Brain Advance Access originally published online on November 17, 2006
Brain 2007 130(3):875-878; doi:10.1093/brain/awl307
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Book Review |
Fibre pathways of the brain
This large, well illustrated volume deals with one aspect of the fibre systems of the brain. The book reports the results of tracing efferent fibre connections from various areas of the cerebral cortex of 32 macaque monkeys. The book would be useful for those wishing to have an anatomical basis for interpreting patterns of connectivity seen in scans, and some of the clinical symptoms that might be associated with interruption of fibre pathways. There is a brief history of prior contributions, and some elegant illustrations from the classical literature. The bulk of the book reports the results of studies of the course of cortically-originating nerve fibres after an injection of a labelled amino acid is placed into a specific region of the monkey cerebral cortex.The study of neural connections has a long history. Early views were changed by later evidence, and old problems clarified. The process continues. The tracing technique used here is useful, but it is not the final word, and it leaves many problems to solve. Here I consider the problem of fibre connections in the brain in a broader, historical context.
Introductory students of neuroscience quickly learn that axons are extensions of nerve cell bodies. This simple truth took well over 100 years to establish. Even when that became established, it was still not at all clear how the axon is formed. The idea that an axon either fires or it does not fire; the ‘all or none law’, also is usually introduced in chapter 1 of introductory texts, seldom with any consideration of how we know this or why it should be true. The early history of some of these questions can help to put our modern views in perspective.
Nerve fibres were recognized long before nerve cells. Early anatomists searched for tube-like structures that could carry vital spirits from the brain to the rest of the body and from the body back to the spinal cord and brain. Galen saw the entire optic nerve as a single tube bringing visual impressions to the brain. It was Anton van Leeuwenhoek, more than any other single anatomist who first described the accurate appearance of a nerve fibre when seen in cross-section (Cole, 1937
). Leeuwenhoek's beautiful drawings of a cut peripheral nerve resemble those which can be achieved with more recent techniques. Leeuwenhoek's (1719) observations are clearest in his drawings of peripheral nerve, but he, like some later anatomists, could not easily distinguish small blood vessels from nerve fibres within the cerebral cortex.
Leeuwenhoek and later authors probably saw nerve cells as well as fibres, calling them ‘globules’, although many of the structures that they described were probably fat rather than nerve cells. Among the first and most elegant descriptions of nerve cells were those of Jan Evagelista Purkinje (1838), who drew the shape and location of the cells which still bear his name. Flask-shaped, Purkinje cells extend in a single layer throughout the entire cortex of the cerebellum. Purkinje's description was published a year before Schwann (1839) formulated the general principle that animals and plants are made up of individual elements called cells. In addition to the accuracy of his drawings, Purkinje's figures hint that there is continuity between nerve cells and nerve fibres. The demonstration that axons arise from nerve cells was made about the same time by Robert Remak (1836). By the late 19th century the appearance of nerve cells was well described, although the word ‘neuron’ was not coined until the last decade of the 19th century by Waldeyer (1891), in summarising the new discoveries of Cajal and others on the structure of elements of the brain and spinal cord.
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A single sensory fibre carrying information from the foot to the brain may be well over a meter in length. In the 19th century there was no agreement about how such axons might be formed. Some thought that the axons were made up of fused individual elements. According to this view, each small segment would be constructed by a single cell. These individual segments would then fuse to form the long fibre connection between the spinal cord and the periphery. It was tissue culture preparations (Harrison, 1907) that showed axons growing out from cultured nerve cells that finally served as critical evidence for an essential continuity between a nerve cell and its axon.
Tracing connections in the nervous system has been based on a variety of techniques. Cajal (1955), despite the brilliance of his descriptions of cell types and fibres had few available methods for establishing distant connections among structures in the brain and spinal cord. He would sometimes trace individual fibres from one part of the brain to another using serial sections of Golgi- stained material, a difficult challenge which Cajal met by studying small animals, often in a juvenile state, hence with smaller brains.
