Neural Plasticity Of Spinal Reflexes Research Paper

1. Organization Of The Spinal Cord

The spinal cord receives from the peripheral nervous system most of the sensory information from both the musculoskeletal system and the visceral organs. Likewise, most motor control passes from the brain through the spinal cord and out to the striate muscles of the musculoskeletal system, and smooth muscles and other effectors of the visceral systems.

Two basic components make up the spinal cord. One is the ‘long-lines’ that transmit information from the input levels to the brain, and other spinal levels. These fibers generally are myelinated axons travelling from the cell bodies of origin in the spinal cord to brainstem and cortical levels, and convey sensory information. Likewise, motor and effector organ information is sent from the cerebral cortex and subcortical areas to the spinal cord along myelinated fiber tracts. These myelinated ascending and descending tracts form the white (colored by the white myelin coatings around the axons) outer aspect of the spinal cord.

The second, more complex area of the cord is the central portion, an ‘H’ shaped inner core, the central gray. Most incoming sensory information travels via the sensory nerves into the top or dorsal aspect of the central gray, where the nerves synapse on interneurons. The interneurons lack the myelin coatings of the long-lines, hence the gray color. The interneurons of the central gray are specialized for collecting and integrating information, and passing it to other areas of the nervous system. It is the interneurons that provide most of the processing power for reflex interactions and for actual alterations of spinal function now being shown.

2. Research Into Spinal Neural Plasticity

Two main areas of research have evolved to investigate possible spinal neural plasticity. The first is the area of behavioral indicators of spinal cord plasticity. Various behavioral tasks and measures have shown alterations in reflex functions that imply underlying neural alterations. In some cases, these studies have led to investigations of underlying neural mechanisms. The second area involves the use of nociceptive (pain) inputs to alter spinal function in studies aimed at investigating underlying neural plasticity. These lines of investigation have produced a body of knowledge that is now being applied to human spinal cord injury rehabilitation and to pain control with encouraging results.

3. Behavioral Indicators Of Spinal Neural Plasticity

For many years the role of spinal circuitry in reflex behaviors has been recognized. However, spinal reflexes, such as arm withdrawal when a finger is burned, were thought to be basically hard-wired, unchanging circuits whose activity might be increased or decreased by descending influences from the brain but that did not actively participate in brain mediated changes like learning. One of the early questions flowing from the search for neural mechanisms of learning and memory was that of what was the smallest unit of the nervous system that could support learning. Since the spinal reflex arcs were easily accessible, simple units of neural circuitry, they quickly attracted the attention of early investigators looking for neural mechanisms of behavioral change.

3.1 Sensitization And Habituation

Researchers have long recognized that spinal reflexes could show some activity alterations. Sherrington (1906) described spinal fatigue or decreases in spinal reflex activity secondary to repeated activation in spinalized animals. The decrease in spinal function was transient, however, and recovered soon after stimulus cessation. The converse process was also recognized; with more intense stimulus inputs, the reflex response could increase, rapidly returning to baseline after the stimulus was discontinued. Groves and Thompson (1970) summarized much of this work and proposed a neural model. With repetitive inputs to the spinal circuits, relatively low intensity stimuli would activate ‘H-type’ interneurons that decreased their activity, resulting in decreased output. Stronger stimuli would also activate an additional circuit whose interneuron activity would increase, resulting in increased output. The resultant behavior would be an algebraic summation of the two output streams and could be decreasing behavior (habituation), no change, or increasing behavior (sensitization).

A variant of sensitization studied for many years is termed spinal fixation (Patterson 1976, 2001). A strong stimulus given to a spinalized animal for 15–45 minutes will produce an alteration of spinal postures that are retained for weeks. This nonassociative behavioral alteration has been shown to be stimulus intensity dependent and to occur as a neural excitability alteration in the interneuron circuits of the cord. It appears to be a longer-term variant of sensitization that occurs with high level nociceptive stimuli. Its behavioral consequences remain obscure, but it may be a process underlying some forms of chronic pain syndromes.

3.2 Classical Conditioning

Classical conditioning is recognized as the simplest form of associative learning. An association between a signaling stimulus (conditioned stimulus or CS) and a response producing stimulus (unconditioned stimulus or UCS) forms when the CS is presented shortly before UCS onset. The CS gradually comes to elicit a response (CR) similar to that evoked initially by the UCS. A considerable body of research beginning in the 1930s (see Patterson 1976) attempted to demonstrate that spinal reflex circuits show the associational learning of classical conditioning. While beset with theoretical and methodological difficulties, the evidence supported the ability of spinal circuits to support long-lasting (days) changes due to temporal association. Other data (e.g., Beggs et al. 1985) indicate that classical conditioning procedures produce a variety of long-term neural alterations closely approximating associative learning in the intact animal. There is some suggestion that the ability of the spinal cord to sustain this neural plasticity decreases for several days after spinal transection, but may return within a few weeks, presumably after neural reorganization.

