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The Human Pain System
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The Human Pain System
Cambridge University Press
9780521114523 - The Human Pain System - Experimental and Clinical Perspectives - By Frederick A. Lenz, Kenneth L. Casey, Edward G. Jones and William D. Willis
Excerpt

1    Discovery of the anterolateral system and its role as a pain pathway

Introduction

On January 19 1911, persuaded by his colleague, the neurologist William Spiller, a Philadelphia surgeon named Edward Martin made a small transverse cut in the spinal cord of a patient suffering from severe pain caused by a tumor affecting the lower end of the spinal column. The cut, made with a thin cataract knife, was no more than 2 mm deep or wide and entered the cord some 3 mm ventral to the entry of a dorsal root in the middle thoracic region. The patient experienced much relief from what had until then been intractable pain (Spiller and Martin, 1912). The operation of “chordotomie” or section of the anterolateral tracts of the spinal cord had been introduced in 1910 by Schüller in work on monkeys in which he was exploring the possibility of using the operation for the alleviation of spastic paralysis and tabetic crises in humans. Spiller argued for the procedure on the basis of clinico-pathological observations that appeared to implicate the anterolateral tracts as pathways for conduction of impulses related to pain and temperature through the spinal cord (Müller, 1871; Gowers, 1879; Spiller, 1905; Petrén, 1910). Reports of other successful cases quickly followed (Beer, 1913; Foerster, 1913) and soon, at the hands of Foerster (1913, 1927; Foerster and Gagel, 1932) in Germany and Frazier (1920) in the United States, cordotomy was to become for a time the surgical method of choice in dealing with intractable pain. With it came renewed interest in the anatomy of the spinothalamic tract, its localization in the spinal cord and its site of termination in the thalamus.

Dorsal roots, somatic sensation and lateralization in the spinal cord

The background to the localization of the pain pathways in the anterolateral columns of the spinal cord is an extensive one and knowledge accrued


slowly as ideas developed about the role of the spinal nerve roots and the spinal cord tracts in somatic sensation. Magendie clearly delineated the dorsal roots of the spinal cord as sensory and the ventral as motor in 1822. Although his claims to priority were questioned by Charles Bell, it is clear from reading Bell's 1811 pamphlet, Idea of a New Anatomy of the Brain, that Bell at that time had little idea of the sensory role of the dorsal roots, conceiving of them as being connected with the dorsal white columns of the cord which he saw as conveying some vaguely described efferent integrative influence from the cerebellum to the body. The ventral roots he saw as conveying a more definite motor influence from the cerebrum via the pyramidal tracts to the muscles. Where he speaks of sensation at all, he implies that sensory impressions may be carried up to the brain via the spinal gray matter. Bell has been found guilty of modifying his later texts to create an impression that he had arrived at conclusions similar to Magendie's many years before (Bell, 1837, 1845). If he had some inkling of the sensory and motor roles of the dorsal and ventral roots he did not reveal it in his pamphlet. Nevertheless, the law of differential polarization of the roots became known as the Bell–Magendie Law. Detailed accounts of this episode in the history of neuroscience can be found in Cranefield (1974) and in Clark and Jacyna (1987).

By the time of Longet (1841, 1842) and Stilling (1842) it was accepted by many that the dorsal roots became continuous with the posterior columns of the cord and that the latter were in some way connected with sensation, but not by all. Brown-Séquard (1849, 1850, 1860), for example, saw the posterior columns as being continuous with the inferior cerebellar peduncle and believed that it was the spinal gray matter that was essential for sensory transmission to higher centers. In a variant of this view, Schiff (1858) thought that while tactile sensation was conveyed via the posterior columns, pain might be transmitted through the gray matter. This is perhaps the first time that a distinction was drawn between the two components of the somatosensory system. Brown-Séquard and Schiff based their interpretations on experimental work in animals in which the spinal cord was fully or partially transected at different levels, the animal then being tested for sensory loss. For Brown-Séquard, section of the dorsal columns led to no loss of sensation below the level of the lesion, while a hemisection led to loss of sensation in the limb or limbs (depending on the level of the hemisection) contralateral to the lesion. A second hemisection made below the first on the opposite side would lead to bilateral sensory loss. From this he concluded that ascending sensory fibers must decussate in the spinal cord. He went on to show in many experiments that anesthesia did not occur unless the gray matter itself was injured. Even with multiple cuts at different levels affecting virtually all white matter tracts there was little diminution of sensation in the lower limbs.