Study of axonal degeneration following nerve injury has played a major part in helping to understand the connections from the spinal cord to the periphery and within the central nervous system. Augustus Waller (1850) cut the lingual nerve of a frog, and studied the resultant changes. Distal to the cut Waller's figure showed the nerve fragmenting and forming droplets. Degeneration of a nerve distal to the injury is still referred to as Wallerian degeneration. Along with the death of the axon in Wallerian degeneration, the myelin also disintegrates. In the 19th century Weigert (1882) and others developed stains for the myelin sheath. If a tract within the brain dies, the dead tract may be revealed by an absence of staining. This technique has been used extensively by neuropathologists to follow the course of fibre degeneration following injury to the brain or its fibre tracts.
The first systematic experiments that used degeneration staining as an experimental technique for tracing fibre connections was based on a method developed by Vittorio Marchi and Aligeri (1885) who found that if an axon is severed from its cell body, the resultant degenerating fibres have an affinity for osmium based staining. Fibre degeneration could now be used for studying connections in the nervous system by placing restricted lesions in the brains of experimental animals, and following the course of the degenerating fibres. Since the Marchi technique is based on staining degenerating myelin, it is biased in favour of the largest axons.
Methods for tracing connections using fibre degeneration continued to improve. Walle Nauta and his colleagues developed a technique for identifying degeneration of the axon itself to study connections. Nauta's (1954) method and its successors, allowed investigators to follow the course and the terminations of much smaller fibres. Those discoveries have formed the basis for much of what is known about connections in the brain.
When a nerve fibre is cut, in addition to degeneration distal to the cut, there usually are retrograde changes in the cell body. Much of our knowledge about connections between spinal motor neurons and muscles came from studying retrograde changes in spinal motor neurons after a peripheral nerve had been cut. Similarly, the basic principles of thalamo-cortical organization were developed by Le Gros Clarke (1932) and Earl Walker (1938) who placed lesions in the cerebral cortex of monkeys, and plotted the location of the resultant retrograde degeneration in the thalamus.
There are pitfalls in relying on a single technique. Study of retrograde degeneration, for example, may give an oversimplified picture of neural connections. Holmes and May (1909) cut the pyramidal tract of a monkey, and showed that the giant Betz cells of lamina V of the motor cortex were now absent. They concluded that they had identified the ‘exact origin of the pyramidal tract’. But later counts by Lassek (1941) showed that whilst there are 50 000 Betz cells, there about a million pyramidal tract fibres, leaving 950 000 additional nerve cells to be identified as the exact origin of the pyramidal tract.
Students of neuroanatomy have typically emphasized the cellular organization of brain and spinal cord. Fibres were just the wires that connected it all together. A few anatomists emphasized fibres. Verhaart (1970) and his students used staining of normal fibres to study the structure of the brain stem and spinal cord. In most of their work they used a stain developed earlier in Sweden by Häggqvist (1948). The Häggqvist method gives a beautiful picture of axons (staining blue) and myelin (staining pink or red). Using this stain, Verhaart and his students described the fibre composition of a number of structures in the brain of man and other mammals. One of Verhhart's students, Van Crevel (1958), used the same staining technique to study the rate at which axons in the central nervous system of mammals disappear after they are cut off from the cell body. Van Crevel counted the number of stained axons in the normal pyramidal tract or optic nerve of cats. In experimental animals he would cut the tract or make a large cortical lesion among its cells of origin. He would allow the animals to survive for a variable period of time, and count the number of surviving axons. Van Crevel's data suggested that it is the largest calibre fibres which degenerate most rapidly.
Until the middle of the 20th century, the study of the connections of nerve fibres was based on studying normal or degenerating fibre tracts, using a light microscope. But there are a great number of very fine axons in the central and peripheral nerves which can not be resolved by the light microscope. The smallest fibres are too small to be seen. The relationship between method and results is clearly seen in successive studies of the rat pyramidal tract. The earliest study used Marchi stain, and concluded that there are 901 fibres in the tract (King, 1910). Later light microscopic studies (Lassek and Rasmussen, 1940) concluded that there are up to 73 000 fibres in the tract. An electron microscopic study of the same structure (Leenen et al. 1982) concluded that there are over 200 000 fibres in the rat pyramidal tract, of which about 60% are unmyelinated.
