E
EAE
Experimental Allergic Encephalitis
Early Mobilization
Definition
Early mobilization is the early resumption of activities of daily living, usually within 24 hours after surgery.
Postoperative Pain, Importance of Mobilisation
ECD
Equivalent Current Dipole
Ectopia, Spontaneous
R
OBERTH. L
AM
OTTEDepartment of Anesthesiology, Yale School of Medicine, New Haven, CT, USA
robert.lamotte@yale.edu
Synonym
Spontaneous Ectopia
Definition
Ongoing nerve impulses produced by an atypical gener- ator (“pacemaker”), often at an abnormal locus in the pri- mary sensory neuron, for example at a site of injury. The ectopic discharges are spontaneous, i.e. endogenously generated by the neuron in the absence of an apparent external stimulus.
Characteristics
The types of injuries that produce spontaneous ectopia (SE) (see
Ectopia, Spontaneous) include axotomy, mechanical trauma such as nerve compression, demyeli- nation and inflammation. However, after each kind of injury, only a subpopulation of neurons exhibits SE.
The SE typically originates in a part of the neuron that is close to the site of injury, and/or within the
dorsal root ganglion (DRG). In addition, SE sometimes also occurs in the neighboring uninjured neurons that presumably activated as a result of the injury (Wu et al. 2002; Ma et al. 2003). The SE in neurons with myelinated (A- fiber) axons typically has a regular pattern (with a more or less constant interval between nerve impulses, e.g.
35–65 ms) that, for some neurons, is continuous and, for others, periodically interrupted by periods of silence resulting in “bursts” (Fig. 1a, b). Other neurons with A-fibers, and most of those with unmyelinated (C-fiber) axons, exhibit an irregular pattern with longer intervals between impulses, e.g. 100–1000 ms or more) (Devor and Seltzer 1999) (Fig. 1c).
Although SE may appear to be endogenous to an elec- trophysiologically recorded hyperexcitable neuron, i.e.
occurs in the absence of experimentally applied stimuli, it can in many instances be modulated (or in some cases produced in silent “injured” neurons) by externally applied mechanical, thermal or chemical stimuli. Such stimuli might normally be present in vivo in the form of body temperature, movement of limbs, local ischemia, anoxia and the presence of inflammatory mediators at the injury site. For example, there is a host of endoge- nous chemical factors that might modulate or induce SE in hyperexcitable neurons, including substances re- leased from sympathetic neurons (e.g. norepinephrine), or from sensory neurons (neuropeptides), or inflamma- tory mediators normally present or released in injured or inflamed tissue (Devor and Seltzer 1999).
SE in Axotomized Sensory Neurons
If the axon of an adult DRG neuron is transected (axo-
tomized), for example by a cut, a severe compression, or
as a result of disease, the end of the portion still connected
to the cell body (soma) may begin to sprout within hours
or days. After the transection of peripheral but not central
(dorsal root) axons, some of these sprouts may regener-
678 Ectopia, Spontaneous
Ectopia, Spontaneous, Figure 1 Typical patterns of injury-induced ectopic discharge recorded intracellularly from the intact DRG. (a) Tonic discharge recorded from an L5- DRG with a myelinated axon, transected 5 days earlier by a spinal nerve ligation (from Ma et al. 2003, Fig. 7). (b) Bursting discharge in a non-axotomized L4 with a myelinated axon, 5 days after transection of the adjacent L5 spinal nerve. Each burst follows an increase in the amplitude of oscillation of the resting membrane potential (Liu et al. 2000, Fig. 1C, action potentials have been truncated). (c) Irregular discharge in an non-axotomized neuron with an unmyelinated axon and a cell body in a ganglion that had been compressed for 6 days by a rod inserted into the intervertebral foramen (from Zhang et al. 1999, Fig. 2E). Voltage scale: 10 mV for (a, b), 20 mV for (c). Time scale:
100 ms for (a), 200 ms for (b), and 500 ms for (c).
ate back to the target tissue and re-establish functional connections. Certain other regenerating sprouts may be- come trapped and entangled forming a structure called a “
neuroma”. A proportion of the injured neurons de- velop SE, which typically originates at the site of injury, but can also originate within the DRG.
After transection of the sciatic nerve, the incidence of SE is initially greater during the first two weeks for neurons with myelinated axons (A-neurons) than those with unmyelinated axons (C-neurons) (Devor and Seltzer 1999). Thereafter, the reverse is true, with SE being more common for C- rather than for A-neurons.
For A-neurons, the incidence of SE is greater for nerve lesions closer to the somata (transection of the spinal- as opposed to the sciatic nerve). However, the reverse is true for C-neurons, where there is virtually no SE after transection of the spinal nerve (Liu et al. 2000). The reasons for these observations must await identification, both of the chemical factors that alter the excitability
of a neuron after axotomy, the cells that release the chemicals, and the events that lead to their release.
Several weeks after a sciatic nerve injury, some pairs of injured nerve fibers develop an abnormal, but stable, electrical (“
ephaptic”) interaction between certain nerve fibers, for example, between the endings of two fibers terminating in a neuroma or within the site of a crush injury. Ephaptic communication can also develop within pairs of fibers that are in close apposition, with patches of demyelination presumably where the glial insulation is absent (Devor and Seltzer 1999). One pos- sible functional consequence of ephaptic connections is that activity in nociceptive afferent nerve fibers are evoked by activity in low-threshold mechanoreceptive, sympathetic or motor nerve fibers.
Ephaptic connections do not form in the DRG. How-
ever, another type of cross-excitation can occur within
the DRG between repetitively discharging neurons
and their passive neighbors. This “cross excitatory dis-
E
Ectopia, Spontaneous 679
charge” is mediated not electrically but by an unknown chemical mediator (Devor and Seltzer 1999).
SE in Intact Sensory Neurons
SE can also develop in intact neurons after either an ax- otomy or, in the absence of axotomy, after a local de- myelination, inflammation or compression of the nerve or the DRG. The SE can originate in the DRG, even in many instances when the site of injury or inflammation appears confined to the peripheral nerve.
After a transection of either a mixed (spinal) nerve or a ventral root (containing only motor nerve fibers) at L5, a low level of SE develops in intact sensory neurons with unmyelinated axons and cell bodies in the adjacent L4 ganglion (Wu et al. 2002). In addition, after a transection of the L5 spinal nerve, the various patterns of SE that develop in the axotomized L5 A-neurons are also found in intact A-neurons with cell bodies in the adjacent L4 DRG (Ma et al. 2003). Thus, the initiation of SE in the DRG may not be due to the absence of an axonally transported signal from the peripheral target, but rather to the retrograde delivery of a positive signal from the injury site to the DRG. Possible signals that might in- duce SE in the somata or distal axons of intact neurons include cytokines such as nerve growth factor (NGF), tumor necrosis factor-α(TNFα),interleukin-1α(IL-1α), IL-1β,andIL-6releasedbyreactivecellsinthetargettis- sue and/or, by Schwann cells surrounding nerve fibers undergoing Wallerian degeneration and by invading macrophages.
Certain neurodegenerative diseases such as multiple sclerosis or injuries produced by nerve entrapment may cause focal demyelination. A proportion of demyeli- nated axons do exhibit SE in the absence of axotomy or a loss of conduction (Kapoor et al. 1997).
