Neurology is the greatest and, I think, the most important ... · The interrelationship of brain and mind are perhaps something we shall never be quite sure of, but something toward

Neurology is the greatest and, I think, the most important, unexplored field in the whole of sci-

ence. Certainly our ignorance and the amount that is to be learned is just as vast as that of outer

space. And certainly too, what we learn in this field of neurology is more important to man. The

secrets of the brain and the mind are hidden still. The interrelationship of brain and mind are

perhaps something we shall never be quite sure of, but something toward which scientists and

doctors will always struggle.

Wilder Penfield (1891–1976) (From the Penfield papers, Montreal Neurological Institute, with permission of literary executors,

Theodore Rasmussen and William Feindel)

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The human nervous system is a specialized complex ofexcitable cells, called neurons. There are many functionsassociated with neurons including: (1) reception ofstimuli; (2) transformation of these stimuli into nerveimpulses; (3) conduction of nerve impulses; (4) neu-ron to neuron communication at points of functionalcontact between neurons called synapses; and (5) theintegration, association, correlation, and interpreta-tion of impulses such that the nervous system may acton, or respond to, these impulses. The nervous systemresembles a well-organized and extremely complexcommunicational system designed to receive infor-mation from the external and internal environment,assimilate, record, and use such information as a basis

for immediate and intended behavior. The ability ofneurons to communicate with one another is one wayin which neurons differ from other cells in the body.Such communication between neurons often involveschemical messengers called neurotransmitters.

The human nervous system consists of the centralnervous system (CNS) and the peripheral nervous sys-tem (PNS). The CNS, surrounded and protected by bonesof the skull and vertebral column, consists of the brainand spinal cord. The term ‘brain’ refers to the followingstructures: brain stem, cerebellum, diencephalon, andthe cerebral hemispheres. The PNS includes all cranial,spinal, and autonomic nerves as well as their ganglia,and associated sensory and motor endings.

C H A P T E R

1

Introduction to the Nervous System

1.1. Neurons 41.1.1. Neuronal Cell Body (Soma) 41.1.2. Axon Hillock 51.1.3. Neuronal Processes – Axons and Dendrites 5

1.2. Classification of Neurons 61.2.1. Neuronal Classification by Function 61.2.2. Neuronal Classification by Number

of Processes 6

1.3. The Synapse 71.3.1. Components of a Synapse 81.3.2. Neurotransmitters and Neuromodulators 81.3.3. Neuronal Plasticity 81.3.4. The Neuropil 9

1.4. Neuroglial Cells 91.4.1. Neuroglial Cells Differ from Neurons 91.4.2. Identification of Neuroglia 9

1.4.3. Neuroglial Function 101.4.4. Neuroglial Cells and Aging 11

1.5. Axonal Transport 111.5.1. Functions of Axonal Transport 121.5.2. Defective Axonal Transport 12

1.6. Degeneration and Regeneration 121.6.1. Axon or Retrograde Reaction 131.6.2. Anterograde Degeneration 131.6.3. Retrograde Degeneration 141.6.4. Regeneration of Peripheral Nerves 141.6.5. Regeneration and Neurotrophic Factors 161.6.6. Regeneration in the Central Nervous

System 16

1.7. Neural Transplantation 16

O U T L I N E

3

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1.1. NEURONS

The structural unit of the nervous system is the neuronwith its cell body (or soma) and numerous elaborateprocesses. There are many contacts between neuronsthrough these processes. The volume of cytoplasm inthe processes of a neuron greatly exceeds that found inits cell body. A collection of neuronal cell bodies in thePNS is a ganglion; a population of neuronal cell bodiesin the CNS is a nucleus. An example of the former is aspinal ganglion and of the latter is the dorsal vagalnucleus – a collection of neuronal cell bodies in the brainstem whose processes contribute to the formation of thevagal nerve [X].

1.1.1. Neuronal Cell Body (Soma)

The neuronal cell body (Fig. 1.1), with complex machin-ery for continuous protein synthesis, has a prominent,central nucleus (with a large nucleolus), variousorganelles, and inclusions such as the chromatophil(Nissl) substance, neurofibrils (aggregates of neurofila-ments), microtubules, and actin filaments (microfila-ments). The neuronal cell body also has a region devoidof chromatophil substance that corresponds to the pointof origin of the axon called the axon hillock (Fig. 1.1).With proper staining and then examined microscopi-cally, the chromatophil substance appears as intenselybasophil aggregates of rough endoplasmic reticulum.There is an age-related increase of the endogenous pig-ment lipofuscin in lysosomes of postmitotic neuronsand in some glial cells of the human brain. Thus lipofus-cin, as a marker of cellular aging, is termed ‘age pig-ment’. Lipofuscin consists of a pigment matrix inassociation with varying amounts of lipid droplets.Another age pigment, neuromelanin makes its appear-ance by 11–12 months of life in the human locuscoeruleus and by about 3 years of life in the human sub-stantia nigra. This brownish to black pigment undergoesage-related reduction in both these nuclear groups andis marker for catecholaminergic neurons.

Neuronal Cytoskeleton

Neurofibrils, microtubules, and actin filaments in theneuronal cell body make up the neuronal cytoskeletonthat supports and organizes organelles and inclusions,determines cell shape, and generates mechanical forcesin the cytoplasm. Injury to the neuronal cell body or itsprocesses due to genetic causes, mechanical damage, orexposure to toxic substances will disrupt the neuronal

cytoskeleton. Neurofibrils, identifiable with the lightmicroscope as linear fibrillary structures, are aggregatesof neurofilaments when viewed with the electronmicroscope. Neurofilaments, a class of intermediate fil-aments, are slender tubular structures 8–14 nm in diam-eter occurring only in neurons. Neurofilaments helpmaintain the radius of larger axons. Microtubules arelonger, have a hollow-core, and an outside diameter ofabout 22–25 nm. Their protein subunit is composed of αand β tubulin. They form paths or ‘streets’ through thecenter of the axoplasm that are traveled by substancestransported from the neuronal cell body and destinedfor the axon terminal. In the terminal, such substancesmay participate in the renewal of axonal membranesand for making synaptic vesicles. Actin filaments(microfilaments, F-actin) found in the neuronal cell bodyand measuring about 7 nm in diameter are composedpredominately of the protein actin.

Neurofibrillary Degenerations

Neurofilaments increase in number, thicken, or becometangled in normal aging and in certain diseases such asAlzheimer’s disease (AD) and Down’s syndrome. Thesediseases are termed neurofibrillary degenerationsbecause of the involvement of neurofilaments. Theeighth leading cause of death among adults in the

4 HUMAN NEUROANATOMY

FIGURE 1.1. Component parts of a typical neuron.

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United States (53,852 deaths in 2002 or 2.2 deaths per100,000 population), is Alzheimer’s disease, an irre-versible degenerative disease with an insidious onset,inexorable progression, and fatal outcome. Alzheimer’sdisease involves loss of memory and independent livingskills, confusion, disorientation, language disturbances,and a generalized intellectual deficit involving personal-ity changes that ultimately result in the loss of identity(‘Mr. Jones is no longer the same person’). Progression ofsymptoms occurs over an average of 5 to 15 years.Eventually patients with Alzheimer’s disease are disori-ented, lose control of voluntary motor activity, becomebedridden, incontinent, and unable to feed themselves.Approximately 4.5 million Americans suffer fromAlzheimer’s disease.

