The neuroplastic phenomenon: a physiologic link between chronic pain and learning.
For over a millennia, people have been trying to understand the complexities of the human mind. Progress has been made in recent centuries through the establishment of cytoarchitectural maps, with most of that progress having been made in the past thirty years. These maps have broken down the brain into dozens of sections according to their structure and function. This mapping process has been complicated by the presence of contralateral and ipsilateral parallel processes, feed-back/feed-forward mechanisms and reverberating loops. Neurons and their synapses are dynamic entities that change from millisecond to millisecond, while simultaneously imbedding information into their fabric.
Although some investigators continue trying to sort through the precise nature of billions of neurons interconnected by trillions of synapses with thousands of overlapping functional patterns, other investigators are appreciating the mind as a dynamic holistic unit, recognizing the importance of integrated and constantly changing structures and functions. No two brains exhibit the exact same structure or function, in fact no two hemispheres of the same brain are alike. Each sensation, thought, feeling, movement and social interaction changes the brain in a way that contributes to the uniqueness of the individual.
There are currently at least two separate areas of research on neuroplasticity phenomenon that may be of interest to nurses. One area is that of learning and memory, the other is chronic pain. This exploration of theoretical and empirical literature describes the physiology of neuroplasticity and identifies the related similarities and differences between learning and chronic pain. Such an undertaking is important to nurses because of the increasing prevalence of chronic pain and the challenges associated with educating patients during brief encounters.
Physiology of Neuroplasticity
Neuroplasticity refers to the ability of neurons to alter their structure and function. Structural changes occur at every level of the nervous system, from enlargement and reshaping of the entire neuron (with newly developed dendritic connections), to changing synaptic quanta in presynaptic fibers and alterations in the number, type and sensitivity of postsynaptic ion channels. Thus, neuroplasticity should be viewed as a dynamic process, not a particular outcome.
These presynaptic and postsynaptic membrane changes occur in response to mediators which are initiated by the postsynaptic membrane. Different types of neuroplastic changes are detailed by Ganong, including: posttetanic potentiation, habituation, sensitization, long-term potentiation and long-term depression. Changes in intracellular calcium ion concentration, related to the effect of the excitatory amino acid (EAA), N-methyl-D-aspartate (NMDA), seems to be the least common denominator underlying all types of neuroplastic changes. The related change of intracellular calcium ion concentration produces a hyperexcitable state within the nerve. The inhibitory amino acid, gamma-aminobutyric acid (GABA), normally counters the effects of NMDA and other excitatory amino acids, by exerting an effect on calcium and chloride ion channels in a way that dampens noxious stimuli.
Each nerve cell employs multiple chemical signals to communicate with other cells and itself. Nerves may use entirely different combinations of chemical messengers at different times in response to changing internal and external environmental conditions. In the presence of excessive excitatory or inhibitory neurotransmitter activation, the number of excitatory receptors or inhibitory receptors decrease in density respectively. The EAAs are believed responsible for the regulation of changes in synaptic plasticity, dendritic and axonal structure.
There are 3 subtypes of EAAs: NMDA, glutamate and aspartate, balanced primarily by GABA. In response to excessive excitatory activation, GABA receptors change in number and function through a phosphorylation process which allows negatively charged chloride ions to dampen the effect of synaptic hyperexcitability. Excessive increases in the concentration of EAAs which are not countered by inhibitory amino acids result in neuron cellular damage and a cascade of events that increases spontaneous nerve firing, escalating EAA concentration and further adding to neuronal destruction.
The type of neuroplastic process which predominates varies with different stages of growth and development. Neuroplastic changes related to the growth of cells and the establishment of new dendritic connections occur more readily in youth because of the relative instability and rapid growth of neurons in children. This type of plasticity is associated with intelligence and creativity. With age, there is a decrease in the number of receptors and established neuroanatomical pathways (including chemical circuits), which dissolve and reform in response to environmental cues. Competing influences must be strong and repetitive for adults to change interneuronal connections and add new synapses. Still, dramatic changes in the intricate circuitry and chemistry of the adult brain occur as a result of sensory, motor, behavioral, environmental or drug-related stimuli. This plasticity appears to be related to changing thoughts and behaviors, and serves the purpose of promoting adaptation by allowing the person some flexibly when responding to changing environmental demands.