Thus, to Brown-Séquard, sensory transmission occurred via the gray matter of the spinal cord and if a longitudinal cut was made down the center of the cord in the lumbosacral or cervical enlargements, there was a bilateral loss of sensation in the lower or upper limbs.

Schiff's conclusions from his experiments were similar but only in relation to pain. He felt that his experiments revealed that tactile and muscular sense impressions were conveyed by the dorsal columns while impressions of pain, cold and heat were conveyed via the gray matter. In these experiments, we are perhaps seeing the first glimmerings of understanding of the decussation of the pain and temperature-related fibers through the anterior commissure of the spinal cord. Had Brown-Séquard's testing for sensory loss gone beyond merely observing if an animal withdrew its limb from a severe pinch, he too may have been able to make the distinction that Schiff made between low-threshold sensory impressions ascending in the dorsal columns and those for pain ascending in the anterolateral columns after decussation in the anterior white commissure. Nevertheless, Brown-Séquard's influence remained strong and in 1876 Ferrier could still maintain that all sensory messages from one side of the body were conveyed up to the brain chiefly on the side opposite the entry of the dorsal roots from that side. Long after it was admitted that the dorsal columns were continuations of the dorsal roots and sensory in character, many neurologists continued to believe that the dorsal root fibers decussated in the gray matter on entering the cord and ascended on the contralateral side (Bramwell, 1884; Ferrier, 1886). For these authors, many dorsal root fibers also decussated via the anterior commissure and ascended through the lateral columns.

The anterolateral funiculus and Gowers' tract

Bastian (1867) had been first to describe ascending degeneration in the ventrolateral aspect of the spinal cord in a case of paraplegia but following Flechsig's (1876) description of the dorsal or, as it was then called, the “direct” spinocerebellar tract it was generally thought that the degenerated fibers Bastian had described were part of this tract. In 1879 Gowers also described ascending degeneration consequent upon a crush lesion at the first lumbar segment in the anterolateral columns of the spinal cord but considered it independent of the dorsal spinocerebellar tracts (Fig. 1.1). He called the tract so delineated the anterolateral ascending tract and thought that it might be concerned with the transmission of painful influences from the opposite side of the body, largely on the basis of observations made earlier on the same patient (Gowers, 1878). In his description, the tract “occupies an irregular area in front of the pyramidal and cerebellar tracts, and degenerates upwards throughout


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Fig. 1.1. Gowers' figure showing the location of ascending degeneration, as visualized by loss of myelin staining, in the gracile and anterolateral fasciculi of the spinal cord following a crush injury at the level of the first lumbar segment. The drawings have been rotated 180° from the original.From Gowers (1879).
the cord. It extends across the lateral column, as a band which fills up the angle between the pyramidal and cerebellar tracts, and it reaches the surface of the cord in front of the latter tract, nearly on a level with the anterior commissure; it then extends forward in the periphery of the anterior column, almost to the anterior median fissure, and up to the direct pyramidal tract when this exists.” He was able to follow the degeneration in this tract into the brainstem and as far rostrally as the midbrain. Although initially influenced by Brown-Séquard and convinced that the anterolateral tract might be a continuation of decussating dorsal root fibers, by 1886 (Gowers, 1886a, 1886b) and having had access to preparations of Mott in which, after dorsal root damage, the ascending degeneration was confined to the dorsal columns, Gowers was able to make the assumption that the cells of origin of the anterolateral tract were located in the contralateral dorsal horn and innervated by dorsal root fibers that ended there.