Inflammatory processes per se can lead to SE in a sub- population of peripheral sensory neurons. In an experi- mental model of immune mediated neuritis, topical ap- plication of Complete Freund’s Adjuvant to a focal re- gion of the sciatic nerve produced ipsilateral cutaneous
hyperalgesia and SE described as irregular, of a slow rate (about 1 Hz), and confined to a subpopulation of unmyelinated and thinly myelinated nerve fibers inner- vating subcutaneous musculoskeletal tissue (Bove et al.
2003).
A
chronic constriction injury (CCI) produced in the rat by a loose ligation of the sciatic nerve is accompanied by a partial axotomy, local inflammation and demyelination in the vicinity of the injury site and ipsilateral cutaneous hyperalgesia. SE in both C- and A-neurons originated at the injury site or within the DRG, and its rate increased by stimulation of sympathetic efferent neurons or by ap- plication of norepinephrine to the DRG or to the injury site. Most of the neurons with SE had transected axons, though a minority conducted through the injury site and thus could be considered as intact (Kajander and Bennett 1992).
A model of chronic compression of the DRG (CCD), which might occur with a laterally herniated disk or foraminal stenosis, was produced in the rat by the inser- tion a rod into the intervertebral foramen, one at L4 and another at L5. This produced cutaneous hyperalgesia in the ipsilateral hind paw and SE, originating in the DRG, in neurons with intact, conducting axons. The SE occurred in both neurons with unmyelinated and myelinated axons, and was exhibited even after the formerly compressed DRGs were removed from the animal and recorded in vitro from the intact ganglion (Zhang et al. 1999).
Cellular Mechanisms of SE
There are similarities in the characteristics of somal hy- perexcitability after seemingly different types of injury such as peripheral or spinal nerve axotomy, periph- eral nerve constriction, or DRG compression without axotomy: these include SE that is regular, bursting or irregular (Fig. 1), lower than normal current thresholds (a lesser magnitude of current injected into the soma required to elicit an action potential), decreased accom- modation (increased firing to an injection of steady, suprathreshold current), and subthreshold membrane potential oscillations (Devor and Seltzer 1999; Ma et al.
2003). These characteristics are exhibited by dissoci- ated somata of the DRG neuron (after prior injury). The dissociated neurons can be labeled by a dye delivered peripherally prior to injury to determine whether the neuron innervated, for example, skin or muscle. For example, a subpopulation of A-neurons with medium size cell bodies, with narrow non-inflected action po- tentials and including some cutaneous but primarily muscle afferents, exhibited spontaneous subthresh- old oscillations of their resting membrane potential or upon depolarization after peripheral or spinal nerve transection (Liu et al. 2002). A-neurons with simi- lar oscillations and action potential properties were recorded intracellularly from the intact ganglion after spinal nerve transection (Liu et al. 2000) or after chronic compression of the ganglion (Zhang et al. 1999), and also from axons after experimentally induced demyeli- nation (Kapoor et al. 1997). Blockers of sodium or potassium currents can respectively block or initiate an increase in the oscillations in these A-neurons (Kapoor et al. 1997; Liu et al. 2001). Of those DRG neurons exhibiting a bursting pattern of SE, the amplitude of ongoing membrane oscillation typically increased just prior to each burst, suggesting that the former triggered the latter (Fig. 1b).
Patch-clamp recordings of isolated currents in disso-
ciated DRG somata provide an insight into the effects
of different injurious/inflammatory conditions in alter-
ing ion channel properties. Dissociated neurons from
lumbar DRGs ipsilateral to a transection of the spinal
or sciatic nerve express a variety of changes in sodium,
potassium and calcium currents. These include an in-
680 Ectopia, Spontaneous
crease and faster repriming of a kinetically fast
TTX- sensitive sodium current (Nav 1.3) and decreases in other currents including a slow TTX-resistant current (Waxman et al. 1999), a high-voltage-activated calcium current (Baccei and Kocsis, 2000), and sustained and transient potassium currents (Everill and Kocsis 1999).
TTX-R current in DRG somata also decreases after CCI (Dib-Hajj et al. 1999). The hyperpolarization cation current (Ih) increases after CCD (Yao et al. 2003). A decrease in potassium current and increase in sodium and/or Ih current could contribute to the decrease in current threshold and accommodation in excitable DRG neurons after nerve injury.
The responses of SE neurons to norepinephrine and inflammatory mediators such as serotonin, histamine, bradykinin and prostaglandin E
2may be intrinsic prop- erties of the cell bodies (somata) of neurons after a nerve injury such as CCI, because they are recorded in vitro from the intact ganglion and from cells that have been acutely dissociated (Petersen et al. 1996).
Ectopia, Spontaneous, Figure 2 Schematic of how pain might be evoked by normal activity in cutaneous dorsal root ganglion (DRG) neurons and by ectopic spontaneous activity after neuronal injury. (a) Normal activity in uninjured neurons. Pain and touch are normally elicited by respective activity in nociceptive- (N1, N2) and low-threshold mechanoreceptive (M) neurons. N terminates onto a spinothalamic tract (STT) neuron (S) whose cutaneous receptive field is shown on the left (large, dashed oval). M projects into the dorsal columns (DC) but sends a collateral axon to S. After a localized injury or inflammation of the skin (such as a minor cut to the skin resulting in release of inflammatory chemicals e.g. from blood vessels, mast cells), activity in N1 releases a neurotransmitter that sensitizes S (“central sensitization”) such that its output in response to nociceptive mechanical stimuli (e.g. a pricking with a stiff hair that activates N2) is increased (contributing to hyperalgesia), and its response to innocuous touch (e.g. lightly stroking the skin that activates M) is enhanced, thereby contributing to touch-evoked allodynia both within and outside (larger dashed oval) the area of injury. (b) Spontaneous ectopic activity (SE) in injured neurons. SE can originate at the site of a local demyelination and/or inflammation (a), from the proximal ends of transected axons forming a neuroma (b), from the DRG of injured or inflamed neurons (c), or as a result of compression/inflammation of the ganglion itself. After axotomy, a loss of input to inhibitory neurons (d) might disinhibit activity in nociceptive STT neurons thereby causing pain of central origin.
In this example, chronic ectopic discharges in N1 could elicit, in addition to pain, central sensitization leading to chronic allodynia and hyperalgesia.
SE in mechanoreceptive afferents mediating touch could elicit abnormal sensations (paresthesiae) and, in the presence of central sensitization, chronic pain
Contribution of SE to Pain, Hyperalgesia and Allodynia
In addition to producing pain and paresthesiae, it is
likely that SE in appropriate primary sensory nocicep-
tive neurons could increase the sensitivity of second
order neurons in the spinal dorsal horn (“central sensiti-
zation”). Central sensitization can occur in the absence
of neuronal injury (Fig. 2a). For example, a local in-
tradermal injection of capsaicin in the arm produces a
wide area of hyperalgesia (enhanced pain to normally
painful stimuli such as a pin prick), and allodynia (pain
to normally non-painful stimuli, such as a touch) to
mechanical stimulation of the skin surrounding the area
exposed to the chemical. The basis for this is believed
to be the lowered threshold responses and increased
suprathreshold responses of spinal nociceptive neurons
in the dorsal horn (LaMotte et al. 1991). Thus, it is
possible that SE, resulting, for example, from nerve
injury, may produce and maintain a state of chronic
central sensitization (Fig. 2b) thereby contributing to a
chronic state of hyperalgesia and allodynia.
