells.

Proprioception - Perception of movement and spatial orientation.

Receptors - Millions of protein molecules, posted like sentinels around a cell membrane to screen the environment for messages addressed to them. Receptors are highly selective, usually responding to only one type of directive. The meeting of a messenger molecule, or ligand, with its receptor initiates a reaction inside the cell that ultimately affects what the cell does.

Rubrospinal tract - One of the major descending nerve pathways from the brain to the spinal cord.

Schwann Cells - Non-nerve cells in the peripheral nervous system, similar to oligodendrocytes in the central nerve system, which wrap around axons to create a protective layer of myelin. They also may promote nerve regeneration following an injury.

Semaphorins - A family of proteins that play a role during axonal development. Semaphorins may inhibit axon growth or help growing axons find their way to their target connections - or both. These proteins act like traffic cops, telling growing axons where they can and cannot go so that they reach their destinations.

Serotonin - One of the groups of chemical messengers known as neurotransmitters that carries out communications in the brain and the body. This molecular messenger travels from neuron to neuron eliciting cellular responses that shape emotions and judgment.

Spasticity - An increase in muscle tone with exaggerated tendon reflexes.

Stem Cells - Self-renewing, primitive cells. When a stem cell divides, it creates another stem cell and a daughter cell that can become a mature cell in any organ in the body.

Sympathetic Nervous System - Controls involuntary functions of the body, such as heart rate and blood pressure.

Synapse - The connection between two neurons that enables them to communicate. Synapses enable nerve impulses to travel through chains of neurons.

Synaptic Adhesion Molecules (SAMs) - Molecules that establish the first contact between two neurons, holding the cell membranes in place while their connection, or synapse, forms.

Synaptogenesis - The process of forming a nerve-to-nerve junction or synapse. After the formation of the synapse is complete, the signal is relayed by the release of a chemical transmitter from one membrane that binds to a receptor in the second membrane.

T-cells - White blood cells that are part of the immune system.

Tactile Allodynia - A condition in spinal cord injured individuals where pain is brought on by stimuli that would not cause pain in healthy individuals.

Vectors - Viruses that have been rendered harmless so they can be used to transport therapeutic genes into target cells.