Neuritic Plaques, Neurofibrillary Tangles andNeuropil ThreadsSmall numbers of plaques and tangles characterize thebrain of normal individuals 65 years of age and over.Neuritic plaques, neurofibrillary tangles, and neuropilthreads, however, are structural changes characteristicof the brains of patients with Alzheimer’s disease. Thesestructural changes may occur in neuronal populationsin various parts of the human brain. Other elementssuch as 10nm and 15nm straight neurofilaments, various-sized dense granules, and microtubule-associated proteins, especially the tau protein, also occur in thisdisease. Neurofibrillary tangles occur in the neuronalcytoplasm and have a paired helical structure that con-sists of pairs of 14–18 nm neurofilaments linked by thincross-bridging filaments that coil around each other atregular 70–90 nm intervals. These paired helical fila-ments, unlike any neuronal organelle and unique to thehuman brain, are formed by one or more modifiedpolypeptides that have unusual solubility properties butoriginate from neurofilament or other normal cytoskele-tal proteins. Antibodies raised against the microtubule-associated protein, tau, are a useful marker thatrecognizes the presence of this protein in these neurofib-rillary tangles. The tau protein helps organize and stabi-lize the neuronal cytoskeleton. Proponents of the ‘Tautheory’ of Alzheimer’s disease suggest that the phos-phorylated form of this protein is a central mediator ofthis disease as it loses its ability to maintain the neuronalcytoskeleton eventually aggregating into neurofibrillarytangles. Neuropil threads (curly fibers) are fine, exten-sively altered neurites in the cerebral cortex consisting ofpaired helical filaments or nonhelical straight filamentswith no neurofilaments. They occur primarily in dendrites.

Degenerating neuronal processes along with an extra-cellular glycoprotein called amyloid precursor proteinor β-amyloid protein (β-AP) form neuritic plaques.These plaques are of three types: primitive plaques com-posed of distorted neuronal processes with a few reac-tive cells, classical plaques of neuritic processes aroundan amyloid core, and end-stage plaques with a centralamyloid core surrounded by few or no processes.Proponents of the ‘amyloid hypothesis’ of Alzheimer’sdisease regard the production and accumulation of β-amyloid protein in the brain and its consequent neu-ronal toxicity as a key event in this disease. In addition tothe amyloid hypothesis and the ‘Tau theory’, other possi-ble causes of Alzheimer’s disease include inflammationor vascular factors.

1.1.2. Axon Hillock

The axon hillock (Fig. 1.1), a small prominence or eleva-tion of the neuronal cell body, gives origin to the initialsegment of an axon. Chromatophil substance is scat-tered throughout the neuronal cell body but reduced inthe axon hillock appearing as a pale region on one sideof the neuronal cell body.

1.1.3. Neuronal Processes – Axons andDendrites

Since most stains do not mark them, neuronal processesor neurites often go unrecognized. Two types of neu-rites characteristic of neurons are axons and dendrites(Fig. 1.1). Axons transmit impulses away from the neu-ronal cell body while dendrites transmit impulses to it.The term axon applies to any long peripheral processextending from the spinal cord regardless of direction ofimpulse conduction.

Axons

The axon hillock (Fig. 1.1) arises from the neuronal cellbody, tapers into an axon initial segment and then con-tinues as an axon which remains near the cell body orextends for a considerable distance before ending as atelodendron [Greek, end tree] (Fig. 1.1). A ‘considerabledistance’ might involve an axon leaving the spinal cordand passing to a limb to activate the fingers or toes. In aseven-foot-tall professional basketball player, the dis-tance from the spinal cord to the tip of the fingers wouldcertainly be ‘a considerable distance’. Long axons usu-ally give off collateral branches arising at right angles tothe axon.

INTRODUCTION TO THE NERVOUS SYSTEM 5

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Beyond the initial segment, axonal cytoplasm lackschromatophil substance but has various microtubule-associated proteins (MAPs), actin filaments, neurofila-ments, and microtubules that provide support and assistin the transport of substances along the entire length ofthe axon. The structural component of axoplasm, theaxoplasmic matrix, is distinguishable by the presence ofabundant microtubules and neurofilaments that formdistinct bundles in the center of the axon.

Myelin

Concentric layers of plasma membranes may insulateaxons. These layers of lipoprotein wrapping material,called myelin, increase the efficiency and speed of saltatory conduction of impulses along the axon.Oligodendrocytes, a type of neuroglial cell, are myelin-forming cells in the CNS whereas neurilemmal(Schwann) cells produce myelin in the PNS. Eachmyelin layer (Fig. 1.1) around an axon has periodic inter-ruptions at nerve fiber nodes (of Ranvier). These nodesbound individual internodal segments of myelin layers.

A radiating process from a myelin-forming cell formsan internodal segment. The distal part of such a processforms a concentric spiral of lipid-rich surface mem-brane, the myelin lamella, around the axon. Multipleprocesses from a single oligodendrocyte form as manyas 40 internodal segments in the CNS whereas in thePNS a single neurilemmal cell forms only one internodalsegment. In certain demyelinating diseases, such asmultiple sclerosis (MS), myelin layers, though normallyformed, are disturbed or destroyed perhaps by anti-myelin antibodies. Impulses attempting to travel alongdisrupted or destroyed myelin layers are erratic, ineffi-cient, or absent.

Dendrites

Although neurons have only one axon, they have manydendrites (Fig. 1.1). On leaving the neuronal cell body,dendrites taper, twist, and ramify in treelike manner.Dendritic trees grow continuously in adulthood.Dendrites are usually short and branching but rarelymyelinated, with smooth proximal surfaces and branch-lets covered by innumerable dendritic spines that givedendrites a surface area far greater than the neuronal cellbody. With these innumerable spines, dendrites form amajor receptive area of a neuron. Dendrites have fewneurofilaments but many microtubules. Larger den-drites, but never axons, contain chromatophil substance.Dendrites in the PNS may have specialized receptors attheir peripheral termination that respond selectively to

stimuli and convert them into impulses, evoking sensa-tions such as pain, touch, or temperature. Chapter 6 hasadditional information on these specialized endings.

1.2. CLASSIFICATION OF NEURONS

1.2.1. Neuronal Classification by Function

Based on function, there are three neuronal types: (1) motor; (2) sensory; and (3) interneurons. Motoneurons(motor neurons) carry impulses that influence the con-traction of nonstriated and skeletal muscle or cause agland to secrete. Ventral horn neurons of the spinalcord are examples of motoneurons. Sensory neuronssuch as dorsal horn neurons carry impulses that yield avariety of sensations such as pain, temperature, touch,pressure, vision, hearing, taste, or smell. Interneuronsrelate motor and sensory neurons by transmittinginformation from one neuronal type to another.

1.2.2. Neuronal Classification by Number of Processes

Based on the number of processes, there are four neuronal types: unipolar, bipolar, pseudounipolar, ormultipolar. Unipolar neurons occur during develop-ment but are rare in the adult brain. Bipolar neurons(Fig. 1.2C) have two separate processes, one from eachpole of the neuronal cell body. One process is an axonand the other a dendrite. Bipolar neurons are in theretina, olfactory epithelium, and ganglia of the vestibu-locochlear nerve [VIII].

The term pseudounipolar neuron (Fig. 1.2A) refersto adult neurons that during development were bipolar


FIGURE 1.2. Neurons classified by the number of processesextending from the soma. A, Pseudounipolar neuron in the spinalganglia. B, Multipolar neuron in the ventral horn of the spinal cord.C, Bipolar neuron typically in the retina, olfactory epithelium, andganglia of the vestibulocochlear nerve [VIII].