E
Ectopic Nerve Impulses 681
References
1. Baccei ML, Kocsis JD (2000) Voltage-Gated Calcium Currents in Axotomized Adult Rat Cutaneous Afferent Neurons. J Neu- rophysiol 83:2227–2238
2. Bove GM, Ransil BJ, Lin HC et al. (2003) Inflammation Induces Ectopic Mechanical Sensitivity in Axons of Nociceptors Inner- vating Deep Tissues. J Neurophysiol 90:1949–55 2003 3. Devor M, Seltzer Z (1999) Pathophysiology of Damaged Nerves
in Relation to Chronic Pain In: Wall PD, Melzack R (eds) Text- book of Pain, 4thedn. Churchill Livingstone London, pp 129–164 4. Dib-Hajj SD, Fjell J, Cummins RR et al. (1999) Plasticity of Sodium Channel Expression in DRG Neurons in the Chronic Constriction Injury Model of Neuropathic Pain. Pain 83:591–600 5. Everill B, Kocsis JD (1999) Reduction of Potassium Currents in Identified Cutaneous Afferent Dorsal Root Ganglion Neurons after Axotomy. J Neurophysiol 82:700–708
6. Kajander KC, Bennett GJ (1992) Onset of a Painful Peripheral Neuropathy in Rat: A Partial and Differential Deafferentation and Spontaneous Discharge in A Beta and A Delta Primary Afferent Neurons. J Neurophysiol 68:734–744
7. Kapoor R, Li YG, Smith KJ (1997) Slow Sodium-Dependent Potential Oscillations Contribute to Ectopic Firing in Mammalian Demyelinated Axons. Brain 120:647–652
8. LaMotte RH, Shain CN, Simone DA et al. (1991) Neurogenic Hy- peralgesia: Psychophysical Studies of Underlying Mechanisms.
J Neurophysiol 66:190–211
9. Liu CN, Michaelis M, Amir R et al. (2000) Spinal Nerve In- jury Enhances Subthreshold Membrane Potential Oscillations in DRG Neurons: Relation to Neuropathic Pain. J Neurophysiol 84:205–215
10. Liu CN, Devor M, Waxman SG et al. (2002) Subthreshold Os- cillations Induced by Spinal Nerve Injury in Dissociated Mus- cle and Cutaneous Afferents of Mouse DRG. J Neurophysiol 87:2009–2017
11. Ma C, Shu Y, Zheng Z et al. (2003) Similar Electrophysiologi- cal Changes in Axotomized and Neighboring Intact Dorsal Root Ganglion Neurons. J Neurophysiol 89:1588–1602
12. Petersen M, Zhang J, Zhang JM et al. (1996) Abnormal Sponta- neous Activity and Responses to Norepinephrine in Dissociated Dorsal Root Ganglion Cells after Chronic Nerve Constriction.
Pain 67:391–397
13. Waxman SG, Dib-Hajj S, Cummins TR et al. (1999) Sodium Channels and Pain. Proc Natl Acad Sci USA 96:7635–7639 14. Wu G, Ringkamp M, Murinson BB et al. (2002) Degeneration
of Myelinated Efferent Fibers Induces Spontaneous Activity in Uninjured C-Fiber Afferents. J Neurosci 22:7746–7753 15. Yao H, Donnelly DF, Ma C et al. (2003) Upregulation of the
Hyperpolarization Cation Current after Chronic Compression of the Dorsal Root Ganglion. J Neurosci 23:2069–2074
Ectopic Activity (Ectopic Discharge)
Definition
Ongoing nerve impulses (action potentials) produced by an atypical generator („pacemaker“) at an abnormal lo- cus in the primary sensory neuron, for example, at a site of injury (e.g. at the axon proximal to the receptive end- ing or at the cell body membrane in the dorsal root gan- glion. The ectopic discharges are spontaneous, i.e. en- dogenously generated by the neuron in the absence of an apparent external stimulus. These action potentials propagate in both directions from the somata, and are thought to contribute to central sensitization in the dor- sal horn. Neuroma afferents usually display spontaneous
i.e. ectopic activity and mechanosensitivity (hence they are excitable). Ectopic excitability in nociceptive affer- ents is a putative mechanism for pain. Ectopic activity in non-nociceptive afferents may also be important if they acquire synaptic efficacy such that central pain signaling neurons are activated.
Drugs Targeting Voltage-Gated Sodium and Calcium Channels
Ectopia, Spontaneous
Neuroma Pain
Neuropathic Pain, Joint and Muscle Origin
Proinflammatory Cytokines
Trigeminal Neuralgia, Diagnosis and Treatment
Ectopic Excitability
Definition
Neuroma afferents display spontaneous activity and mechanosensitivity (hence they are excitable). This ac- tivity is ectopic in the sense that neural activity normally arises in the terminals of sensory fibers in the innervated structures. Ectopic excitability in nociceptive afferents is a putative mechanism for pain. Ectopic activity in non-nociceptive afferents may also be important if they acquire synaptic efficacy such that central pain signaling neurons are activated.
Ectopic, Spontaneous
Neuroma Pain
Ectopic Mechanosensitivity
Definition
Neuromas are mechanosensitive in the sense that me- chanical stimuli applied to them evoke neural activity and sensation. The mechanosensitivity is ectopic, as pain is not evoked by mechanical stimulation along the course of healthy nerves.
Ectopic, Spontaneous
Neuroma Pain
Ectopic Nerve Impulses
Definition
Anomalous generation of impulses along nerve fibers.
The type of symptom usually indicates the kind of fiber originating ectopic activity, which can be motor, sensory (with different submodalities) or autonomic.
Ectopia, Spontaneous
Ectopic Activity (Ectopic Discharge)
Painless Neuropathies
682 Edema
Edema
Definition
The accumulation of excessive fluid in the intercellular spaces of subcutaneous tissue. This can be caused by an increased permeability of the microvascular endothe- lium, resulting in leakage of vascular components into tissue.
Inflammation, Modulation by Peripheral Cannabi- noid Receptors
EDT
Electrodiagnostic Testing (Studies)
Education
Information and Psychoeducation in the Early Man- agement of Persistent Pain
Education and Chronicity
Pain in the Workplace, Risk Factors for Chronicity, Demographics
EEG
Electroencephalogram/Electroencephalography
Effect Size
N
IKOLAIB
OGDUKDepartment of Clinical Research, Royal Newcastle Hospital, University of Newcastle, Newcastle, NSW, Australia
nbogduk@mail.newcastle.edu.au Synonyms
Efficacy; effectiveness; Attributable Effect Definition
Effect size is a measure of how effective a treatment is when applied to a group of patients. It can be used to measure by how much a group of patients improves after treatment, or by how much a particular treatment is better than another treatment to which it is compared.
Characteristics
For any outcome variable, a group of patients will typi- cally exhibit a normal distribution of values (Fig. 1). That distribution will have a mean value ( μ) and a standard deviation (sd). About 68% of the patients will express a value between one standard deviation less than the mean value, and one standard deviation greater. The outcome measure may be pain scores or any other outcome of in- terest.
If that group of patients undergoes a treatment, their out- come variables will change, but will again assume a nor- mal distribution (Fig. 2). The change in their scores will be reflected by the difference between the mean values before ( μ
0) and after ( μ
1) treatment.
Whether or not the change is a clinically meaningful one depends on the magnitude of the change with respect to the spread of values, before and after treatment. A given change in mean values may not be impressive if the patients exhibit a wide spread of values (Fig. 3a). Un-
Effect Size, Figure 1 In a sample of patients, the values of any outcome measure will assume a normal distribution. The mean value (μ) represents the average value. The spread of the values is reflected by the standard deviation (sd).
Effect Size, Figure 2 Before treatment, a group of patients express values of an outcome measure are distributed in a normal fashion around a mean value (μ0). After treatment, they express values distributed around a new mean value (μ1).