Being in direct, constant interaction with the environment, it is not surprising that the information transmitted by the nervous system could determine behavior. After all, the nervous system subserves the functions of sensation, learning, memory, visceral control and motor function, which are all affected by the environment. The activation of specific polyfunctional biologically active protein molecules produced by nerves (eg, epinephrine, vasopressin, endorphins, etc) do result in specific behavioral patterns, which are complex and to a certain extent elicit predictable responses. Given the complex design of the central nervous system with built in redundancies, balances and the capacity to cognitively override these effects, the degrees of response to stimuli can vary greatly from person to person, or within the same person over time.
An example of protein determinants of behavior are those associated with the stress response. Activation of proopiomelanocortin (POMC) production, the attention-arousal-anxiety complex of the locus ceruleus, and the dopaminergic pathways are all activated in response to environmental stress. POMC is rapidly broken down into adrenocorticotropic hormone (ACTH), endorphin and melanocyte stimulating hormones (MSH); as a result the "fight or flight" response is stimulated, pain threshold is elevated and anti-inflammatory action of glucorticoids is enhanced. As a result of locus ceruleus activation, tyrosine hydroxylase is activated which increases the production and release of norepinephrine which in turn increases attentiveness, vigilance and anxiety, further reinforcing locus ceruleus activation. A cycle which sustains a high level of arousal, attention, vigilance and anxiety is perpetuated until long after the stimulus is removed. Substance P and the dopaminergic pathways also are activated by environmental stress and can have an effect on thoughts, feelings and actions taken in response to the particular environmental threat. These chemical redundancies in the brain are further evidence that we need to abandon the viewpoint that we can fragment the brain and attribute one feeling or one disease to one neurologic pathway or simply one neurotransmitter.
The extent to which different systems and subsystems respond to a specific stimuli can be determined by previous neuroplastic changes related to the perceived meaning of that stimuli. What remains unexplored is the extent to which neuroplastic changes are related to unseen, or as yet unknown interpersonal, imperceptible phenomenon. Over 200 years ago, Benjamin Franklin defined a new branch of science he termed animal magnetism, now called hypnosis, to try to describe the way that one person can greatly influence the thoughts, actions and well-being of others. Other, unseen influences were described by Black who examined the evidence that cohabiting females (both animals and humans) tend to synchronize their menstrual periods because of the effect imperceptible olfactory stimuli (pheromones) have on the neurohormonal system. Thus, neurohormonal protein complexes should be viewed as influences, rather than determinants of behavior affected by internal (neuroplastic) as well as external factors.
Neuroplasticity of Learning
Learning results in measurable changes in neurologic structure and function. Learning which is short-term and transient, lasting for no more than a few weeks, primarily involves changes in the size and chemical make-up of quanta stored in the presynaptic terminals. Long-term learning involves a process of neuron structural changes with a modification neuron structure and interconnections with other nerve cells. During this process, growing axons can recognize appropriate target cells, suggesting the neuroplasticity of learning is an organized rather than random or chaotic process.
Striking a balance between the excitatory and inhibitory amino acids plays a key role in the neuroplastic changes associated with learning, memory and sensory-motor control. The primary amino acid associated with use-dependent synaptic plasticity, NMDA, exerts its effect by regulating the receptors which allow the passage of highly-charged calcium and magnesium ions. The non-NMDA excitatory amino acids mediate fast excitatory synaptic transmission of receptors which regulate the lower charged sodium and potassium ions. These EAAs play a key role in the long term changes associated with learning through a process of phosphorylation of the glutamate receptors in the hippocampus. The inhibitory neurotransmitter, GABA, exerts an effect on these EAAs, promoting organized processes and preventing the possibility of chaotic, neurodestructive changes.