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but their two processes eventually came together andfused to form a single, short stem. Thus, they have a sin-gle T-shaped process that bifurcates, sending one branchto a peripheral tissue and the other branch into the spinalcord or brain stem. The peripheral branch functions as a dendrite – the central branch as an axon. Pseudo-unipolar neurons are sensory and in all spinal ganglia,the trigeminal ganglion, geniculate ganglion [VII], glos-sopharyngeal, and vagal ganglia. Both branches of aspinal ganglionic neuron have similar diameters and thesame density of microtubules and neurofilaments. Theseorganelles remain independent as they pass from theneuronal cell body and out into each branch. A specialcollection of pseudounipolar neurons in the CNS is thetrigeminal mesencephalic nucleus.

Most neurons are multipolar neurons in that theyhave more than two processes – a single axon andnumerous dendrites (Fig. 1.1). Examples includemotoneurons and numerous small interneurons of thespinal cord, pyramidal neurons in the cerebral cortex,and Purkinje cells of the cerebellar cortex. Multipolarneurons are divisible into two groups according to thelength of their axon. Long-axon multipolar (Golgi typeI) neurons have axons that pass from their neuronalcell body and extend for a considerable distance beforeending (Fig. 1.3A). These long axons form commis-sures, association, and projection fibers of the CNS.

Short-axon multipolar (Golgi type II) neurons haveshort axons that remain near their cell body of origin(Fig. 1.3B). Such neurons are numerous in the cerebralcortex, cerebellar cortex, and spinal cord.

1.3. THE SYNAPSE

Under normal conditions, the dendrites of a neuronreceive impulses, carry them to its cell body, and thentransmit those impulses away from the cell body via theneuronal axon to a muscle or gland causing movementor yielding a secretion. Because of this unidirectionalflow of impulses (dendrite to cell body to axon), neuronsare said to be polarized. Impulses also travel from oneneuron to another through points of functional contactbetween neurons called synapses (Fig. 1.4). Such junc-tions are points of functional contact between two neu-rons for purposes of transmitting impulses. Simply put,the nervous system consists of chains of neurons linkedtogether at synapses. Impulses travel from one neuronto the next through synapses. Since synapses occurbetween component parts of two adjacent neurons, thefollowing terms describe most synapses: axodendritic,axosomatic, axoaxonic, somatodendritic, somatosomatic,and dendrodendritic. Axons may form symmetric orasymmetric synapses. Asymmetric synapses containround or spherical vesicles and are distinguished by athickened, postsynaptic density. They are presumablyexcitatory in function. Symmetric synapses contain flat-tened or elongated vesicles, pre- and postsynaptic mem-branes that are parallel to one another but lack a


FIGURE 1.3. Multipolar neurons classified by the length oftheir axon. A, Long-axon multipolar (Golgi type I) neurons haveextremely long axons; B, Short-axon (Golgi type II) multipolar neu-rons have short axons that end near their somal origin.

FIGURE 1.4. Ultrastructural appearance of an interneuronalsynapse in the central nervous system with presynaptic (A) and post-synaptic (B) parts.

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thickened postsynaptic density. Symmetric synapses arepresumably inhibitory in function.

1.3.1. Components of a Synapse

Most synapses have a presynaptic part (Fig. 1.4A), anintervening measurable space or synaptic cleft of about20 to 30 nm, and a postsynaptic part (Fig. 1.4B). Thepresynaptic part has a presynaptic membrane (Fig. 1.4) –the plasmalemma of a neuronal cell body or that of one of its processes, associated cytoplasm with mito-chondria, neurofilaments, synaptic vesicles (Fig. 1.4),cisterns, vacuoles, and a presynaptic vesicular grid con-sisting of trigonally arranged dense projections that forma grid. Visualized at the ultrastructural level, presynapticvesicles are either dense or clear in appearance, andoccupy spaces in the grid. The grid with vesicles is acharacteristic ultrastructural feature of central synapses.

Presynaptic vesicles store chemical substances orneurotransmitters synthesized in the neuronal cellbody. Upon arrival of a nerve impulse at the presynapticmembrane, there is the release of small quantities (quan-tal emission) of a neurotransmitter through the presy-naptic membrane by a process of exocytosis. Releasedneurotransmitter diffuses across the synaptic cleft toactivate the postsynaptic membrane (Fig. 1.4) on thepostsynaptic side of the synapse thus bringing aboutchanges in postsynaptic activity. The postsynaptic parthas a thickened postsynaptic membrane and some asso-ciated synaptic web material, collectively called the post-synaptic density, consisting of various proteins andother components plus certain polypeptides.

1.3.2. Neurotransmitters andNeuromodulators

Over 50 chemical substances are identifiable as neuro-transmitters. Chemical substances that do not fit theclassical definition of a neurotransmitter are termedneuromodulators. Acetylcholine (ACh), histamine,serotonin (5-HT), the catecholamines (dopamine, nor-epinephrine, and epinephrine), and certain aminoacids (aspartate, glutamate, γ-aminobutyric acid, andglycine) are examples of neurotransmitters. Neuropep-tides are derivatives of larger polypeptides that encom-pass more than three-dozen substances. Cholecystokinin(CCK), neuropeptide Y (NPY), somatostatin (SOM),substance P, and vasoactive intestinal polypeptide(VIP) are neurotransmitters. Classical neurotrans-mitters coexist in some neurons with a neuropeptide.Almost all of these neurotransmitters are in the human

brain. On the one hand, neurological disease may altercertain neurotransmitters while on the other hand theiralteration may lead to certain neurological disorders.Neurotransmitter deficiencies occur in Alzheimer’sdisease where there is a cholinergic and a noradrener-gic deficit, perhaps a dopaminergic deficit, a loss ofserotonergic activity, a possible deficit in glutamate,and a reduction in somatostatin and substance P.

1.3.3. Neuronal Plasticity

Because of enormous changes that occur during devel-opment, the nervous system is modifiable or said to be‘plastic’. The term neuronal plasticity refers to thisphenomenon. Changes continue to occur in the maturenervous system at the synaptic level as we learn, create,store and recall memories, and as we age. Alterations insynaptic function, the development of new synapses,and the modification or elimination of those alreadyexisting are examples of synaptic plasticity. With expe-rience and stimulation, the nervous system is able toorganize and reorganize synaptic connections. Age-related synaptic loss occurs in the primary visual cor-tex, hippocampal formation, and cerebellar cortex inhumans.

Another aspect of synaptic plasticity involves changesaccompanying defective development and some neuro-logical diseases. Defective development may result inspine loss and alterations in dendritic spine geometry inspecific neuronal populations. A decrease in neuronalnumber, lower density of synapses, atrophy of the den-dritic tree, abnormal dendritic spines, loss of dendriticspines, and the presence of long, thin spines occur in thebrains of children with mental retardation. Deteriorationof intellectual function seen in Alzheimer’s disease maybe due to neuronal loss and a distorted or reduced den-dritic plasticity – the inability of dendrites of affectedneurons to respond to, or compensate for, loss of inputs,loss of adjacent neurons, or other changes in themicroenvironment.

Fetal Alcohol Syndrome

Prenatal exposure to alcohol, as would occur in aninfant born to a chronic alcoholic mother, may result inFetal Alcohol Syndrome. Decreased numbers of den-dritic spines and a predominance of spines with long,thin pedicles characterize this condition. The signifi-cance of these dendritic alterations in mental retarda-tion, Alzheimer’s disease, Fetal Alcohol Syndrome,and other neurological diseases awaits further study.


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1.3.4. The Neuropil

The precisely organized gray matter of the nervous sys-tem where most synaptic junctions and innumerablefunctional interconnections between neurons and theirprocesses occur is termed the neuropil. The neuropil isthe matrix or background of the nervous system.