E
Effect Size 683
Effect Size, Figure 3 Graphic representations of the relative significance of a given change in mean values, before and after treatment, with respect to the spread of values exhibited by a group of patients. (a) The change in mean values is not greater than the spread of values in the group. Many patients after treatment have scores like those of many patients before treatment. (b)The same change in mean values is appreciably larger than the spread of values. The scores of most patients after treatment are outside the range of scores before treatment.
der those conditions, the change is not impressive, for it is encompassed by the extent to which patients nor- mally differ in their values. After treatment, many pa- tients still have scores that others had before treatment, which means that they have not improved categorically.
The treatment does not render patients different from pa- tients before treatment.
The same change, however, may be more impressive if it is appreciably greater than the normal spread of val- ues (Fig. 3b). Under those conditions, most patients have scores after treatment, which are outside the range of scores before treatment. This attests to a definite cate- gorical improvement. After treatment, most patients are distinctly better than patients before treatment.
The qualitative significance of a change can, therefore, be expressed as a ratio between the change in mean values and the distribution of values. Specifically, the
effect size is the ratio between the difference in the mean value of a selected outcome measure, and the standard deviation of that value. Some authorities rec- ommend that the distribution of values be expressed as the pooled standard deviation of the samples before and after treatment, but the simplest method is to use the standard deviation of the sample before treatment.
Under that definition:
Effect size = μ
1− μ
0sd
This equation yields a single number that indicates how effective the intervention has been. That number can be translated into a verbal description that gauges the effect size (Table 1).
Effect sizes can be calculated to determine by how much a group of patients responds to a particular treatment.
Separate effect sizes can be calculated for patients un- dergoing a particular treatment, and patients undergoing a comparison or control treatment. Those effect sizes can be compared, in order to determine the extent to which a treatment is better than control; or a relative effect size
Effect Size, Table 1 Verbal translations of selected effect sizes
Effect Size Descriptor
0.00 nil
0.20 small
0.50 medium
0.80 large
can be calculated by using the mean scores of the treat- ment group and the control group after treatment, and the standard deviation of the control group.
Utility
The attraction of effect size is that it provides, in a sin- gle number, a measure of how much a group of patients improves after treatment, or by how much a treatment achieves outcomes better than those of a control treat- ment. Different treatments can be compared according to the magnitude of their effect sizes.
A disadvantage of effect size is that it only describes the effect of treatment on a group of patients as a whole. It does not relate to individual patients. It does not indicate what chances a given patient has of benefiting, or by how much.
A further disadvantage stems from a statistical idiosyn- crasy. Since the calculation of effect size requires mean values and standard deviations, the outcome variables must be normally distributed. If outcomes are not nor- mally distributed, a mean value and, therefore, effect size, cannot be calculated.
Meta-Analysis
Oswestry Disability Index
Psychological Aspects of Pain in Women
Psychology of Pain, Efficacy
References
1. Cohen J (1977) Statistical Power Analysis for the Behavioural Sciences. Academic Press, New York, pp 20–23, 40
684 Effective Analgesia
Effective Analgesia
Definition
Effective analgesia is the provision of adequate analge- sia to enable the patient to perform „activities of daily living“.
Postoperative Pain, Importance of Mobilisation
Effectiveness
Definition
The objective of any treatment is to relieve the problems that a patient suffers. For a patient with pain, the objec- tive may be to relieve their pain, or it may be to relieve one or other of the other problems that they suffer, such as psychological distress or disabilities in everyday ac- tivities or work.
Effectiveness is a particular property of a treatment that indicates how well it achieves these objectives under av- erage or typical conditions, e.g. when average practition- ers perform the treatment on typical patients encoun- tered in their practice. In this regard, effectiveness is dis- tinguished from efficacy, which indicates how well the treatment works under ideal conditions.
Effectiveness is usually established by studies con- ducted after studies have determined the efficacy of a treatment. Efficacy studies pave the way for effective- ness studies by showing how well a treatment can work.
Studies of effectiveness are undertaken to determine if the treatment works sufficiently well under average conditions to justify its wholesale application.
As a rule, the efficacy of a treatment will usually be greater than its effectiveness. In some instances, a treatment may well have efficacy, but it might lack effectiveness. Although it works under ideal condi- tions, the results of the treatment might be confounded by the other problems that patients in typical practice present; or average practitioners may not be as skilled in providing the treatment as experts are.
A treatment may not necessarily work for all domains of a patient’s problems. It may work for one but not for oth- ers. The effectiveness of a treatment, therefore, should be qualified by the domain for which it works, e.g. effi- cacy for relief of pain, efficacy for depression, efficacy for return to work. Qualifying treatments in this man- ner avoids misinterpretation and misrepresentation, lest patients expect that because a treatment works for one symptom it will work for another.
The assessment of effectiveness is based on measuring the changes of outcome measures after treatment, and comparing them with changes after control treatments.
Efficacy can be expressed statistically in terms of num- ber needed to treat (NNT) or effect-size.
Attributable Effect and Number Needed to Treat
Effect Size
Efficacy
Effectiveness Measure
Central Pain, Outcome Measures in Clinical Trials
Effect Size
Efficacy
Definition
The objective of any treatment is to relieve the problems that a patient suffers. For a patient with pain, the objec- tive may be to relieve their pain, or it may be to relieve one or other of the other problems that they suffer, such as psychological distress or disabilities in everyday ac- tivities or work.
Efficacy is a particular property of a treatment that indi- cates how well it achieves these objectives under optimal conditions, e.g. when experts perform the treatment on ideal patients, i.e. those with a clear-cut diagnosis of the problem to be treated, and no other problems that might interfere with the results of treatment. In this regard, ef- ficacy is distinguished from
effectiveness, which in- dicates how well the treatment works under less ideal conditions.
One purpose of determining the efficacy of a treatment is to set a benchmark, which indicates how well the treatment can work. Under less than ideal conditions, however, that benchmark might not be achieved. There- fore, although practitioners might aspire to achieve the same results as those encountered in efficacy studies, they should not necessarily expect to achieve those results. The patients that they treat may not be as ideal as those recruited to a study.
Another, more subtle purpose of an efficacy study is to identify treatments that do not work. If a treatment does not work in expert hands on ideal patients, it is highly unlikely to work under normal or average conditions. In essence, if a treatment has no efficacy, it is unlikely to have effectiveness.
A treatment may not necessarily work for all domains of a patient’s problems. It may work for one but not for oth- ers. If a treatment has efficacy, it should be qualified by the domain for which it works, e.g. efficacy for relief of pain, efficacy for depression, efficacy for return to work.
Qualifying treatments in this manner avoids misinter-
pretation and misrepresentation, lest patients expect that
because a treatment works for one symptom it will work
for another.
E
Electrodiagnosis and EMG 685
The assessment of efficacy is based on measuring the changes of outcome measures after treatment, and com- paring them with changes after control treatments. Ef- ficacy can be expressed statistically in terms of number needed to treat (NNT) or effect-size.
Attributable Effect and Number Needed to Treat
Effect Size
Opioid Responsiveness in Cancer Pain Management
Efficacy of Drugs
Definition
It is possible to express the efficacy of a drug in terms of a fraction of the total receptor population (fractional receptor occupancy) that an agonist must occupy to yield a given effect. The number of receptors to be oc- cupied is inversely proportional to the intrinsic activity.
As the amount of the remaining un-occupied receptors depends on this property, the larger the receptor reserve, the greater the intrinsic efficacy. It has been suggested that the degree of tolerance is inversely related to the reserve of spare opioid receptors.