Memory systems encode, consolidate and retrieve memories. Generally, sensory information placed into long-term memory is said to be learned. Indeed without memory, learning as we know it could not occur. Two memory subsystems, the declarative system which primarily uses in explicit learning related to knowledge, and the procedural memory system which relies on implicit learning related to skills, have separate structures and functions.
A person needs to pay attention to sensory information, have an intact memory system and be motivated to remember the information for explicit learning to occur. This involves intact systems throughout the brain, including the ascending reticular activating system in the brainstem for arousal, thalamus and parietal lobes for selective attention, and prefrontal region for the vigilance and concentration required to learn.
The sensory information is sent to the limbic (emotion-related) structures including the hi hippocampus and amygdala and cortical (thought-related) regions of the brain. The amygdala contributes to the storage of associated emotions and plays an important role in reshaping emotionally-charged memories before sending the information to the hippocampus for sorting and storage. If the information is deemed to be threatening, the amygdala either buries the memories where conscious recollection is inhibited, dissociation is facilitated or the information is fragmented in a fashion so that only small portions of the traumatic experience can be recalled at a given time.[1,3] Thus "scare tactics" used during patient education will be more likely to hinder learning than pleasant emotions which may facilitate the recall of information as relayed.
The hippocampi sort the essential information and code it to match similar information. The short-term memory is stored in the hippocampal formation for about four weeks before it is stored in the neocortex by some unknown process before being committed to long-term memory. Once categorized, the information is sent to the cortex where it is associated and integrated with existing long term memories. Long-term memories are stored in the cortical regions of the temporal, parietal and occipital lobes. The left hemisphere is better able to store information that involves sequential analysis, such as facts, words, numbers and theories. The right hemisphere is believed better suited to store memories which are more holistic, such as art, music and the recognition of people, places and things.
A different type of neuroplasticity is related to the implicit learning associated with long-term improvements in knowledge, psychomotor skills, memory and sensitivity. Whereas explicit knowledge requires conscious recall (memory) of information, implicit knowledge is often exhibited without conscious effort or awareness.
Implicit learning, such as procedural memories or those related to skills, require repetition of motor activities over time. This type of learning includes such things as cooking, driving a car, starting an intravenous line (IV) or performing cardiopulmonary resuscitation (CPR). Once a sufficient level of competence is attained, the person can remember and perform the procedure months, even years later. The exact location or mechanism of procedural learning is not well defined, however, it is believed to involve the cortical and subcortical motor regions, basal ganglia, brainstem and cerebellar regions.
Despite all the attention given to neuroplastic changes in the brain, learning also is associated with changes in other parts of the body as well as psychosocial and behavioral changes. Wolpaw addresses the importance of neuroplastic changes that occur in the spinal cord. He points out that skills like walking, playing a musical instrument or excelling in a sport take months, even years to perfect and must be "over learned" before they are performed unconsciously. The spinal stretch reflex model he tested supported the hypothesis that bilateral spinal and supraspinal plasticity occurs with this type of learning. He further presents data which supports that continued repetition is required in order to perform these skills at a high level.
Thus a nurse who has not inserted an IV for an extended period of time may cognitively remember the procedure, however the spinal and supraspinal nerves might have "forgotten," resulting in a less than precise, perhaps clumsy performance. Less tangible nursing skills may also rely on this type of learning. Benner and Tanner described how expert nurses are able to recognize subtle patterns, connect present observations to similar past experiences and use their common sense, clinical knowledge and skills as well as intuition to anticipate and meet complex patient needs. One is left to ponder if these exemplar cases are related to implicit learning, or if intuition represents a completely different process.