1.4. NEUROGLIAL CELLS

Although the nervous system may include as many as1012 neurons (estimates range between 10 billion and 1 trillion – the latter seems more likely), it has an evenlarger number of neuroglial cells. Neuroglial cells arein both the central and peripheral nervous system.Ependymocytes, astrocytes, oligodendrocytes, andmicroglia are examples of central glia; neurilemmalcells and satellite cells are examples of peripheral glia.Satellite cells surround the cell bodies of neurons.

Although astrocytes and oligodendrocytes arise fromectoderm, microglial cells arise from mesodermal elements (blood monocytes) that invade the brain inperinatal stages and after brain injury. In the develop-ing human cerebral hemispheres, the appearance ofmicroglial elements goes hand in hand with the appear-ance of vascularization.

1.4.1. Neuroglial Cells differ from Neurons

Neuroglial cells differ from neurons in at least the fourfollowing ways: (1) they have only one kind of process;(2) they are separated from neurons by an intercellularspace of about 150–200 Å and from each other by gapjunctions across which they communicate; (3) they can-not generate impulses but display uniform intracellularrecordings and have a potassium-rich cytoplasm; (4) astrocytes and oligodendrocytes retain the ability todivide, especially after injury to the nervous system.Virchow, who coined the term ‘neuroglia’, thought thesesupporting cells represented the interstitial connectivetissue of brain – a kind of ‘nerve glue’ (‘Nervenkitt’) inwhich neuronal elements are dispersed. An aqueousextracellular space separates neurons and neuroglialcells and accounts for about 20% of total brain volume.Neuroglial processes passing between the innumerableaxons and dendrites in the neuropil, serve to compart-mentalize the glycoprotein matrix of the extracellularspace of the brain.

1.4.2. Identification of Neuroglia

Identifying neuroglial cells in sections stained by rou-tine methods such as hematoxylin and eosin is difficult.Their identification requires special methods such asmetallic impregnation, histochemical, and immuno-cytochemical methods. Astrocytes are identifiable usingCajal’s gold chloride sublimate technique, microglia by del Rio-Hortega’s silver carbonate technique, andoligodendrocytes by silver impregnation methods.Immunocytochemical methods are available for thevisualization of astrocytes using the intermediate fila-ment cytoskeletal protein glial fibrillary acidic protein(GFAP). Various antibodies are available for the identi-fication of oligodendrocytes and microglia. Microglialcells are identifiable in the normal human brain with aspecific histochemical marker (lectin Ricinus communisagglutinin-1) or identified under various pathologicalconditions with a monoclonal antibody (AMC30).

Astrocytes

Two kinds of astrocytes – protoplasmic (Fig. 1.5A) andfibrous (Fig. 1.5B), are recognized. Astrocytes have a lighthomogeneous cytoplasm and nucleoplasm less densethan that in oligodendrocytes. Astrocytes are stellatewith the usual cytoplasmic organelles and long, fine,perikaryal filaments and particulate glycogen as dis-tinctive characteristics. These astroglial filaments areintermediate in size (7–11 nm) and composed of glial


FIGURE 1.5. Types of neuroglial cells in humans. A, Proto-plasmic astrocyte in the cerebral gray matter stained by Cajal’s goldchloride sublimate method. B, Fibrous astrocyte in the cerebral whitematter stained by Cajal’s gold chloride sublimate method. This glio-cyte usually has a vascular process extending to nearby blood vesselsor to the cortical or ventricular surface. C, Oligodendrocyte revealedby a silver impregnation method. This small cell (10–20 µm in diam-eter) is in the deep layers of the cerebral cortex. D, Microglial cellrevealed by the del Rio-Hortega silver carbonate method. These cellsare evenly and abundantly distributed throughout the cerebral cortex.

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fibrillary acidic protein. Their radiating and taperingprocesses, with characteristic filaments and particles,often extend to the surface of blood vessels as vascularprocesses or underlie the pial covering on the surface ofthe brain as pial processes.

Protoplasmic astrocytes occur in areas of gray matterand have fewer fibrils than fibrous astrocytes. Fibrousastrocytes have numerous glial filaments and occur inwhite matter where their vascular processes expand insheetlike manner to cover the entire surface of nearbyblood vessels forming a perivascular glial limitingmembrane. Processes of fibrous astrocytes completelycover and separate the cerebral cortex from the pia-arachnoid as a superficial glial limiting membranewhereas along the ventricular surfaces they form theperiventricular glial limiting membrane. Astrocyticprocesses cover the surfaces of neuronal cell bodies andtheir dendrites, surround certain synapses, and separatebundles of axons in the central white matter. Fibrousastrocytes with abnormally thickened and beadedprocesses occur in epileptogenic foci removed duringneurosurgical procedures.

Oligodendrocytes

The most numerous glial element in adults, called oligo-dendrocytes (Fig. 1.5C), are small myelin-forming cellsranging in diameter from 10–20 µm, with a dense nucleusand cytoplasm. This nuclear density results from a sub-stantial amount of heterochromatin in the nuclearperiphery. Athin rim of cytoplasm surrounds the nucleusand densely packed organelles balloon out on one side.Oligodendrocytes lack the perikaryal fibrils and particu-late glycogen characteristic of astrocytes. Their cytoplasmis uniformly dark with abundant free ribosomes, riboso-mal rosettes, and randomly arranged microtubules,25 nm in diameter, that extend into the oligodendrocyteprocesses and become aligned parallel to each other.Accumulations of abnormal microtubules in the cyto-plasm and processes of oligodendrocytes, called oligo-dendroglial microtubular masses, are present in braintissue from patients with such neurodegenerative dis-eases as Alzheimer’s disease and Pick’s disease.

Oligodendrocytes are identifiable in various parts ofthe brain. Interfascicular oligodendrocytes accumulatein the deeper layers of the human cerebral cortex inrows parallel to bundles of myelinated and nonmyeli-nated fibers. Perineuronal oligodendrocytes form neu-ronal satellites in close association with neuronal cellbodies. The cell bodies of these perineuronal oligoden-drocytes contact each other yet maintain their myelin-forming potential, especially during remyelination of

the CNS. Perineuronal oligodendrocytes are the mostmetabolically active of the neuroglia. Associated withcapillaries are the perivascular oligodendrocytes.

Microglial Cells

Microglial cells are rod-shaped with irregular processesarising at nearly right angles from the cell body(Fig.1.5D). They have elongated, dark nuclei and denseclumps of chromatophil substance around a nuclearenvelope. Cytoplasmic density varies, with few mito-chondria (often with dense granules), little endoplasmicreticulum, and occasional vacuoles. Microglia are oftenindented or impinged on by adjacent cellular processesand are evenly and abundantly distributed throughoutthe cerebral cortex. In certain diseases, microglial cellsare transformable into different shapes, elongating andappearing as rod cells or collecting in clusters formingmicroglial nodules. Microglial cells are CNS-adaptedmacrophages derived from mesodermal elements(blood monocytes).

1.4.3. Neuroglial Function

Neuroglial cells are partners with neurons in the struc-ture and function of the nervous system in that theysupport, protect, insulate, and isolate neurons.Neuroglial cells help maintain conditions favorable forneuronal excitability by maintaining ion homeostasis(external chloride, bicarbonate, and proton homeostasisand regulation of extracellular K� and Ca�� ) while preventing the haphazard flow of impulses. Impairmentof neuroglial control of neuronal excitability may be acause of epilepsy (also called focal seizures) in humans.About 2.7 million people in the United States areafflicted with focal seizures consisting of sudden, exces-sive, rapid, and localized electrical discharge by smallgroups of neurons in the brain. Every year another181,000 people develop this disorder.