Opioid Responsiveness in Cancer Pain Management
Efficacy Study
Definition
Efficacy studies determine the effects of specific treat- ments. In order to do this, studies are carried out where as many possible likely confounding factors are controlled by the careful selection of patients and standardized im- plementation of the treatment. Specific treatments are compared with highly controlled alternative treatments including those designed as a placebo, i.e. treatments in which the presumed active ingredients have been ex- cluded. The randomized controlled trial is the de facto standard for efficacy studies. In contrast, effectiveness studies aim to determine whether the treatment may be generalized to the real world across a range of patient populations, therapists and delivery settings.
Effect Size
Psychology of Pain, Efficacy
Effleurage
Massage and Pain Relief Prospects
Effort Headache
Primary Exertional Headache
Eicosanoids
Definition
Eicosanoids refer to any product derived from arachi- donic acid, an unsaturated fatty acid found in the plasma membrane of neurons. Eicosanoids are lipids that in- clude prostaglandins, prostacyclins, thromboxanes, and leukotrienes. The eicosanoids can collectively mediate almost every aspect of the inflammatory response.
Immunocytochemistry of Nociceptors
Prostaglandins, Spinal Effects
Electrical Stimulation Induced Analgesia
Stimulation-Produced Analgesia
TENS, Mechanisms of Action
Electrical Stimulation Therapy
Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of Muscle Pain
Electrical Therapy
Transcutaneous Electrical Nerve Stimulation
Electro-Acupuncture (EA)
Definition
Electrical stimulation through one or more pairs of acupuncture needles.
Acupuncture Mechanisms
Electroanalgesia
Transcutaneous Electrical Nerve Stimulation Out- comes
Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of Muscle Pain
Electrodiagnosis and EMG
D. P
AULH
ARRIESPain Treatment Center, Lexington, KY, USA pharries@yahoo.com
Synonyms
Electromyography; nerve conduction studies
686 Electrodiagnosis and EMG
Definition
Electrodiagnosis includes nerve conduction studies and electromyography (EMG). Nerve conduction studies are the measurement of electrical transmission within nerves as the result of an artificial, electrical or mag- netic stimulus. EMG is the measurement of electrical activity within a muscle for diagnostic purposes. EMG is unfortunately incorrectly regarded by many as being synonymous with electrodiagnostic studies.
Characteristics Nerve Conduction Studies Physiology
When a peripheral nerve is stimulated electrically, ac- tion potentials will be evoked in all the axons within that nerve. By recording from the nerve, the combined re- sponse of those axons can be obtained. Generally, how- ever, only the signals from the larger, faster, myelinated fibers are recorded. In clinical practice, impulses from slow fibers do not contribute significantly to the electro- diagnostic results.
Two types of nerve injury occur: axonal and demyeli- nating. These usually occur together to some degree, but one is usually predominant. The pattern of injury helps in diagnosis.
In demyelinating nerve injuries, the nerve remains in- tact, and continues to function; but the demyelination results in slowing of the conduction velocity. In a severe demyelinating nerve injury, conduction block appears.
In conduction block, the impulses are slowed to such an extent that they cease to propagate, resulting in a drop in amplitude. A drop in amplitude of 50% is normally re- quired to diagnose conduction block. It should be noted that conduction block is as a result of a focal lesion in the nerve membrane. Despite there being a drop in am- plitude there is no axonal injury.
In axonal injury, the nerve is damaged, and the affected axons cease to function. The degree of nerve damage is proportional to the number of its axons that are affected.
Those axons that still function will generally conduct at a normal velocity; but there will be fewer of them. So, the amplitude of activity recorded from the nerve will be reduced.
If a nerve is transected, the effects depend on the location of the injury with respect to the cell bodies of the nerve.
If sensory nerves are transected distal to the dorsal root ganglion, axons distal to the site of injury will degenerate and exhibit no function and, therefore, no conduction.
Proximal to the lesion, however, the axons will remain intact, and will conduct at normal velocity. If the lesion is in the dorsal root, the entire peripheral nerve remains connected to the dorsal root ganglion, and will exhibit normal function throughout. For motor nerves, the cell bodies lie in the spinal cord. When transected, the axons distal to the lesion will degenerate and cease to function, while their proximal ends will remain intact.
Sensory
Sensory testing is performed by stimulating a nerve, and then recording a response in the nerve, either distal or proximal to the site of stimulation. A waveform known as the SNAP (Sensory Nerve Action Potential) is ob- tained. From the waveform the amplitude and peak la- tency are measured. The conduction velocity is defined as the distance between stimulator and recoding elec- trode, divided by the time from stimulation to peak la- tency.
Motor
Motor testing is performed by stimulating a nerve and recording from the muscles that it supplies. A Com- pound Muscle Action Potential (CMAP) is obtained.
This waveform is very different to the SNAP, as it represents the response of a muscle, not a nerve. The impulse is effectively magnified at least 100 fold by the neuromuscular junction. The latency is measured to the onset of the impulse. Due to the transit time across the neuromuscular junction, velocity cannot simply be cal- culated from distance/time. Instead, two readings have to be taken, typically by stimulating the nerve at two locations at least 10 cm apart, and recording from the same location. The nerve conduction velocity is given by (distance between Proximal and Distal stimulation sites)/(time to onset latency from proximal stimula- tion–time to onset latency from distal stimulation) H-Reflex
When a muscle nerve is stimulated, impulses are propa- gated both distally and proximally from the site of stim- ulation. The orthodromic propagation occurs along mo- tor axons, and elicits a response in the muscle, called the M wave. The antidormic propagation occurs in all mus- cle afferent fibers. These travel to the spinal cord where they synapse on anterior horn cells, which are activated.
Their impulses then pass orthodromically into the nerve, and eventually reach the muscle, where they evoke a sec- ond response, called the H wave. This is the electrophys- iological equivalent of the stretch reflex.
The H wave is best seen at low stimulation voltages prior to the production of the M wave. The reason for this is that amplification of the stimulus occurs at the spinal cord.
H reflexes can only be consistently obtained from the gastrocnemius, upon stimulation of the tibial nerve; and to a lesser degree the flexor carpi radialis, upon stimu- lation of the median nerve.
F-Wave
Upon stimulation of a muscle nerve, antidromic activ-
ity also occurs in the motor axons. When these impulses
reach the anterior horn cell, some can be “reflected” in
the axon. They eventually reach the muscle and evoke a
third response, called the F wave. A relatively high stim-
ulus is required to produce these waves. They can, how-
ever, be obtained from any nerve.
E
Electrodiagnosis and EMG 687
Somatosensory Evoked Potentials (SSEP)
A peripheral nerve with sensory fibers is repeatedly stim- ulated. Small changes in voltage are detected as the im- pulse passes into the spinal cord and then onto the brain.
SSEP is useful in determining where in the CNS a delay in conduction occurs. Traditionally, it has been used to help diagnose Multiple Sclerosis. Today it is often used during spinal surgery to warn a surgeon of compromise to neural structures.
Current Perception Threshold (CPT)
In this test, a small electrical current is applied to an ex- tremity. The patient indicates when they can first feel the current. CPT has been used in an attempt to pick up neuropathy, and also to determine which patients will be able to cooperate during sensory testing while perform- ing Radiofrequency neurotomy. CPT has been used on an experimental basis in evaluating radiculopathy and in CRPS (Yamashita 2002).