The transmission and perception of pain is a complex multidimensional process. Before exploring how neuroplastic changes may affect pain perception, the physiological processes related to hitting a "funny bone" will be described. Most people have hit their elbow the wrong way which compresses the nerve bundle and elicits a response that is similar to a simultaneous stimulation of all tactile and nocciceptive receptors at once. Because a person may momentarily feel hot, cold, tickle or various other sensations, it is often called the "funny bone."
At the time of impact, A-delta fibers send sharp, tingling messages of pain to the dorsal horn of the spinal cord at a rate of 40 miles per hour. When the impulse reaches the axonal terminal, presynaptic vesicles release quanta of neurotransmitters, such as substance P. This substance P activates ion channels on the postsynaptic membrane which allows an influx of positively charged ions to spark an electrical impulse.
A stream of these impulses travel along the neospinothalmic tract, carrying messages of pain to the thalamus. From there, the presynaptic membranes release their quanta, which activate the third order neurons to send the message of this pain to higher centers where we think, feel and respond to the stimuli. This pain message is almost instantly perceived as sharpness.
Meanwhile, unmyelinated C-fibers are traveling a similar, but slower (3 miles per hour) path. The message is transmitted by a similar process described above, to a deeper layer of the spinal cord, the paleospinothalamic tract. En route to the brain, projections of this tract stimulate the reticular formation, periaqueductal gray, hypothalamus and both the medial and intralaminar thalamic nuclei, before connecting with the limbic system and higher centers of the brain.
Moments after the sharp A-delta messages are perceived, the dull aching C-fiber signals take over. These discomforts are often more bother-some to the person, perhaps because of related limbic system activation. The common behavioral response to rub or apply heat or cold to the site stimulates A-beta fibers to fire. These race to the brain at 200 miles per hour and affect the central nervous system in a way that reduces the perception of pain. Whether this counterstimulation works by distracting attention from the pain, or by stimulating descending inhibitory pain control systems is unclear. The descending pain modulation system runs parallel to the pain fibers, involving the cortical and diencephalic systems, mesencephalic systems (periaquaductal gray) to the nucleus rapine magnus which exerts an effect on the dorsal horn.
A primary way that pain modulation occurs is through the endogenous opiate system, first described in 1975 by Hughes and associates. Since that description of the discovery of two endogenous opiates, an entire system of endogenous opiates as well as the role of the serotonin and norepinepherine systems in modulating pain have been described. When the endorphin system is activated, opiate receptor sites are filled with endorphins that block the release and slow the production of chemical messengers of pain (substance P) from the presynaptic membrane. This prevents the opening of postsynaptic ion channels, which would allow sodium, potassium and other positively charged ions to rush into the neuron, thus transmission of painful messages is inhibited.
Clinical evidence supporting the descending control of the gates is offered by the effectiveness of pain relief by methods such as intraspinal or intraventricular infusions of opioids. Electrical stimulation of the spinal cord, pituitary gland, limbic system and deep brain structures all have demonstrated an ability to reduce pain.[10,23] Evidence that suggests a broader focused, multisystem model is utilized; this includes physiologic evidence of endorphins in different parts of the brain, midbrain, spinal cord, gastrointestinal tract, genitourinary tract and musculoskeletal systems.[13,14] The notion that endorphins are keys capable of only closing the ion channels is in question because they have been found at times to increase the perception of pain. It is also "well established that pain reflects complex, linked neuroendocrine responses that go far beyond a sensory alarm system," (p.76) beyond the nervous system and perhaps beyond the limits of the body.