Flechsig, in myelogenetic studies in 1876, had differentiated the direct spinocerebellar tract as a tract whose axons myelinated earlier than those of the adjacent pyramidal tract and he had followed it into the inferior cerebellar peduncle. In 1885 Bechterew identified two additional ascending tracts lying ventral and medial to the dorsal spinocerebellar tract that myelinated one or two months later than that tract. These he referred to as the lateral and anterior ground bundles and traced them into the reticular formation of the medulla oblongata. It was within these ground bundles that Gowers' anterolateral tract lay. At about the same time, Löwenthal (1885) in experimental studies in animals made the first clear distinction between the dorsal spinocerebellar tract which he followed into the inferior cerebellar peduncle, and a cerebellar component of Gowers' tract which he followed into the superior cerebellar peduncle. Later, Edinger (1889, 1890) in further myelogenetic studies in cats was able to identify fibers crossing in the anterior commissure, ascending in the anterior and lateral ground bundles, and eventually reaching as far as the diencephalon. Edinger was confident that these fibers arose from cells located in the base of the dorsal horn


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Fig. 1.2. Edinger's scheme of a cross section of the human spinal cord demonstrating the organization of the central gray matter and the cellular origins of ascending and efferent fiber pathways. Fibers arising from cells in the base of the dorsal horn decussate in the anterior commissure and ascend in the anterolateral tract of the opposite side.From Edinger (1889).
that were innervated by incoming dorsal root fibers (Fig. 1.2), although his evidence came mostly from his studies of fish and amphibians.

Tract tracing by the Marchi method

The next advances came from the use of the Marchi technique to trace degenerating fibers in the spinal cords of humans suffering from spinal lesions or in those of monkeys subjected to experimental lesions. In this technique, introduced by Marchi and Algeri in 1886, the fragmentation of the myelin sheaths of axons undergoing Wallerian (anterograde) degeneration can be selectively impregnated with osmic acid and stand out against a clear background. The first successful use of the technique of relevance to the afferent pathways of the spinal cord came in the study of Mott made in 1895 on monkeys (Fig. 1.3). It was a landmark study that served to resolve many of the inconsistencies in the manner in which contemporary neurologists viewed the sensory pathways


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Fig. 1.3. Location of Marchi-stained degenerating fibers in the spinal cord, brainstem and diencephalon of a monkey following a median longitudinal section of the spinal cord in the lumbar region.From Mott (1895).
of the spinal cord. In the first part of his investigation, Mott sectioned the dorsal roots of several spinal nerves in the lumbosacral region, observing that all degeneration of fibers above the level of the lesion was confined to the gracile fasciculus of the same side, an observation that served to end the debate about laterality in the dorsal columns and whether dorsal root fibers decussated on entry into the cord. He was also able to note the topography in the gracile fasciculus, with lower-entering fibers being pushed into the dorsomedial aspect of the fasciculus by higher-entering fibers.


In a second set of experiments, Mott made a median section of the cord in the region of the last thoracic and first three lumbar segments. In these cases he observed symmetrical degeneration in the anterolateral columns of both sides. He was able to distinguish degeneration in the dorsal spinocerebellar tract from that in the other tracts by reason of the size of its fibers and the fact that degeneration in it was more severe on the side of the cord in which more gray matter and thus more of Clarke's column was damaged. Ventral to this he observed a superficially placed ventral spinocerebellar tract, a tract that he had earlier traced to the superior cerebellar peduncle (Mott, 1892; Tooth, 1892); separated from this by normal fibers was a more deeply located tract whose fibers could be traced to the level of the superior colliculus and some of them beyond to the level of the thalamus. These fibers, he said, form “in all probability the crossed sensory tract of Edinger.” He was, however, unwilling to ascribe a precise function to the tract and he did not identify it as a pathway uniquely concerned with pain.

In his third set of experiments, Mott undercut the dorsal column nuclei in order to sever the arcuate fibers leaving the ventral aspects of these nuclei. He traced the ensuing degeneration across the decussation of the medial lemniscus, saw it ascending in the medial lemniscus and traced it into the posterolateral aspect of the contralateral thalamus. In this, he was confirming experimentally the deductions of Mahaim (1893) who argued that since only modest degeneration occurred in the lemniscus following complete retrograde degeneration of the lateral thalamus due to cortical lesions, the lemniscus must terminate in that part of the thalamus and not continue, as some had suggested, directly to the cerebral cortex.