EMG
In order to study the activity of a muscle in detail, a fine needle is inserted into it, and the recorded waveforms are examined during three separate phases:
1. at rest;
2. with the patient still, but moving the needle to “pro- voke” the muscle;
3. during voluntary contraction of muscle.
The results are interpreted in the context of responses from other muscles in the same or different myotome, or peripheral nerve distribution.
The EMG provides information regarding the muscle itself, the neuromuscular junction and the motor axon.
Classically, in axonal motor injury, fibrillations and pos- itive sharp waves will be seen three weeks after injury, and will persist for many months. These both represent signs of muscle membrane instability. The muscle is eas- ily provoked by the needle and responds by producing these waveforms. In chronic cases, fibrillations and pos- itive sharp waves become less evident.
Indications
The indications for nerve conduction studies and EMG in Pain Medicine are contentious. Pain is mediated by small diameter afferents, but these are not sampled by nerve conduction studies or EMG. Any relationship to pain is circumstantial or surrogate.
Radiculopathy
The Taxonomy of Pain (Merskey and Bogduk 1994) de- fines a radiculopathy as: “objective loss of sensory and or motor function as a result of conduction block in ax- ons of a spinal nerve or its roots”. This is synonymous with a demyelinating injury. The electromyographer de- fines radiculopathy as a lesion proximal to the dorsal root ganglion.
If the lesion is proximal to the dorsal root ganglion, the peripheral sensory nerve will have normal nerve con- duction studies. If there is an axonal injury to the motor nerve, conduction studies may demonstrate reduced am- plitude in motor nerves. If there is a pure demyelinating lesion of the motor root, then nerve conduction studies will be normal.
The H-reflex can in theory identify demyelinating sensory and motor root involvement. Unfortunately, the H-reflex is only of limited value in diagnosing S1 radiculopathy (American Academy of Electrodiag- nostic Medicine 1998; Dumitru 1995).
EMG will detect a radiculopathy that has axonal motor involvement. EMG abnormalities, when present, are clearest 3–30 weeks after onset of the axonal injury.
SSEP has been evaluated in radiculopathy and found not to be clinically useful (American Academy of Electrodiagnostic Medicine (1998).
It can be deduced from basic physiological principles that EMG and Nerve Conduction studies will not pick up pure sensory radiculopathies or pure demyelinating motor neuropathies. EMG can be invaluable in dif- ferentiating between radiculopathy and other causes of motor weakness. The AAEM mini monograph on radiculopathy claims that electrodiagnostic studies can pick up the vast majority of radiculopathies using EMG (American Academy of Electrodiagnostic Medicine (1998). Clearly this will not be the case in pure sensory radiculopathies.
The difficulty in determining validity of electrodiagnos- tic testing in radiculopathy stems from disagreement with regards to the definition of radiculopathy (Merskey and Bogduk 1994; American Academy of Electrodiag- nostic Medicine 1998), and the absence of a criterion standard.
Peripheral Neuropathy
EMG and nerve conduction studies, together with nerve biopsy, are the diagnostic tests of choice for peripheral neuropathies. Unfortunately, the information gained does not in any way help with the management of pain, except in very rare instances where the cause of the neuropathy can be effectively treated.
Plexopathy
Differentiating radiculopathy from plexopathy can be done very elegantly using nerve conduction studies and EMG. Together with MRI it is the test of choice.
Peripheral Nerve Injuries
In peripheral nerve injuries, nerve conduction studies and EMG can provide data that help determine progno- sis, site of lesion, and need for surgical intervention.
Complex Regional Pain Syndrome
Electrodiagnosis can help differentiate between type 1
and type 2 CRPS. CPT studies are asymmetric in CRPS,
but do not correlate with pain (Yamashita 2002).
688 Electrodiagnostic Testing (Studies)
Utility
Electrodiagnostic studies are explicitly designed to study loss of function in sensory and motor nerves.
However, they have no direct application for the inves- tigation of pain. They might be used to obtain details in patients with a painful peripheral neuropathy or plexopathy, but such cases would be uncommon.
Although commonly used to investigate patients with spinal and
radicular pain, nerve conduction studies and EMG have no proven utility in such patients (Bog- duk and Govind 1999; Bogduk 1999). They may confirm certain features of radiculopathy, but radiculopathy and
radicular pain are not synonymous.
References
1. American Academy of Electrodiagnostic Medicine (1998).
AAEM Minimonograph 32: The Electrodiagnostic Examination in Patients with Radiculopathies. Muscle Nerve 21:1612–1631 2. Bogduk N (1999) Medical Management of Acute Cervical Radic- ular Pain: An Evidence-Based Approach. Newcastle Bone and Joint Institute, Newcastle, pp 67–69
3. Bogduk N, Govind J (1999) Medical Management of Acute Lum- bar Radicular Pain: An Evidence-Based Approach. Newcastle Bone and Joint Institute, Newcastle, pp 53–58
4. Dumitru D (1995) Electrodiagnostic Medicine. Hanley and Bel- fus, Philadelphia
5. Merskey H, Bogduk N (1994) Classification of Chronic Pain, 2ndedn. IASP Press, Seattle, p 16
6. Yamashita T (2002) A Quantitative Analysis of Sensory Function in Lumbar Radiculopathy using Current Perception Threshold Testing. Spine 27:1567–70
Electrodiagnostic Testing (Studies)
Synonyms EDT Definition
Electrodiagnostic studies are those that involve the use of electrical stimulation.
Traditional evaluation of the peripheral nervous system uses electrical stimuli to measure nerve conduction ve- locity (NCV) and muscle function (electromyography, EMG). This testing can be painful, but is objective, re- quiring no cognitive input from the person being tested for a response to the stimuli.
Carpal Tunnel Syndrome
Causalgia, Assessment
Electroencephalogram/
Electroencephalography
Synonym EEG
Definition
Synchronized extracellular currents in a few square cen- timeters of cortex generate electrical potentials measur- able with electrodes on the scalp. The signal is low-pass filtered to 50 Hz.
Insular Cortex, Neurophysiology and Functional Imaging of Nociceptive Processing
Thalamotomy for Human Pain Relief
Electrolytic Lesion
Definition
Electrolyticlesion is a procedure that can produce death of neurons and nerve fibers in a nervous center by passing an electrical current through an electrode. The extent of the lesion depends on the intensity and duration of the injected current.
Lateral Thalamic Lesions, Pain Behavior in Animals
Post-Stroke Pain Model, Thalamic Pain (Lesion)
Thalamotomy
Electromyography
Definition
This is a method of studying the electrical activity of a muscle by recording action potentials from the contract- ing muscle fibers, and is used to assess the level of mus- cular arousal. In newborn infants, the usual way of doing this is through surface electrodes applied to the overly- ing skin. However, in adults, for diagnostic purposes, it is useful to employ concentric needle electrodes that are inserted through the skin and into the muscle fibers them- selves. The analogue signal from the electrical activity is either recorded on an oscilloscope, or more usually dig- itized and displayed via computer, where more complex waveform analysis can be conducted.
Electrodiagnosis and EMG
Infant Pain Mechanisms
Psychophysiological Assessment of Pain
Electron Microscopy
Definition
Electron Microscope is a high-resolution imaging tech- nique using electron beams.
Toxic Neuropathies
E
EMG-Assisted Relaxation 689
Electrophysiological Mapping
Definition
Electrophysiological mapping is the recording of elec- trical responses in the brain in response to a stimulus that is applied to the body.