Neuroglial cells control neuronal metabolism byregulating substances reaching neurons such as glu-cose and lipid precursors, and by serving as a dumpingground for waste products of metabolism. They arecontinually communicating with neurons serving as ametabolic interface between them and the extracellularfluid, releasing and transferring macromolecules, andaltering the ionic composition of the microenviron-ment. They also supply necessary metabolites to axons.Neuroglial cells terminate synaptic transmission byremoving chemical substances involved in synaptictransmission from synapses.


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Astrocytes are involved in the response to injuryinvolving the CNS. A glial scar (astrocytic gliosis) formsby proliferation of fibrous astrocytes. As neurons degen-erate during the process of aging, astrocytes proliferateand occupy the vacant spaces. The brains of patientsolder than 70 may show increased numbers of fibrousastrocytes. The intimate relationship between neuronsand astrocytes in the developing nervous system has ledto the suggestion that this relationship is significant innormal development and that astrocytes are involved inneuronal migration and differentiation. Astrocytes in tis-sue culture are active in the metabolism and regulation ofglutamate (an excitatory amino acid) and γ-aminobutyricacid (GABA) an inhibitory amino acid. Astrocytesremove potential synaptic transmitter substances such asadenosine and excess extracellular potassium.

Astrocytes may regulate local blood flow to and fromneurons. A small number of substance P-immuno-reactive astrocytes occur in relation to blood vessels ofthe human brain (especially in the deep white matterand deep gray matter in the cerebral hemispheres). Such astrocytes may cause an increase in blood flow inresponse to local metabolic changes. Astrocytes in tissueculture act as vehicles for the translocation of macromol-ecules from one cell to another.

Oligodendrocytes are the myelin-forming cells inthe CNS and are equivalent to neurilemmal cells in thePNS. Each internodal segment of myelin originates froma single oligodendrocyte process, yet a single oligoden-drocyte may contribute as many as 40 internodal seg-ments as it gives off numerous sheetlike processes. A substantial number of oligodendrocytes in the whitematter do not connect to myelin segments. Pathologicprocesses involving oligodendrocytes may result indemyelination. Oligodendrocytes related to capillarieslikely mediate iron mobilization and storage in thehuman brain based on the immunocytochemical local-ization in human oligodendrocytes of transferrin (themajor iron binding and transport protein), ferritin (aniron storage protein), and iron.

Microglia are evident after indirect neural traumasuch as transection of a peripheral nerve in which casethey interpose themselves between synaptic endings andthe surface of injured neurons (a phenomenon calledsynaptic stripping). Microglial cells are also involved inpinocytosis perhaps to prevent the spread of exogenousproteins in the CNS extracellular space. They aredynamic elements in a variety of neurological conditionssuch as infections, autoimmune disease, and degenera-tion and regeneration. Microglial cells are likely antigen-presenting cells in the development of inflammatorylesions of the human brain such as multiple sclerosis.

Proliferation and accumulation of microglia occursnear degenerating neuronal processes and in close associ-ation with amyloid deposits in the cerebral and cerebellarcortices in Alzheimer’s disease. Microglia may processneuronal amyloid precursor protein in these degenerat-ing neurons leading to the formation and deposition of apolypeptide called β-amyloid in neuritic plaques. Thus,microglial cells are likely involved in the pathogenesis ofamyloid deposition in Alzheimer’s disease.

Based on their structure, distribution, macrophage-likebehavior, and the observation that they can be induced toexpress major histocompatibility complex (MHC) anti-gens, microglia are thought to form a network of immunecompetent cells in the central nervous system. Microglialcells (and invading macrophages) are among the cellulartargets for the human immunodeficiency virus-1 (HIV-1)known to cause acquired immunodeficiency syndrome(AIDS). Infected microglia presumably function to releasetoxic substances capable of disrupting and perhapsdestroying neurons leading to the neurological impair-ments associated with the AIDS. Another possibility isthat destruction of the microglia causes an alteredimmune-mediated reaction to the AIDS virus and otherpathogens in these patients.

1.4.4. Neuroglial Cells and Aging

Oligodendrocytes show few signs of aging but astro-cytes and microglia may accumulate lipofuscin withage. There is a generalized, age-related increase in thenumber of microglia throughout the brain. Age-relatedastrocytic proliferation and hypertrophy are associatedwith neuronal loss. A demonstrated decrease in oligo-dendrocytes remains unexplained. Future studies ofaging are sure to address the issue of neuroglial cellchanges and their effect on neurons.

1.5. AXONAL TRANSPORT

Neuronal processes grow, regenerate, and replenishtheir complex machinery. They are able to do thisbecause proteins synthesized in the neuronal cell bodyreadily reach the neuronal processes. Axonal transportis the continuous flow (in axons and dendrites) of a range of membranous organelles, proteins, andenzymes at different rates and along the entire lengthof the neuronal process. A universal property of neu-rons, axonal transport, is ATP dependent, oxygen andtemperature dependent, requires calcium, and proba-bly involves calmodulin and the contractile proteins


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actin and myosin in association with microtubules.Axonal transport takes place from the periphery to theneuronal cell body (retrograde transport) and from theneuronal cell body to the terminal ending (anterogradetransport).

Rapid or fast axonal transport, with a velocity of50–400 mm/day, carries membranous organelles. Slowaxonal transport, characterized by two subcomponentsof different velocities, carries structural proteins, gly-colytic enzymes, and proteins that regulate polymeriza-tion of structural proteins. The slower subcomponent(SCa) of slow axonal transport, with a velocity of1–2 mm/day, carries assembled neurofilaments andmicrotubules. The faster subcomponent of slow axonaltransport, with a velocity of 2–8 mm/day carries pro-teins that help maintain the cytoskeleton such as actin(the protein subunit of actin filaments), clathrin, fodrin,and calmodulin as well as tubulin (the protein subunitof microtubules), and glycolytic enzymes. The size of aneuronal process does not influence the pattern or rateof axonal transport.

1.5.1. Functions of Axonal Transport

Anterograde transport plays a vital role in the normalmaintenance, nutrition, and growth of neuronal processessupplying the terminal endings with synaptic transmit-ters, certain synthetic and degradative enzymes, andwith membrane constituents. One function of retrogradetransport is to recirculate substances delivered byanterograde transport that are in excess of local needs.Structures in the neuronal cell body may degrade orresynthesize these excess substances as needed. Half theprotein delivered to the distal process returns to the neu-ronal cell body. Retrograde transport, occurring at therate of 150–200 mm/day, permits the transfer of worn-out organelles and membrane constituents to lysosomesin the neuronal cell body for digestion and disposal.Survival or neurotrophic factors, such as nerve growthfactor (NGF) reach their neuronal target by this route.Tetanus toxin, the poliomyelitis virus, and herpes sim-plex virus gain access to neuronal cell bodies by retro-grade transport. Retrograde axonal transport can thusconvey both essential and harmful or noxious sub-stances to the neuronal cell body.

1.5.2. Defective Axonal Transport

The phenomenon of defective axonal transport maycause disease in peripheral nerves, muscle, or neurons.Mechanical and vascular blockage of axonal transport in

the human optic nerve [II] causes swelling of the opticdisk (papilledema). Senile muscular atrophy may resultfrom age-related adverse effects on axoplasmic trans-port. Certain genetic disorders (Charcot–Marie–Toothdisease and Déjerine–Sottas disease), viral infections(herpes zoster, herpes simplex, poliomyelitis), and metabolic disorders (diabetes and uremia) manifest areduction in the average velocity of axonal transport.Accumulation of transported materials in the axon ter-minal may lead to terminal overloading and axonalbreakdown causing degeneration and denervation.Interference with axonal transport of neurofilamentsmay be a mechanism underlying the structural changesin Alzheimer’s disease (neurofibrillary tangles and neu-ritic plaques) and other degenerative diseases of the CNS.In the future, retrograde transport may prove useful inthe treatment of injured or diseased neurons by apply-ing drugs to terminal processes for eventual transportback to the injured or diseased neuronal cell body.

