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AHMADU BELLO UNIVERSITY, ZARIA - NIGERIA FACULTY OF MEDICINE DEPARTMENT OF HUMAN PHYSIOLOGYNEUROPHYSIOLOGY (HPHY 305) Rabiu AbduSSALAM Magaji, Ph.D.E-mails: email@example.com; firstname.lastname@example.org
Learning Objectives At the end of this lecture, it is expected that the student would be able to: List and describe the parts of the nervous system and their components List the various types of glia and their functions. Name the parts of a neuron and their functions. Describe the role of myelin in nerve conduction. List the types of nerve fibers found in the mammalian nervous system.
Need for Review Excitable Tissues Nerves (Structures and functions) Muscles (Structures and functions) Organization of the Nervous System in general Organization of the Central Nervous System (CNS)specifically Anatomy of the different parts of the brain
Organization of the Nervous System - OriginIn the developing embryo, the Nervous system (NS) developsfrom ectoderm, that forms the neural plate.The neural plate differentiates into neural tube and a neuralcrest.The neural tube then differentiates into the Central NervousSystem (CNS), which consists of the Brain and the Spinalcord.The neural crest gives rise to most of the Peripheral NervousSystem (PNS), which consists of 12 pairs of cranial nervesand 31 pairs of spinal nerves.
The Central Nervous System The brain develops at the cranial end of the embryonic neural tube. By the end of the first month of development, three (3) Primary vesicles are formed: Forebrain (Prosencephalon), the Midbrain (Mesencephalon), and the Hindbrain (Rhombencephalon). A week later, the forebrain gives rise to the Telencephalon and the Diencephalon, and the hindbrain gives rise to the Metencephalon and the Myelencephalon resulting in a total of five (5) secondary vesicles.
In adults: Telencephalon develops intoCerebral hemispheres. Diencephalon gives rise to the Thalamus and the Hypothalamus and other structures. Mesencephalon becomes the Midbrain. Mylencephalon becomes Medulla oblongata. The Metencephalon gives rise to medulla oblongata, pons and the Pons and the the midbrain form the adult Cerebellum. Brain stem.
Subdivisions of the Central Nervous System The central nervous system (defined as the brain and spinalcord) is usually considered to have seven basic parts: spinal cord, medulla, pons, cerebellum, midbrain, diencephalon, and cerebral hemispheres
Running through all of these subdivisions are fluid-filledspaces called ventricles These ventricles are the remnants of the continuous lumeninitially enclosed by the neural plate as it rounded to becomethe neural tube during early development. Variations in the shape and size of the mature ventricularspace are characteristic of each adult brain region. The brainstem surrounds the 4th ventricle (medullaand pons) and cerebral aqueduct (midbrain).
The forebrain encloses the 3rd and lateral ventricles. The diencephalon and cerebral hemispheres (telencephalon) are collectively called the forebrain, and they enclose the 3rd and lateral ventricles, respectively. Within the brainstem are the cranial nerve nuclei thateither receive input from the cranial sensory ganglia via thecranial sensory nerves, or give rise to axons that constitutethe cranial motor nerves.
OVERVIEW OF NEUROPHYSIOLOGY The nervous system can be divided into two parts: the central nervous system (CNS), which is composed ofthe brain and spinal cord, and the peripheral nervous system, which is composed ofnerves that connect the CNS to muscles, glands, and senseorgans. Neurons are the basic building blocks of the nervoussystem. The human brain contains about 100 billion neurons. It also contains 10–50 times this number of glial cells orglia.
Structure and location of the three functional classes of neurons. *Efferent autonomic nerve pathways consist of a two-neuron chain between the CNS and the effector organ.
The CNS is a complex organ; it has been calculated that 40% of the human genes participate, at least to a degree, in its formation.Glia Cells The word glia is Greek for glue; for many years, glia were thought to function merely as connective tissue. However, these cells are now recognized for their role in communication within the CNS in partnership with neurons. Unlike neurons, glial cells continue to undergo cell division in adulthood and their ability to proliferate is particularly noticeable after brain injury. There are two major types of glia, microglia and macroglia.
Microglia arise from macrophages outside of the CNS and arephysiologically and embryologically unrelated to other neural celltypes. Microglia are scavenger cells that resemble tissue macrophagesand remove debris resulting from injury, infection, and disease. There are three types of macroglia: oligodendrocytes, Schwanncells, and astrocytes. Oligodendrocytes and Schwann cells are involved in myelinformation around axons in the CNS and peripheral nervous system,respectively. Astrocytes, which are found throughout the brain, are of twosubtypes:
Fibrous astrocytes, which contain many intermediate filaments are found primarily in white matter; and the Protoplasmic astrocytes are found in gray matter and have a granular cytoplasm.• Both types of astrocytes send processes to blood vessels, where they induce capillaries to form the tight junctions making up the blood–brain barrier.• The blood–brain barrier prevents the diffusion of large or hydrophilic molecules (e.g., proteins) into the cerebrospinal fluid and brain, while allowing diffusion of small molecules. The astrocytes also send processes that envelop synapses and the surface of nerve cells.