Thalamic Nuclei Involved in Pain, Cat and Rat
Electrophysiology
Definition
Electrophysiology is the science and branch of physiol- ogy that pertains to the flow of ions in biological tissues and, in particular, to the electrical recording techniques that enable the measurement of this flow. It is useful for studying response properties of neurons.
Amygdala, Pain Processing and Behavior in Animals
Cancer Pain Model, Bone Cancer Pain Model
Electrotherapy
Definition
Electrotherapies are techniques, including TENS, CFS and acupuncture, used to stimulate nerve fibers or recep- tors to achieve analgesia or itch relief.
Cutaneous Field Stimulation
Modalities
Eligibility
Disability Evaluation in the Social Security Admin- istration
Elimination
Definition
The elimination of a drug characterizes its irreversible loss from the body due to excretion or metabolism into another chemical molecule.
NSAIDs, Pharmacokinetics
Elimination Half-Life (t1/2)
Definition
The elimination half-life (t
1/2) of a drug describes the time needed to reduce the drug concentration in blood, plasma or serum to one-half. The elimination half-life may be influenced by a variation in urinary excretion (pH), intersubject variation (e.g. polymor- phic enzymes), age, drug-drug interactions and dis- eases (especially renal and liver diseases). Elimination means the annihilation of the administered drug, not its metabolites, from the body by biliary, urinary or other pathways of excretion (e.g. lung, skin, etc.) or rather biotransformation through metabolism.
NSAIDs, Pharmacokinetics
Opioid Rotation
Elmiron ®
Definition
Pentosan Polysulfate Sodium; a commonly prescribed medication for IC. Structure similar to glycosaminogly- can layer of bladder mucosa.
Interstitial Cystitis and Chronic Pelvic Pain
Embolism
Postoperative Pain, Venous Thromboembolism
Emergence
Definition
Emergence is the process by which a system of interact- ing elements spontaneously acquires a qualitatively new pattern and structure that is unpredictable from knowl- edge of the individual elements.
Consciousness and Pain
EMG-Assisted Relaxation
Definition
EMG-assisted relaxation is a form of biofeedback that employs information about muscle tension levels in or- der to facilitate overall relaxation.
Biofeedback in the Treatment of Pain
690 Emotional Factors/Reactions
Emotional Factors/Reactions
Definition
Strong and roughly appropriate reaction to a significant event, tagged by an affective label, in the environment of the species. Emotional components arise from moti- vational and autonomic changes with a modulation by individual experience and a subjective perception. In the case of pain: defensive/aversive behavior with a myriad of autonomic changes and the avoidance learning (fear) of the noxious event.
Hypothalamus and Nociceptive Pathways
Multidimensional Scaling and Cluster Analysis Ap- plication for Assesssment of Pain
Pain in the Workplace, Risc Factors of Chronicity, Psychosocial Factors
Parabrachial Hypothalamic and Amydaloid Projec- tions
Empathic
Definition
Making an effort to understand what the patient is think- ing, feeling, and wanting. Being empathic often includes reflecting one’s understanding of the patient back to the patient in the form of reflective listening.
Chronic Pain, Patient-Therapist Interaction
Employment Assessment
Vocational Assessment in Chronic Pain
ENaC/DEG
Definition
ENaC/DEG is a family of ion channel proteins, several gated by low pH, for example the ASIC channel.
Species Differences in Skin Nociception
Enamel
Definition
Enamel is the hardest biological tissue known and forms the crown of the tooth. It overlies the softer and more flexible dentin.
Dental Pain, Etiology, Pathogenesis and Management
Enantiomer of Tramadol
Definition
Enantiomer of Tramadol refers to one of the two stereoisomers that comprise tramadol, a racemate.
Drugs with Mixed Action and Combinations, Empha- sis on Tramadol
Encephalopathy
Definition
Encephalopathy is a frequent symptom in cerebral vas- culitis; manifestation of systemic vasculitides and the isolated angiitis of the central nervous system.
Headache Due to Arteritis
Encoding of Noxious Information in the Spinal Cord
R
OBERTC. C
OGHILLDepartment of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC, USA
rcoghill@wfubmc.edu Synonyms
Nociceptive processing; Spinal Cord Nociception, En- coding of Noxious Stimuli
Definition
The encoding of noxious information by the spinal cord is the process by which information from
Primary Af- ferents/Neurons is assimilated, integrated, and prepared for transmission to central nervous system regions im- portant in nociception and nociceptive reflex modula- tion. Information from
descending modulation sys- tems of the brain can strongly shape afferent information processing at the spinal level and contributes substan- tially to spinal nociceptive processing.
Characteristics
The subjective sensory experience of pain is multi-
dimensional and encompasses a conscious appreciation
of the intensity, location, quality and temporal aspects of
a stimulus that damages (or holds the potential to dam-
age) the integrity of the body. Given that the experience
of pain evoked by a noxious stimulus is largely built
upon sensory information ascending from the spinal
cord to the brain, information about the subjectively
available sensory features of a noxious stimulus must
necessarily be encoded and transmitted by neurons
within the spinal cord.
E
Encoding of Noxious Information in the Spinal Cord 691
The processing of nociceptive information within the spinal cord grey matter is accomplished by neurons with two broad classes of response properties,
wide dynamic range neurons (WDR) and
nociceptive specific neurons (NS). WDR neurons were the first class of nociceptive neurons to be identified (Wall and Cronly-Dillon 1960) and were named on the basis of their responsiveness to a wide range (i.e. noxious and innocuous) of stimulus intensities (Mendell 1966).
NS neurons were identified several years later in 1970 (Christensen and Perl 1970). As their name implies, NS neurons respond exclusively to noxious stimulus intensities. Both classes of neurons are interspersed through laminae I, II, IV, V, VI, VII, and X of the spinal cord grey matter. However, NS neurons tend to predominate in the marginal layers of the dorsal horn, while WDR neurons predominate in the deeper lamina.
Both classes of neurons project supraspinally to brain regions involved in pain and/or pain modulation. Since their discovery, debate has raged over the functional significance of both NS and WDR neurons.
Much of the current understanding of spinal nocicep- tive processing is significantly limited by the failure to explore and appreciate how populations of spinal neurons work together to encode pain. In particular, the contribution of WDR neurons to the encoding of noxious stimuli cannot be understood if the responses of single WDR neurons are considered in isolation.
Single WDR neurons respond with equal vigor to both noxious and innocuous stimuli and are, therefore, inca- pable of encoding a distinction between a noxious and innocuous stimulus. However, these cells have complex
receptive field properties that result in population re- sponses being markedly different from the responses of single neurons within that population. WDR neu- rons have a small, central receptive field zone in which both noxious and innocuous stimuli evoke increases in discharge frequencies (see
discharge frequency).
This central receptive field zone is surrounded by a larger peripheral zone in which only noxious stimuli are sufficient to elicit increases in discharge frequency.
Both receptive field zones have gradients of sensitivity, such that progressively greater discharge frequencies are evoked as the noxious stimulus is applied progres- sively closer to the central receptive field zone. If the stimulated region of the body surface is sufficiently large to encompass multiple, overlapping peripheral receptive field zones of WDR neurons, then a noxious stimulus would recruit far more WDR neurons than an innocuous stimulus of equal size. Thus, the total output of the WDR population would be far greater for the noxious stimulus. Functional imaging studies of the spinal cord have confirmed that noxious stimuli produce far greater rostro-caudal recruitment of neuronal activ- ity than innocuous stimuli (Coghill et al. 1993a) and strongly suggest that the output of populations of WDR neurons is sufficient to support a subjective distinction
between noxious and innocuous stimuli. Importantly, both NS and WDR neurons are activated by noxious stimuli under most conditions and both probably work together to encode distinctions between noxious and innocuous stimuli.