Neuroplastic Changes with Chronic Pain
Unrelieved severe pain changes the structure and function of the nervous system in such a way that prolongs and intensifies the pain experience. If pain is intense or prolonged, a wind-up phenomenon occurs where signals get caught in reverberating loops, which further prolong and intensify the noxious stimuli. Coderre, Katz, Vaccarino and Melzack present compelling clinical and experimental evidence that unrelieved pain results in neuroplastic changes in the spinal cord that account for many severe and debilitating pain syndromes. In addition to complex changes in nerve structure, higher levels of excitatory amino acids, neuropeptides and intracellular calcium levels make it easier for pain to be triggered by nonpainful stimuli. These neuroplastic changes in the spinal cord and brain could account for severe and debilitating pain even months or years after the painful stimuli is removed providing an explanation for the development and perpetuation of incurable chronic pain syndromes. The fact that the intensity and duration of chronic pain is greater than the extent of tissue damage suggests that the damage is in the central nervous system, not only the tissue at the "source" of the pain. Thus chronic ankle pain is understandable even if an ankle x-ray is negative. A more appropriate way to identify pathology would be through neurophysiologic studies of the spinal cord, not anatomic studies of the ankle.
With elevated levels of positive ions within interneurons, the pain threshold is lowered and the cells are said to be sensitized. Sensitization of the central nervous system is reflected by spontaneous neuron firing, reduced thresholds or increased responsivity to afferent inputs, prolonged after-discharges to repeated stimulation and the expansion of the peripheral receptive field of dorsal horn neurons. Thus, if pain is not relieved in an expedient fashion, sensitization occurs which intensifies, spreads and prolongs the transmission of pain messages. With this sensitization, stimuli that is not normally painful hurts. A similar process occurs with acute febrile illness when even the contact with clothing or linen may be perceived as painful.
In the wake of prolonged stimuli and sensitization, an intracellular build-up of calcium ions further increases sensitivity, while stimulating protein synthesis which initiates the process of nerve growth in the affected and surrounding neurons. As the pain fibers grow and make new connections, the pain spreads and persists while the inhibitory nerves which serve to dampen messages of pain are slowly destroyed and the neurochemical systems related to control of EAAs, serotonin, norepinepherine, opiates and GABA become dysfunctional.[4,10] When unpleasant stimuli persists for longer than 24 hours, this process begins, particularly with the small, unmyelinated C-fibers that are associated with the more bothersome type of pain.
Neuroplastic Similarities Between Learning and Pain
It appears that the basic organizing scheme of the brain is that of anatomic reciprocity with checks, balances and redundancies in place to ensure survival and permit flexible adaptation to environmental changes. Interactions occur throughout the various levels of the nervous systems. Neuroplasticity for both learning and pain are described in terms of two basic processes. One type of neuroplasticity involves neuron growth and the establishment of new intracellular connections. The other type involves chemical, or related changes in the synapses which regulate presynaptic quanta and postsynaptic receptors. Related to this second type, NMDA release regulates postsynaptic calcium ion concentration, which could damage the central nerves if left unchecked. Another interesting similarity is that both information for learning and pain pass though the arousal center of the reticular formation and the emotion-related limbic system before cognitive processing occurs.
Both learning and pain are complex multidi-mensional phenomenon that affect every aspect of the person, physically, psychologically, behaviorally, cognitively, culturally and spiritually, not just tiny zones in the central nervous system. The opposite can also be said to be true, that physical, psychological, behavioral, cognitive, cultural and spiritual characteristics of the person affect what is learned and how pain is experienced. Further, the learning and the pain that is experienced today is capable of changing nerve patterns in a way that will affect future learning or pain.
Neuroplastic Differences Between Learning and Pain
It became clear after conducting this investigation that learning and chronic pain were different neuroplastic processes. Whereas learning is an adaptive controlled process with properly functioning checks and balances, chronic pain is chaotic, unchecked and maladaptive. The excessive and prolonged stimulation of NMDA channels increases nerve irritability related to high intracellular calcium ion concentration and produce a sensitized state. If endorphins are present, or opiate pain relievers provided on a long-term basis, the normal checks and balances of sodium and potassium ions can not protect the interneuron from NMDA destruction. The sprouting of new nerve growth that occurs with pain is chaotic and often times sets up reverberating loops that prolong and intensify pain despite the lack of new nocciceptive input.