Neurons are polarized transmitters of nerve impulsesand active chemical processors with bi-directional com-munication through various small molecules, peptides,and proteins. Information exchange involving a chemi-cal circuit is as essential as that exchanged by electricalconduction. These chemical and electrical circuits workin a complementary manner to achieve the extraordi-nary degree of complex functioning characteristic of thehuman nervous system.

1.6. DEGENERATION AND REGENERATION

The traditional view is that during development newlygenerated neurons and synapses form but that thisprocess of neuronal generation, termed neurogenesis,does not occur in the adult primate brain. Recent obser-vations in adult macaques indicate that neurogenesisdoes occur in several regions of the cerebral cortex andthat these newly produced neurons extend axons. Theareas of the brain where these new neurons appear areinvolved in learning and memory. With the exceptionof recently discovered human neuroblasts that migrateto the olfactory bulb via a lateral ventricular extension,once destroyed most mature neurons in the CNS dieand are not replaced. After becoming committed to anadult class or population and synthesizing a neuro-transmitter, a neuron loses the capacity for DNA syn-thesis and thus also for cell division. The implicationsof this are devastating for those who have sufferedCNS injury. Some 222,000 to 285,000 people are living


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with spinal cord injuries with nearly 11,000 new casesevery year in the United States. An additional 4860individuals die each year before reaching the hospital.Another 2,000,000 patients have suffered brain traumaor other injury to the head with over 800,000 new caseseach year. Thus, the inability of the adult nervous systemto add neurons or replace damaged neurons as needed isa serious problem to those afflicted with CNS injury.

1.6.1. Axon or Retrograde Reaction

Degeneration of neurons is similar in the CNS and PNS.One exception is the difference in the myelin-formingoligodendrocytes in the CNS in contrast to the myelin-forming neurilemmal cells of the PNS. Only hours afterinjury to a neuronal process, perhaps because of a signalconveyed by retrograde axonal transport, a geneticallyprogrammed and predictable series of changes occur ina normal neuronal cell body (Fig. 1.6A). These collectivechanges in the neuronal cell body are termed the axon orretrograde reaction. One to three days after the initialinjury the neuronal cell body swells and becomesrounded (Fig. 1.6B), the cell wall appears to thicken, andthe nucleolus enlarges. These events are followed bydisplacement of the nucleus to an eccentric position (Fig.1.6C), widening of the rough endoplasmic reticulum,and mitochondrial swelling. Chromatophil substance at this time undergoes conspicuous rearrangement – aprocess referred to as chromatolysis involving fragmen-tation and loss of concentration of chromatophil sub-stance causing loss of basophil staining by injured

neurons (Fig. 1.6D). Chromatolysis is prominent about15–20 days after injury.

Along with the axon reaction, there are alterations inprotein and carbohydrate synthesis occurring in thechromatolytic neuron. DNA-dependent RNA synthe-sis seems to play a key role in this process. As the axonreaction continues, there is increased production of freepolyribosomes, rough endoplasmic reticulum, neuro-filaments, and an increase in the size and number oflysosomes. The axon reaction includes a dramatic pro-liferation in perineuronal microglia leading to a dis-placement of synaptic terminals on the neuronal cellbody and stem dendrites causing electrophysiologicaldisturbances.

The sequence of events characteristic of an axonreaction depends, in part, on the neuronal system andage as well as the severity and exact site of injury. If leftunchecked the axon reaction leads to neuronal dissolu-tion and death. If the initial injury is not severe, theneuronal nucleus returns to a central position, the chromatophil substance becomes concentrated, andthe neuronal cell body returns to normal size.

Initial descriptions of chromatolysis suggested itwas a degenerative process caused by neuronal injury.Recent work suggests chromatolysis represents neu-ronal reorganization leading to a regenerative process.As part of the axon reaction, the neuronal cell bodyshifts from production of neurotransmitters and high-energy ATP to the production of lipids and nucleotidesneeded for repair of cell membranes. Thus, chromato-lysis may be the initial event in a series of metabolicchanges involving the conservation of energy andleading to neuronal restoration.

1.6.2. Anterograde Degeneration

Transection of a peripheral nerve, such as traumaticsection of the ulnar nerve at the elbow, yields proximaland distal segments of the transected nerve. Changestaking place throughout the entire length of the distalsegment (Fig. 1.7) are termed anterograde (Wallerian)degeneration. Minutes after injury, swelling andretraction of neurilemmal cells occur at the nerve fibernodal regions. Twenty-four hours after injury, themyelin layer loosens. During the next two to threedays, the myelin layer swells, fragments, globulesform, and then the myelin layer disrupts about dayfour. Disappearance of myelin layers by phagocytosistakes about six months. A significant aspect of thisprocess is that the endoneurial tubes and basementmembranes of the distal segment collapse and fold butmaintain their continuity. About six weeks after injury


FIGURE 1.6. Changes in the neuronal cell body during theaxon reaction. A, Normal cell. B, Swollen soma and nucleus with disruption of the chromatophil substance. C, and D, Additionalswelling of the cell body and nucleus with eccentricity of the nucleusand loss of concentration of the chromatophil substance.

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there is fragmentation and breakdown of the cyto-plasm of the distal segment.

1.6.3. Retrograde Degeneration

Changes occurring in the proximal segment (Fig. 1.7)of a transected peripheral nerve are termed retrogradedegeneration. One early event at the cut end of theproximal stump is the accumulation of proteins. As thestump seals the axon retracts, and a small knob orswelling develops. Firing stops as the injured neuronrecovers its resting potential. Normal firing does notoccur for several days. Other changes are similar tothose taking place in the distal segment except that theprocess of retrograde degeneration in the proximal

segment extends back only to the first or second nervefiber node and does not reach the neuronal cell body(unless the initial injury is near the soma).

1.6.4. Regeneration of Peripheral Nerves

Although the degenerative process is similar in theCNS and PNS, the process of regeneration is not com-parable. In neither system is there regeneration of neu-ronal cell bodies or processes if the cell body is seriouslyinjured. Severance of the neuronal process near the cellbody will lead to death of the soma and no regenera-tion. For the neuronal process to regenerate, the neu-ronal cell body must survive the injury. Only about 25%of those patients with surgically approximated severedperipheral nerves will experience useful functionalrecovery.

Many events occur during regeneration of peripheralnerves. The timing and sequence of those events isunclear. Regenerating neurons shift their metabolicemphasis by decreasing production of transmitter-related enzymes while increasing production of sub-stances necessary for the growth of a new cytoskeletonsuch as actin (the protein subunit of actin filaments) andtubulin (the protein subunit of microtubules). There isan increase in axonal transport of proteins and enzymesrelated to the hexose monophosphate shunt. Axonalsprouting from the proximal segment of a transectednerve during regeneration is a continuation of theprocess of cytoskeletal maintenance needed to sustain aneuronal process and its branches.

A tangible sign of regeneration, the proliferation ofneurilemmal cells from the distal segment, takes placeabout day four and continues for three weeks. A 13-foldincrease in these myelin-forming cells appears in theremains of the neurolemma, basal lamina, and the persisting endoneurial connective tissue. Mechanismsresponsible for the induction of neurilemmal cell prolif-eration are unclear. Human neurilemmal cells main-tained in cell culture will proliferate if they make contactwith the exposed plasmalemma of demyelinated axons.