To date, the neural mechanisms which encode the intensity of a noxious stimulus represent the best under- stood dimension of spinal nociceptive processing. Both NS and WDR neurons exhibit monotonic increases in discharge frequencies as the intensity of noxious stimu- lation increases, so both classes of neurons are capable of contributing to the subjective experience of pain intensity. However, WDR neurons are more sensitive to smaller changes in stimulus intensity in that they have steeper stimulus-response curves than NS neurons (Price et al. 1978). Furthermore, the stimulus-response functions obtained from WDR neurons closely parallel those obtained from human psychophysical studies (Price et al. 1978). Finally, WDR neurons encode sufficiently small distinctions in
noxious stimulus intensity to support behavioral discriminative capac- ity (Maixner et al. 1986). Population recruitment also appears to be a critical dimension in the encoding of stimulus intensity. Progressive increases in noxious stimulus intensity recruit a progressively greater rostro- caudal distribution of neuronal activity (Coghill et al.
1991).
Mechanisms supporting the encoding of stimulus loca- tion by spinal cord neurons remain poorly understood (see
noxious stimulus location). There is, however, a clear somatotopic organization, with caudal body regions being represented in the caudal spinal cord and rostral body regions being represented in the rostral spinal cord. There is also a medio-lateral organization, where distal structures are represented in the medial aspect of the dorsal horn and proximal structures are represented in the lateral aspect of the dorsal horn.
Clearly, a significant degree of spatial processing and modulation occurs at the spinal level. In spinal cord transected animals, spinally mediated reflex withdrawal responses are appropriate for the body site stimulated.
Furthermore, these responses can be modulated in a complex and elegant fashion when multiple body sites are stimulated simultaneously (Le Bars et al. 1979;
Morgan 1999). Such interactions probably serve to
generate the most appropriate withdrawal response to
complex, multi-focal painful stimuli and underscore
the fact that the spinal cord is equipped to both process
and utilize spatial information. It remains unknown if
this spinally processed spatial information can become
subjectively available. Both NS and WDR neurons may
participate in the encoding of spatial information. NS
neurons appear to be ideally suited for the encoding of
stimulus location based on their relatively small and
well-localized receptive fields. The complex receptive
fields of WDR neurons could also yield population
responses with a high degree of spatial information, but
692 Encoding of Noxious Stimuli
no existing data have confirmed such population-based encoding of stimulus location. However, population- based mechanisms may be significantly involved in the perceptual radiation of pain. Since recruitment of spatially remote neuronal populations occurs during intense noxious stimulation, such recruitment may contribute substantially to the experienced spatial dis- tribution of a painful stimulus (Price et al. 1978; Coghill et al. 1991).
The encoding of
stimulus quality (i.e. the subjective experience of burning, stinging, crushing, pinching etc.) has been minimally explored. A subclass of NS neuron, however, receives selective input from A-δ afferents that respond solely to noxious mechanical information. Such neurons would be well positioned to encode a distinc- tion between noxious mechanical and noxious thermal information. WDR neurons receive input from a num- ber of different classes of primary afferents and appear unlikely to make a clear contribution to the encoding of stimulus quality.
The experience of pain has multiple temporal aspects derived from interactions between differing popula- tions of primary afferents and spinal cord neurons. In particular, when a noxious stimulus is applied to the distal portion of an extremity, the distinction between information carried by rapidly conducting (Aδ) noci- ceptors and slowly conducting (C) nociceptors becomes sufficiently amplified to become subjectively available.
The sharp, well-localized pain sensation that is first perceived (
first pain) is thought to arise largely from information transmitted by Aδ nociceptors, while the later, more diffuse burning sensation (
second pain) is thought to reflect information arising from C noci- ceptors. Both NS and WDR neurons have convergent input from Aδand C fibers and exhibit responses that would be consistent with their ability to support first and second pain. In the case of prolonged, repetitive noxious stimulation, C afferents undergo progressive decreases in their discharge frequencies. However, if inter-stimulus intervals are sufficiently brief, the discharge frequencies of spinal nociceptive neurons actually increase and perceived pain increases over time. This progressive
temporal summation has been termed “
wind-up” (Mendell and Wall 1965). Neu- rons in both the deep and superficial laminae exhibit such temporal summation and could be sufficient to subserve temporal summation of pain and to overcome progressive diminution of C afferent input. In the case of maintained pain, NS and WDR neurons exhibit differ- ing responses over the course of prolonged nociceptive stimuli. NS neurons exhibit prolonged responses to mechanical stimuli but exhibit significant adaptation to prolonged thermal stimuli. In contrast, WDR neurons exhibit prolonged responses to both heat and capsaicin pain. As such, either class of neuron appears sufficient to encode the duration of prolonged nociceptive stimuli of the appropriate modality (Coghill et al. 1993b).
The processing and encoding of nociceptive information by spinal cord neurons is both complex and elaborate.
Clearly multiple spinal cord regions interact during the processing of noxious information. Neurons in the su- perficial dorsal horn can modulate the responses of neu- rons in deeper laminae (Suzuki et al. 2002). Spatially re- mote stimuli can modulate responses of ongoing stimuli (Le Bars et al. 1979; Morgan 1999). Significant gaps in our understanding of these processes represent substan- tial obstacles to the better understanding and treatment of pain. Although much work as been done at the level of the single neuron, much more work is needed to under- stand how populations of nociceptive neurons encode the magnitude, spatial and temporal features of noxious stimuli.
References
1. Christensen BN, Perl ER (1970) Spinal neurons specifically ex- cited by noxious or thermal stimuli: marginal zone of the dorsal horn. J Neurophysiol 33:292–307
2. Coghill RC, Price DD, Hayes RL et al. (1991) Spatial distribution of nociceptive processing in the rat spinal cord. J Neurophysiol 65:133–140
3. Coghill RC, Mayer DJ, Price DD (1993a) The roles of spatial recruitment and discharge frequency in spinal cord coding of pain: a combined electrophysiological and imaging investigation.
Pain 53:295–309
4. Coghill RC, Mayer DJ, Price DD (1993b) Wide dynamic range but not nociceptive specific neurons encode multidimensional features of prolonged repetitive heat pain. J Neurophysiol 69:703–716
5. Le Bars D, Dickenson AH, Besson JM (1979) Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain 6:283–304
6. Maixner W, Dubner R, Bushnell MC et al. (1986) Wide-dynamic- range dorsal horn neurons participate in the encoding process by which monkeys perceive the intensity of noxious heat stimuli.
Brain Res 374:385–388
7. Mendell LM (1966) Physiological properties of unmyelinated fiber projection to the spinal cord. Exp Neurol 16:316–332 8. Mendell LM, Wall PD (1965) Response of single dorsal cord cells
to peripheral cutaneous unmyelinated fibres. Nature 206:97–99 9. Morgan MM (1999) Paradoxical inhibition of nociceptive neu- rons in the dorsal horn of the rat spinal cord during a nociceptive hindlimb reflex. Neuroscience 88:489–498
10. Price DD, Hayes RL, Ruda M et al. (1978) Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. J Neurophysiol 41:933–947 11. Suzuki R, Morcuende S, Webber M et al. (2002) Superficial
NK1-expressing neurons control spinal excitability through ac- tivation of descending pathways. Nat Neurosci 5:1319–1326 12. Wall PD, Cronly-Dillon JR (1960) Pain, itch, and vibration. Arch
Neurol 2:365–375