This body of research is also uncovering new treatment strategies, such as neuroprotective agents to be used after head or neck trauma and neurotropic drugs to enhance the memory and learning capabilities of patients with Alzheimer's disease. By further understanding how neuroplastic changes work, providers can be better prepared to manage abnormal tone and spontaneous nerve firing in patients with other types of neurologic impairments. Interventions directed at regions contralateral to affected zones have been found to maximize neurologic structural and functional changes during periods of recovery.
Nurses should remember that knowledge and skills are learned and remembered in different parts of the central nervous system. When trying to teach a person about a procedure or skill, the patient needs to practice that skill repeatedly, not merely be informed about what they need to do. Final evaluation of whether or not the patient has really implicitly learned the skill and incorporated it into their "unconscious" patterns of behavior can not be made until four weeks of practice has past.
Nurses also need to know that if severe pain is permitted to go unrelieved for more than 24 hours, neuroplastic changes, which contribute to the development of incurable chronic pain syndromes may occur. As for the treatment of chronic pain, a better understanding is needed of how long-term opiate use affects neuroplastic changes. There is evidence that long-term use of opioids in some individuals can induce a hyperexcitable state similar to chronic pain, whereas other individuals do not develop chronic pain syndromes with appropriate opioid therapy. Whether this is the result of physiologic or psychosocial reinforcement is unclear; however, a more desirable approach to chronic pain treatment than long-term opioid therapy may be cognitive-behavioral therapy which teaches patients thought patterns and coping skills that help reduce pain while enhancing self-control and autonomy. In a way, this type of therapy is using an adaptive form of neuroplasticity (learning) to combat a maladaptive form (chronic
It is clear that internal and external stimuli are capable of producing structural and functional changes in biobehavioral patterns. Cognitive-behavioral therapy effects changes in patients by helping them to change their thoughts, and subsequently their emotional and behavioral responses. The resultant change in thoughts, feelings and coping skills has demonstrated its effectiveness in reducing distress and improving function for chronic pain patients across many studies. Drug therapy also effects biobehavioral changes, however the mechanism is different than the teaching methods described. Often times the combination of drug and "talk" therapy produces larger and quicker effects as each works on a different point on the mind-brain cycle.
There is a fascinating body of literature emerging that is changing our understanding of how the mind and the body work. As more is known about the ways that nerves work in adaptive and maladaptive circumstances, new assessments and treatment approaches will emerge. The study of neuroplasticity in humans has been difficult to date. New methods of investigation using functional imaging techniques as described by Karni and colleagues allows investigators to actually visualize and measure the neurologic changes that are occurring. There is enough physiologic evidence to support the notion that chronic pain is a learned, albeit maladaptive, phenomenon, however diagnostic technologies to confirm the presence of specific neuroplastic changes in chronic pain patients have yet to be developed.
After a millennia of study, science is beginning to understand how sensory processing, learning and memory occur through changes in the relationships between nerve cells. Further understanding of how people are able to literally change their mind through neuroplastic processes is a challenge for this new millennia. Ultimately, this understanding is sure to provide insights into the workings of perception, intelligence and consciousness.
This project was supported in part by the Boston College University Fellowship Program. The author wishes to thank Honor Arnstein, Joanne Willens and Ann Rolfe for their support and assistance with this manuscript. The role of Marjory Gordon who encouraged perseverance during the early stages of this review is acknowledged.
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Questions or comments about this article may be directed to. Paul M. Arnstein, PhD, RN, CS, 12 Oxalis Way, Concord, New Hampshire 03303. He is a clinical nurse specialist at Concord Hospital in Concord, New Hampshire and a University Fellow at Boston College in Massachusetts.
Copyright [C] American Association of Neuroscience Nurses 0047-2603/96/2903/0179$1.25
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|Author:||Arnstein, Paul M.|
|Publication:||Journal of Neuroscience Nursing|
|Date:||Jun 1, 1997|
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