Principal types of glial cells in the nervous system (Adapted from Medical Physiology: a Systems Approach byHershel and Michael. McGraw-Hill Company, 2011).
Functions of the NeurogliaAstrocytes Physically support neurons in proper spatial relationships Serve as a scaffold during fetal brain development Induce formation of blood–brain barrier Help transfer nutrients to neurons Form neural scar tissue Take up and degrade released neurotransmitters Take up excess K to help maintain proper brain-ECF ion concentration and normal neural excitability Enhance synapse formation and strengthen synaptic transmission via chemical signaling with neurons Communicate by chemical means with neurons and among themselves
Oligodendrocytes Form myelin sheaths in CNSMicroglia Play a role in defense of brain as phagocytic scavengers Release nerve growth factorEpendymal Cells Line internal cavities of brain and spinal cord Contribute to formation of cerebrospinal fl uid Serve as neural stem cells with the potential to form new neurons and glial cells
Glial cells of the central nervous system. The glial cells include the astrocytes, oligodendrocytes, microglia, and ependymalcells
The peripheral nervous system transmits information from theCNS to the effector organs throughout the body.It contains 12 pairs of cranial nerves and 31 pairs of spinalnerves.The cranial nerves have rather well-defined sensory andmotor functions.Spinal nerves are named on the basis of the vertebral levelfrom which the nerve exits (cervical, thoracic, lumbar,sacral, and coccygeal).These nerves include motor and sensory fibers of muscles,skin, and glands throughout the body.
Food for Thought“A basic principle to remember when studyingthe brain is that one function, even anapparently simple one such as bending yourfinger, will involve multiple brain regions (aswell as the spinal cord). Conversely, onebrain region may be involved in severalfunctions at the same time. In other words,understanding the brain is not simple andstraightforward”.
THE SPINAL CORD The spinal cord is the major pathway for information owingback and forth between the brain and the skin, joints, andmuscles of the body. In addition, the spinal cord contains neural networksresponsible for locomotion. If the spinal cord is severed, there is loss of sensation fromthe skin and muscles as well as paralysis, loss of the ability tovoluntarily control muscles. The spinal cord is divided into four regions (cervical,thoracic, lumbar, and sacral), named to correspond to theadjacent vertebrae.
Each spinal region is subdivided into segments, and eachsegment gives rise to a bilateral pair of spinal nerves. Just before a spinal nerve joins the spinal cord, it divides intotwo branches called roots. The dorsal root of each spinal nerve is specialized to carryincoming sensory information. The dorsal root ganglia, swellings found on the dorsal rootsjust before they enter the cord, contain cell bodies of sensoryneurons. The ventral root carries information from the CNS tomuscles and glands.
In cross section, the spinal cord has a butter y- or H-shapedcore of gray matter and a surrounding rim of white matter. Sensory fibers from the dorsal roots synapse withinterneurons in the dorsal horns of the gray matter. The dorsal horn cell bodies are organized into two distinctnuclei, one for somatic information and one for visceralinformation. The ventral horns of the gray matter contain cell bodies ofmotor neurons that carry efferent signals to muscles andglands. The ventral horns are organized into somatic motor andautonomic nuclei. Efferent fibers leave the spinal cord via the ventral root.
The white matter of the spinal cord is the biological equivalentof fiber-optic cables that telephone companies use to carry ourcommunications systems. White matter can be divided into a number of columnscomposed of tracts of axons that transfer information up anddown the cord. Ascending tracts take sensory information to the brain. Theyoccupy the dorsal and external lateral portions of the spinal cord. Descending tracts carry mostly efferent (motor) signals fromthe brain to the cord. They occupy the ventral and interior lateralportions of the white matter.
Propriospinal tracts (proprius, one’s own) are those thatremain within the cord. The spinal cord can function as a self-contained integratingcenter for simple spinal re exes, with signals passing from asensory neuron through the gray matter to an efferent neuron. In addition, spinal interneurons may route sensoryinformation to the brain through ascending tracts or bringcommands from the brain to motor neurons. In many cases, the interneurons also modify information as itpasses through them. Reflexes play a critical role in the coordination of movement.
Neural Growth and Regeneration The elaborate networks of nerve-cell processes thatcharacterize the nervous system are remarkably similar in allhuman beings and depend upon the outgrowth of specificaxons to specific targets. Development of the nervous system in the embryo beginswith a series of divisions of precursor cells that can developinto neurons or glia. After the last cell division, each neuronal daughter celldifferentiates, migrates to its final location, and sends outprocesses that will become its axon and dendrites. A specialized enlargement, called the growth cone, formsthe tip of each extending axon and is involved in finding thecorrect route and final target for the process.