The results of Mott's study, although by no means directly implicating the anterolateral pathway in central pain mechanisms, were sufficiently clear-cut to resolve all preexisting controversies about the lateralization of the ascending pathways associated with the sensory nerve roots of the spinal cord. Gowers immediately accepted the new findings and his description of the spinal sensory pathways in the third edition (1899) of his textbook on Diseases of the Nervous System, unlike its predecessors, reads like any early modern textbook of neuroanatomy (Gowers and Taylor, 1899). In reviewing his clinical experience at this point, Gowers was ready to conclude that following a unilateral cord lesion pain is always lost on the contralateral side of the body below the lesion. But he was not prepared to concede that anything other than muscular sense (that is proprioception) was conveyed by the dorsal columns. He still considered that touch, along with pain and temperature, were conveyed via the contralateral anterolateral columns. And because loss of pain or temperature can be dissociated after cord lesions, he felt that they could be conveyed by paths that did not run together.


In the years following Mott's work, the application of the Marchi technique to the spinal cords and brains of patients who had died within a few weeks of sustaining spinal cord injuries served to confirm the observations of Mott and to show the comparable organization of the various tracts of the anterolateral white matter in the human spinal cord. A number of these revealed degeneration of anterolateral fibers that ascended as far as the midbrain and thalamus, separating them from fibers ascending only as far as the superior cerebellar peduncle (Patrick, 1893, 1896; Hoche, 1896; Sölder, 1897; Worotynski, 1897; Quensel, 1898; Rossolimo, 1898; Tschermak, 1898; Amabilino, 1901; Henneberg, 1901; Thiele and Horsley, 1901; Collier and Buzzard, 1903; Dydyński, 1903; Marburg, 1903; Petrén, 1901, 1910; Rothmann, 1903; Bruce, 1910; Goldstein, 1910). It was largely the reports of Petrén and Goldstein, along with his own case report of 1905, that influenced Spiller in determining to pursue anterolateral cordotomy as a treatment for alleviating pain in his patient. Although some of the reports listed are brief and relatively superficial, others are quite extensive and very comprehensively illustrated, often with high quality photomicrographs that clearly reveal the capacity of the Marchi technique to demonstrate degenerating fiber tracts against a clear background. It is from these studies that detailed knowledge of the organization of ascending tracts in the lateral white matter of the spinal cord and their central courses and terminations was built up. In 1901, for example, Thiele and Horsley could delineate four tracts: the direct cerebellar tract of Flechsig, renamed the fasciculus spino-cerebellaris dorsolateralis by Barker (1899); Gowers' tract or the fasciculus spino-cerebellaris ventralis, as renamed by Barker; the fasciculus spino-tectalis, originally called the spino-quadrigeminal system by Mott; the fasciculus spino-thalamicus, as named by Mott. They were also able to identify spino-vestibular fibers which Collier and Buzzard (1903) were later to call a tract in its own right. As Barker (1899) put it in his extensive and influential review, the original tract of Gowers had become revealed as a combination of several independent fiber systems. It was largely at his suggestion that the name, Gowers' tract, became restricted to the ventral spinocerebellar tract.

Mott's study had clearly delineated the course of the ascending components of the old Gowers' anterolateral system, tracing the ventral spinocerebellar, spinotectal and spinothalamic fibers through the medulla oblongata in a position lateral to the inferior olivary nucleus, then ventrolateral to the superior olivary nucleus and so up to the level of the entering trigeminal nerve, at which point the ventral spinocerebellar fibers passed up lateral to the spinal tract of the trigeminal nerve to gain the brachium conjunctivum and entry into the anterior medullary velum of the cerebellum. The spinotectal and spinothalamic fibers continued ventromedial to the spinal tract before joining the fibers of the


lateral lemniscus with which they ascended to a more dorsal position. The spinotectal fibers turned medially to end in the deep layers of the superior colliculus while the spinothalamic fibers continued on past the inferior colliculus to enter the posteroventral aspect of the thalamus, passing medial to the medial geniculate body in association with fibers of the medial lemniscus. In Mott's (1895) view, the spinothalamic fibers ended in the same part of the ventral nucleus of the thalamus as the fibers of the medial lemniscus but he had little detailed information and it remained for Quensel (1898) to demonstrate this conclusively in the brain of a human patient who had suffered from a spinal cord lesion.