Band Fibers, Growth Cones and Filopodia

Proliferating neurilemmal cells send out cytoplasmicprocesses called band fibers (Fig. 1.7E) that bridge thegap between the proximal and distal segments of a sev-ered nerve. As the band fibers become arranged in lon-gitudinal rows, they serve as guidelines for the growthcones, bulbous and motile structures with a core oftubulin surrounded by actin that arise from the axonal


FIGURE 1.7. Sequential steps (A–F) in the degeneration andregeneration in the proximal and distal segments of a transected neu-ronal process. In the proximal segment, degeneration extends back tothe first or second nerve fiber node. Anterograde degeneration existsthroughout the entire distal segment. Proliferation of neurolemmo-cytes from the distal segment forms a bridge across the transectionpaving the way for an axonal sprout to find its way across the gapand eventually form a new process of normal diameter and length.

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sprouts of the proximal segment. Microtubules and neu-rofilaments, though rare in growth cones, occur behindthem and extend into the base of the growth cone, fol-lowing the growth cones as they advance. Cytoskeletalproteins from the neuronal cell body such as actin andtubulin enter the growth cones by slow axonal transport24 hours after initial injury. The rate of construction of anew cytoskeleton behind the advancing growth conelimits the outgrowth of the regenerating process. Suchconstruction depends on materials arriving by slowtransport that are available at the time of axonal injury.The unstable surface of a parent growth cone yields twotypes of protrusions – many delicate, hairlike offspringcalled filopodia (microspikes) and thin, flat lamellipo-dia (lamella) both of which are filled with denselypacked actin filaments forming the motile region of the growth cone. Neuronal filopodia (Fig. 1.7D) are10–30 µm long and 0.2 µm in diameter and evident at thetransection site extending from the proximal side andretracting as they try to find their way across the scaffoldof neurilemmal cells. After they make contact with theirtargets, extension of the filopodia ceases. There is suc-cessive addition of actin monomers at the apex of thegrowth cone with an ensuing rearward translocation ofthe assembled actin filaments. Both guidance and elon-gation of neuronal processes are essential featuresunderlying successful regeneration. Such guidance isprobably due to the presence of signaling molecules inthe extracellular environment. In addition to their role inregeneration, growth cones play a role in the develop-ment of the nervous system allowing neuronal processesto reach their appropriate targets.

At the transection site, growth cones progress at therate of about 0.25 mm/day. If the distance between theproximal and distal stumps is not greater than1.0–1.5 mm, the axonal sprouts from the proximal sideeventually link up with the distal stump. As noted ear-lier, the endoneurial tubes and basement membranes of the distal segment collapse and fold but maintaintheir continuity. Growth cones invade the persistingendoneurial tubes and advance at a rate of about1.0–1.5 mm/day. A general rule for growth of peripheralnerves in humans is one inch per month. After transec-tion of the median nerve in the axilla, nine months maybe required before motor function returns in the musclesinnervated by that nerve and 15 months before sensoryfunction returns in the hand. After injury to a majornerve to the lower limb, 9–18 months is required beforemotor function returns. If a motor nerve enters a sensoryendoneurial tube or vice versa, the process of regenera-tion will cease. If one kind of sensory fiber (one that car-ries painful impulses) enters the endoneurial tube of

another kind of sensory fiber (one that carries tactileimpulses), then abnormal sensations called paresthesias(numbness, tingling, or prickling) may appear in theabsence of specific stimulation.

After a regenerated process crosses the transectionsite and enters the appropriate endoneurial tube, regen-eration is still incomplete. The new process must be ofnormal diameter and length, remyelination must occur,and the original site of termination be identified witheventual re-establishment of appropriate connections. Ifthe regenerating nerve is a motor nerve, it must find themuscle it originally innervated. A regenerating sensorynerve must innervate an appropriate peripheral recep-tor. Reduced sensitivity and poor tactile discriminationwith peripheral nerve injuries is a result of misguidanceof regenerating fibers and poor reinnervation. Regrowingfibers may end in deeper tissues and in the palm ratherthan in the fingertips – the site of discriminative tactilereceptors. Poor motor coordination for fine movementsobserved in muscles of the human hand after peripheralnerve section and repair may be the result of misdirec-tion of regenerating motor axons.

Collateral Sprouting

Collateral sprouts may arise from the main axonalshaft of uninjured axons remaining in a denervatedarea. Such collateral sprouting, representing anattempt by uninjured axons to innervate an adjacentarea that has lost its innervation, is often confused withaxonal sprouts that originate from the proximal seg-ment of injured or transected neuronal processes.Collateral sprouting from adjacent uninjured axonsmay lead to invasion of a denervated area and restora-tion of sensation in the absence of regeneration byinjured axons thus leading to recovery of sensation.

Neuromas

If the distance between the severed ends of a transectedprocess is too great to reestablish continuity, the growingfibers from the proximal side continue to proliferateforming a tangled mass of endings. The resultingswollen, overgrown mass of disorganized fibers and con-nective tissue is termed a traumatic neuroma or nervetumor. A neuroma is usually firm, the size of a pea, andforms in about three weeks. When superficial, incorpo-rated in a dense scar, and subject to compression andmovement, a neuroma may be the source of considerablepain and paresthesias. Neuromas form in the brain stem,spinal cord, or on peripheral nerves. In most peripheralnerve injuries, the nerve is incompletely severed and


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function is only partially lost. Blunt or contusive lacera-tions, crushing injuries, fractures near nerves, stretchingor traction on nerves, repeated concussion of a nerve andgunshot wounds may produce neuromas in continuity.Indeed, in about 60% of such cases, neuromas in continuity develop. A common example is Morton’smetatarsalgia – an interdigital neuroma in continuityalong the plantar digital nerves as they cross the trans-verse metatarsal ligament. Wearing ill-fitting high heeledshoes stretches these nerves bringing them into contactwith the ligament. Other examples are intraoral neuro-mas that form on the branches of the inferior alveolarnerve (inferior dental branches and the mental nerve) oron branches of the maxillary nerve (superior dentalplexus), amputation neuromas in those who have hadlimbs amputated, and bowler’s thumb which resultsfrom repetitive trauma to a digital nerve.

1.6.5. Regeneration and Neurotrophic Factors

Regeneration of a peripheral nerve requires an appro-priate microenvironment (a stable neuropil, sufficientcapillaries, and neurilemmal cells), and the presence ofcertain neurotrophic factors such as nerve growth fac-tor (NGF), brain-derived neurotrophic factor (BDNF),or neurotrophin-3. Absorption of these factors by theaxonal tip and their retrograde transport will influencethe metabolic state of the neuronal cell body and sup-port neuronal survival and neurite growth. Other sub-stances attract the tip of the growth cone or axonalsprout thus determining the direction of growth.