3.3 Instrumental Conditioning

When the behavior to be learned is not simply evoked by a UCS, but is the result of some activity of the organism that is rewarded or punished by a stimulus, the learning is attributed to instrumental learning (see Grau et al. 1998). A typical spinal instrumental conditioning situation involves the omission of a nociceptive stimulus if the spinalized animal’s leg does not fall below a preset level. The leg gradually comes to rest at a higher level (increased muscle tension) with repeated trials. A particularly interesting variant of spinal instrumental conditioning has been shown by Wolpaw (Carp and Wolpaw 1994). Intact monkeys were conditioned instrumentally to increase or decrease the excitability of a simple spinal circuit. The conditioning procedure involved no nociceptive (pain) stimuli, unlike most spinal conditioning procedures, and took weeks to complete, as opposed to hours for most spinal conditioning. After conditioning was complete, spinal transection, isolating the spinal circuits, did not abolish the spinal excitability changes. Thus, the alterations produced by training procedures involving stimuli processed at cortical levels, but primarily activating spinal circuits, resulted in neural alterations at the spinal level.

The ability of spinal circuits to respond to positive (reward) or negative (punishment) contingencies by increases or decreases in behavioral responses indicates that the range of neural plasticity in spinal cord circuits is not limited to simple stimulus driven pattern changes. Thus, the current data strongly suggest that spinal circuits can undergo both short-and long-term alterations that affect behavior.

4. Neural Mechanisms Of Spinal Cord Plasticity

The search for mechanisms of spinal neural plasticity has been heavily driven by the need to understand certain types of chronic pain syndromes. With the realization that spinal circuits can be active participants in information processing, and can both amplify and decrease information transmission, it has become apparent that spinal circuits may also affect nociceptive or pain signal transmission from the body to the brain, where pain perception occurs. Many pain states are now recognized as having a component of a ‘central pain state,’ essentially a component that is generated in the spinal circuitry itself (see, e.g., Dubner and Gold 1999). Since pain is perceived at the conscious level, neural inputs to the brain coming from an injured body structure are perceived as pain in that structure. If these brain inputs were generated not in the peripheral structure, but in the spinal centers between the body and the brain, the perceived pain would still be felt as occurring in the body. Thus, a central pain state can occur with little or no actual physical damage or ongoing input from the body.

Many investigations of spinal plasticity secondary to nociceptive inputs have been in spinal or intact animals with an irritant injected into a leg joint to produce inflammation that lasts for hours or days (e.g., Woolf and Costigan 1999). The long-lasting nociceptive inputs terminate primarily on the interneurons in the upper layers of the spinal gray matter. The impulses are transmitted to lower order interneurons and thence to motor outputs as well as to the long-line axons for transmission to the brainstem and cortex.

The effects of even fairly short bursts of high intensity nociceptive inputs to the spinal interneurons can be dramatic. Increases in interneuron excitability similar to that shown with the behavioral studies of sensitization occur quickly and appear to be alterations in the presynaptic terminals of the input neurons coming from nociceptors at the injury site. The terminals release more neural transmitter with each activation of the afferent neuron, thus increasing the overall activation of the spinal interneurons. With continued inputs, alterations occur that increase the sensitivity of the interneuron membranes to transmitters. In addition, other substances such as nitric oxide (NO) and substance p (a neurotransmitter) are released into the general area of the activated interneurons and act to increase the excitability of other interneurons. Thus, not only the directly involved circuits, but neighboring circuits can become over activated. Also, certain genes of the interneurons will be activated, producing increases in numbers of membrane NMDA receptors that further increase the sensitivity of the interneurons to neurotransmitters (see, e.g., Dubner and Ruda 1992). Further nociceptive input begins a biochemical reaction that results in the death of inhibitory interneurons that normally dampen the activity of the spinal networks. Additionally, over days, there appears to be sprouting of processes from the excitatory interneurons to other interneurons forming new excitatory synapses. The overall result of this neural plasticity is to temporarily, then permanently, increase the overall excitability of the spinal circuits responsible for processing nociceptive input.

5. Implications For Spinal Function

Evidence from behavioral and learning studies of spinal processes shows that spinal reflex circuits have an inherent capacity for alterations subsequent to stimulus inputs. The understanding of underlying neural mechanisms from these studies seem to implicate the same types of processes that have been found to underlie alterations seen with pain inputs. From these data, some generalizations can be made. Spinal reflex circuits have an inherent capacity for change due to both simple activation and in response to certain stimulus patterns, such as temporal proximity. Nociceptive inputs are especially potent in producing excitability changes in neural function, but nonnociceptive inputs, over a longer time, can also produce alterations. The alterations include shortterm changes lasting from seconds to minutes, longer lasting alterations measured in hours or days, intermediate term changes lasting days and weeks, and finally, semipermanent to permanent changes.

The implications for understanding pain generation and control as well as spinal cord injury rehabilitation are dramatic (e.g., Wickelgren 1998). Central pain is one of the most intractable medical problems known. Without a peripheral site of pain generation, common methods of pain reduction are almost useless, and medications affecting central pain perception (e.g., morphine) often leave the patient severely incapacitated. Understanding the mechanisms underlying spinal circuit excitability alterations will allow the central changes to be stopped or aborted. Learning how to alter excitability of reflex patterns by behavioral interventions will allow increasingly effective rehabilitation for humans with spinal cord injuries to a degree not even imagined a few years ago. Coupled with a greater understanding of how to encourage spinal neurons to regenerate through areas of injury and even how to transplant new neural tissue into injured areas, these techniques are changing the way spinal injury and chronic central pains states are treated.

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