The status of the ascending afferent pathways of the spinal cord was summed up in an extensive review in Brain in 1906 by May. In this, he examined the peripheral afferent fibers, dorsal root ganglion cells, the primary and secondary afferent pathways to which they contributed, and the thalamo-cortical projections to the postcentral gyrus, in the light of the recent division of common sensation by Head and his colleagues into three forms: deep or pressure sensibility; epicritic or discriminative cutaneous sensibility; and protopathic or pain and intense thermal sensibility (Head and Sherren, 1905; Head et al., 1905). After a lengthy consideration of the recent histological work of Cajal (1894a, 1894b, 1900, 1902), the tract tracing experiments described above, and a detailed consideration of the clinical literature, he concluded that “the different factors underlying muscular sensibility . . . pass . . . along the [homolateral] posterior columns,” that “the impulses that underlie the sensation of touch ascend in the same paths as those for pressure, viz., in the uncrossed posterior column, and later in the crossed anterior column,” and that “the conduction of painful impulses . . . occurs . . . chiefly in the lateral and slightly in the anterior column, and is almost entirely crossed . . . .” He went on to say, however, that “the corresponding homolateral path may assume a more important role during the process of compensation in disease” and “the conduction of impulses of heat and cold, occurs in separate paths [from those concerned with pain], chiefly in the lateral column, and is almost entirely, if not entirely, crossed . . . .” Here is a summing up of the position adopted by clinical neurologists at that time. By 1914 and the publication of Dejerine's Sémiologie des affections du système nerveux (Dejerine, 1914), the anatomy of the pathway leading from dorsal root fibers through dorsal horn cells to the contralateral anterolateral quadrant and the ascent to and termination of many of these secondary fibers in the thalamus was firmly established.

Unmyelinated fibers and pain

It was a new histological technique that permitted a new step to be taken towards understanding the pain pathways. Ranson's discovery of the


pyridine silver method permitted him to reveal the presence of unmyelinated fibers in peripheral nerves and in the dorsal spinal roots in numbers that often exceeded those of the myelinated fibers (Ranson, 1911, 1912, 1913, 1914). Impressed with Head's ideas of protopathic and epicritic sensibility, Ranson (1914) suggested that the fine unmyelinated fibers might be concerned with pain and temperature sensation. He discovered that the fine fibers were peripheral processes of small dorsal root ganglion cells and found that as their central processes approached the spinal cord they became concentrated in the fascicles making up the lateral divisions of each root. Entering the cord lateral to the apex of the dorsal horn, they branched within Lissauer's tract (Lissauer, 1886), the branches extending over no more than one or two segments. He thought that they terminated in the substantia gelatinosa which he therefore saw as a “mechanism for the reception and conduction of pain and temperature sensations.” In experiments in which he made knife cuts of the medial or lateral divisions of the entering dorsal roots in cats, he was able to demonstrate that the fine fibered lateral divisions undoubtedly were important for mediating the transmission of painful stimuli (Ranson and Billingsley, 1916). His experiments attempting to demonstrate the central pathways conveying painful impressions centrally in the spinal cord were less successful, although he was able to show that the vasomotor reflexes that often accompany a painful experience could be altered following interruption of the anterolateral funiculus (Ranson and Von Hess, 1915).

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Fig. 1.31. Camera lucida drawings of sagittal sections from a rhesus monkey thalamus, showing the distribution of cerebellothalamic fibers (dots) as labeled by autoradiography following an injection of tritiated amino acids in the dentate and interposed nuclei, and of spinothalamic fibers (dashes) as labeled by axonal degeneration following a spinal hemisection in the same animal. The spinothalamic terminals extend from the ventral posterior lateral (VPL) nucleus (the terminal nucleus for medial lemniscal fibers) into the ventral lateral posterior (VLp) nucleus (the terminal nucleus for cerebellothalamic fibers).Redrawn from Asanuma et al. (1983).



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