1.6.6. Regeneration in the Central NervousSystem

Regeneration of axons occurs in certain nonmyelinatedparts of the mammalian CNS such as the neurohypo-physis (posterior lobe of the pituitary gland) in the dog,retinal ganglionic cell axons and olfactory nerves in mice,and in the corticospinal tract of neonatal hamsters.However, the process of CNS regeneration leading torestoration of function is invariably unsuccessful inhumans. Several theories attempt to explain this situa-tion. The barrier hypothesis suggests that mechanicalobstruction and compression due to formation of a denseglial scar at the injury site impedes the process of axonalgrowth in the human CNS. Such dense scar formation orastrocytic gliosis is the result of the elaboration of astro-cytes in response to injury. This glial scar forms an insur-mountable barrier to effective regeneration in the CNS.Remyelination, accompanied by astrocytic gliosis, takes

place in the CNS if axonal continuity is preserved.Myelin, in the process of degeneration, releases activepeptides such as axonal growth inhibitory factor (AGIF)and fibroblast growth factor (FGF). AGIFs may lead toabortive growth of most axons whereas the FGFs areapparently responsible for the deposition of a collage-nous scar. The observation that the breakdown of myelinin the PNS is unaccompanied by elaboration of AGIFsseems to strengthen this hypothesis. The presence ofthese growth promoting and growth inhibiting mole-cules along with the formation of glial scars offers a greatchallenge to those seeking therapeutic methods to aidthose with CNS injury.

Efforts are underway to determine if neurons of theCNS are missing the capability of activating necessarymechanisms to increase production of ribosomal RNA.Other attempts at restoring function in the injuredspinal cord involve removing the injured cord regionand then replacing it with tissue from the PNS.

Inherent neuronal abilities and the properties of theenvironment (neuropil, local capillaries, and the pres-ence of repulsive substrates or inhibitors of neurite out-growth) are responsible for the limited capacity for CNSregeneration. Neuroglial cells, by virtue of their abilityto produce trophic and regulatory substances plus theirability to proliferate forming a physical barrier to regen-eration, also play an essential role in regeneration. A minimum balance exists between the capacity ofaxons to regenerate and the ability of the environment tosupport regeneration. CNS regeneration in humans isan enigma awaiting innovative thinking and extensiveresearch. Success in this endeavor will bring joy to mil-lions of victims of CNS injury and their families.

1.7. NEURAL TRANSPLANTATION

In light of the absence of CNS regeneration leading torestoration of function in humans, there is a great deal ofinterest in the possibility of neural transplantation as ameans of improving neurological impairment due toinjury, aging, or disease. Sources of donor material forneural transplants are neural precursor cells from humanembryonic stem cells, adult cells or umbilical cords, gan-glia from the PNS (spinal and autonomic ganglia andadrenal medullary tissue), and cultured neurons. Othersources are genetically modified cell-lines capable ofsecreting neurotrophic factors or neurotransmitters.

Focal brain injuries, diseases of well-circumscribedchemically defined neuronal populations, identifiablehigh-density terminal fields, areas without highly


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specific point-to-point connections, or regions wheresimple one-way connections from the transplant wouldbe functionally effective, are likely to profit from neuraltransplantation. Neurological diseases such asAlzheimer’s and Parkinson’s disease, are characterizedby a complex set of signs and symptoms with damage tomore than one region and more than one neurotransmit-ter involved, such that patients suffering from these dis-eases might not benefit from a single neural transplantbut may require dissimilar transplants in different loca-tions. Because these diseases are also progressive anddegenerative, it is possible that the transplant itself willbe subject to the same progressive and degenerativeprocess. An equally disconcerting prospect is that withadditional degeneration of the brain, the signs andsymptoms ameliorated by the original transplant maydisappear, replaced by a new set of signs and symptomsthat might require a second transplant for their allevia-tion. Finally, because of the age of most patients withthese diseases it is likely that they have other physicalconditions that might necessitate selecting for treatmentonly those who do not have other underlying conditionsor who have a very early stage of the disease.

Another approach to this problem that would cir-cumvent the risks and ethical issues associated withneural transplantation would be to administer neu-rotrophic factors to support neuronal survival or pro-mote growth of functional processes. An excitingdevelopment in this regard is the isolation of a proteincalled glial cell line-derived neurotrophic factor (GDNF),which promotes the survival of dopamine-producingneurons in experimental animals. In Parkinson’s dis-ease, there is restricted damage to a well-defined groupof dopamine-producing neurons in the midbrain. Such aneurotrophic agent might prevent or reverse the signsand symptoms of this chronic, degenerative disease. An additional option would be to investigate the initialchanges in the brain that lead to a particular neurologicalimpairment and seek a means of preventing suchchanges. Much work remains before neural transplanta-tion becomes a useful and practical form of therapyleading to complete functional recovery from neurolog-ical injuries, diseases, or age-related changes.

FURTHER READING

Abbott NJ, Ronnback L, Hansson E (2006) Astro-cyte–endothelial interactions at the blood–brain barrier.Nat Rev Neurosci 7:41–53.

Allen NJ, Barres BA (2005) Signaling between glia and neu-rons: focus on synaptic plasticity. Curr Opin Neurobiol15:542–548.

Ambrosi G, Virgintino D, Benagiano V, Maiorano E, Bertossi M,Roncali L (1995) Glial cells and blood–brain barrier in thehuman cerebral cortex. Ital J Anat Embryol 100 (Suppl 1):177–184.

Antel J (2005) Oligodendrocyte/myelin injury and repair as afunction of the central nervous system environment. ClinNeurol Neurosurg 108:245–249.

Baumann N, Pham-Dinh D (2001) Biology of oligodendro-cyte and myelin in the mammalian central nervous system.Physiol Rev 81:871–927.

Farber K, Kettenmann H (2005) Physiology of microglialcells. Brain Res Rev 48:133–143.

Hering H, Sheng M (2001) Dendritic spines: structure,dynamics and regulation. Nat Rev Neurosci 2:880–888.

Hyman SE (2005) Neurotransmitters. Curr Biol 15:R154–R158.

Itzev DE, Ovtscharoff WA, Marani E, Usunoff KG (2002)Neuromelanin-containing, catecholaminergic neurons inthe human brain: ontogenetic aspects, development andaging. Biomed Rev 13:39–47.

Koehler RC, Gebremedhin D, Harder DR (2006) Role of astro-cytes in cerebrovascular regulation. J Appl Physiol 100:307–317.

Masland RH (2004) Neuronal cell types. Curr Biol 14:R497–R500.

McLaurin JA, Yong VW (1995) Oligodendrocytes and myelin.Neurol Clin 13:23–49.

Newman EA (2003) New roles for astrocytes: regulation ofsynaptic transmission. Trends Neurosci 26:536–542.

Oberheim NA, Wang X, Goldman S, Nedergaard M (2006)Astrocytic complexity distinguishes the human brain.Trends Neurosci 29:547–553.

Pellerin L (2005) How astrocytes feed hungry neurons. MolNeurobiol 32:59–72.

Riga D, Riga S, Halalau F, Schneider F (2006) Brain lipo-pigment accumulation in normal and pathological aging.Ann NY Acad Sci 1067:158–163.

Roy S, Zhang B, Lee VM, Trojanowski JQ (2005) Axonal trans-port defects: a common theme in neurodegenerative dis-eases. Acta Neuropathol (Berl) 109:5–13.

Sherman DL, Brophy PJ (2005) Mechanisms of axonensheathment and myelin growth. Nat Rev Neurosci6:683–90.

Stevens B (2003) Glia: much more than the neuron’s side-kick. Curr Biol 13:R469–R472.

Torrealba F, Carrasco MA (2004) A review on electronmicroscopy and neurotransmitter systems. Brain Res Rev47:5–17.

Tyler WJ, Murthy VN (2004) Synaptic vesicles. Curr Biol14:R294–R297.

Volterra A, Meldolesi J (2005) Astrocytes, from brain glue tocommunication elements: the revolution continues. NatRev Neurosci 6:626–640.

Wigley C (2004) Nervous system. In: Standring S, Editor-in-Chief. Gray’s Anatomy. 39th ed, pp 43–68. Elsevier/Churchill Livingstone, London.


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