In Weiss and Hiscoe (1948) tied a silk ligature around a peripheral nerve, and studied the resultant changes in the diameter of the nerve over time. They noted that on the side of the cell body there was a clear swelling, and a much smaller swelling on the distal side of the ligature. Something that flows down the nerve fibres was blocked by the ligature, so the nerve swelled. In the 1970s, techniques were developed that were based on such axonal transport for following the course and termination of nerve fibres. Kristensson et.al. (1971) injected Evans Blue, and later horseradish peroxidase (HRP) into muscles, After a period of time the injected label would appear in the cell bodies of spinal motor neurons. Initially it was thought that HRP was transported only in the retrograde direction, but soon it became apparent that the methods are equally useful for studying orthograde transport as well.
Max Cowan (1972) and his associates at Washington University in Saint Louis developed a new and different method for tracing nerve connections, using orthograde transport of radioactively labelled substances. They replaced the hydrogen in amino acids, typically leucine or proline, with tritium. They showed that the labelled amino acid is incorporated into proteins which were then transported from the cell body to the periphery. By arranging an appropriate time between the injection and the death of the animal, the course of axons could be revealed by sectioning the tissue, coating it in the dark with a silver solution, and allowing the radioactivity to expose silver grains over the sections. The sections are then developed, much like a photographic film, revealing the labelled fibres and their terminals. The technique of radiographic tracing of labelled nerve fibres forms the basis for the experimental work presented in this book.
When I first taught in an anatomy course there were many brains available for teaching. Students were encouraged to shell out gray matter using their fingers or an orange stick to reveal the U fibres linking adjacent gyri, and the long association bundle that link remote parts of the cerebral cortex. The autoradiographic technique as used by Schmahmann and Pandya is clearly a major advance over more primitive methods for establishing connections. As such it is useful to have a systematic description of the efferent target of each of the major cortical areas in monkeys. The anatomical data can prove helpful for interpreting some of the results of correlated activation that is seen in scans, and some of the clinical deficits that might be caused by interruption of fibre pathways.
The book is titled ‘Fiber Systems of the Brain’. A more exact title would be cortico-cortical connections of the macaque brain. Useful as it is, it deals only sketchily with some questions, and not at all with some others. In addition to connections from one region to another, the cerebral cortex has reciprocal connections with its major input, the thalamus, and it projects its output by way of two great efferent fibre systems; the basal ganglia and the cerebellum by way of a relay in the pontine nuclei. The thalamic and basal ganglia connections are sketchily described. The pontine connections are referred to by the author's published previously papers on the problem.
The cerebral cortex consists of a laminated sheet of nerve cells and their supporting tissues. Different regions of the cortex differ in the patterns of cells and fibres that they contain. Francesco Gennari (1782) first noticed a prominent white stripe that is present about halfway between the pial surface and the white matter, and which is most clearly visible in the occipital lobe. Gennari's observation was the first of many that demonstrate that the cerebral cortex is not uniform in structure. The 19th century histologists showed that each lamina of cortex is characterized and defined by its cell types. Physiologists have typically emphasized the properties of each column of cortex, paying rather less attention to differences among the cortical laminae. Cells in different cortical layers have different targets. In the rat barrel field, for example, all of the cells in lamina Vb project to the pontine nuclei (Mercer et al., 1990). All of the cells in lamina Va project to the basal ganglia. Most of the projections to the thalamus arise from cells in lamina VI. It is the superficial laminae, layers II and III, that provide most of the cortico-cortical connections. None of these differential connections of different laminae would be revealed by the techniques used here.
The autoradiographic analysis presented in this book represents an advance in our understanding of cortico-cortical connections. However, we need to complement anterograde tracing with other techniques such as retrograde tracing, chemoarchitecture, electron micrography, neurophysiology etc. to appreciate more fully the nature of cortical organization. Much of this work is available in the literature.
The book has much to recommend it. There is a useful historical introduction. There are some beautiful pictures reproduced from the old literature. Autoradiographic tracing represents significant advance over much of the early work which was usually based on simple dissection of hardened brains. But there is a bit more to learn.
Department of Anatomy
University College London
London, UK
E-mail: ucgamig{at}ucl.ac.uk
Acknowledgements
I was guided to the early literature on the structure of nerve fibres by the excellent volume by Clarke and O'Malley (1968); The Human Brain and Spinal Cord. I thank my friends and colleagues Drs Karen Berkley, Pauline Field, and Alan Gibson who read an earlier draft of this review.
References
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