As the axon grows, it is guided along the surfaces of othercells, most commonly glial cells. Which particular route is followed depends largely onattracting, supporting, deflecting, or inhibiting influencesexerted by several types of molecules. Some of these molecules, such as cell adhesionmolecules, reside on the membranes of the glia andembryonic neurons. Others are soluble neurotropic factors (growth factors forneural tissue) in the extracellular fluid surrounding the growthcone or its distant target.
Once the target of the advancing growth cone is reached,synapses are formed. The synapses are active, however, before their finalmaturation occurs, and this early activity, in part, determinestheir final use. During these intricate early stages of neural development,which occur during all trimesters of pregnancy and into infancy,alcohol and other drugs, radiation, malnutrition, and virusescan exert effects that cause permanent damage to thedeveloping fetal nervous system.
A normal, although unexpected, aspect of development of thenervous system occurs after growth and projection of the axons. Many of the newly formed neurons and synapses degenerate. In fact, as many as 50 to 70 percent of neurons die byapoptosis in some regions of the developing nervous system! Exactly why this seemingly wasteful process occurs isunknown although neuroscientists speculate that in this wayconnectivity in the nervous system is refined, or “fine tuned.” Although the basic shape and location of existing neurons inthe mature central nervous system do not change, the creationand removal of synaptic contacts begun during fetal developmentcontinue, albeit at a slower pace, throughout life as part ofnormal growth, learning, and aging.
Division of neuron precursors is largely complete beforebirth, and after early infancy new neurons are formed at aslower pace to replace those that die. Severed axons can repair themselves, however, andsignificant function regained, provided that the damage occursoutside the central nervous system and does not affect theneuron’s cell body. After repairable injury, the axon segment now separatedfrom the cell body degenerates. The proximal part of the axon (the stump still attached to thecell body) then gives rise to a growth cone, which grows out tothe effector organ so that in some cases function is restored.
In contrast, severed axons within the central nervous systemattempt sprouting, but no significant regeneration of the axonoccurs across the damaged site, and there are no well-documented reports of significant function return. Either some basic difference of central nervous systemneurons or some property of their environment, such asinhibitory factors associated with nearby glia, prevents theirfunctional regeneration. In humans, however, spinal injuries typically crush ratherthan cut the tissue, leaving the axons intact. In this case, a primary problem is self-destruction (apoptosis)of the nearby oligodendroglia, because when these cells dieand their associated axons lose their myelin coat, the axonscannot transmit information effectively.
PROTECTION AND NOURISHMENT OF THE BRAIN Due to the very delicate nature of the CNS tissue and the factthat its damaged nerve cells cannot be replaced, makes itimperative that this fragile, irreplaceable tissue be wellprotected Four (4) major features help protect the CNS from injury:1. It is enclosed by hard, bony structures. The cranium (skull)encases the brain, and the vertebral column surrounds thespinal cord.2. Three protective and nourishing membranes called themeninges,lie between the bony covering and the nervoustissue.3. The brain “floats” in a special cushioning fluid known as thecerebrospinal fluid (CSF).
4. A highly selective blood–brain barrier limits access of bloodborne materials into the vulnerable brain tissue. The role of the first of these protective devices, the bonycovering, is self-evident while the latter three protectivemechanisms warrant further discussion.Meninges The three meningeal membranes wrap, protect, and nourishthe central nervous system. From the outermost to the innermost layer they are the duramater, the arachnoid mater, and the pia mater (Mater means“mother,” indicative of these membranes’ protective andsupportive role).
The dura mater is a tough, inelastic covering that consistsof two layers (dura means “tough”). Usually, these layers adhere closely, but in some regionsthey are separated to form blood filled cavities, dural sinuses,or in the case of the larger cavities, venous sinuses. Venous blood draining from the brain empties into thesesinuses to be returned to the heart. Cerebrospinal fluid also reenters the blood at one of thesesinus sites. The arachnoid mater is a delicate, richly vascularized layerwith a “cobwebby” appearance (arachnoid means “spiderlike”).
The space between the arachnoid layer and the underlyingpia mater, the subarachnoid space, is filled with CSF. Protrusions of arachnoid tissue, the arachnoid villi,penetrate through gaps in the overlying dura and project intothe dural sinuses. CSF is reabsorbed across the surfaces of these villi into theblood circulating within the sinuses. The innermost meningeal layer, the pia mater, is the mostfragile (pia means “gentle”). It is highly vascular and closely adheres to the surfaces of thebrain and spinal cord, following every ridge and valley.
In certain areas it dips deeply into the brain to bring a richblood supply into close contact with the ependymal cells lining theventricles. This relationship is important in the formation of CSF, a topic towhich we now turn our attention.
Cerebro-Spinal Fluid (CSF) Cerebrospinal fluid is formed primarily by the choroidplexuses found in particular regions of the ventricles. Choroid plexuses consist of richly vascularized, cauliflower-like masses of pia mater tissue that dip into pockets formed byependymal cells. Cerebrospinal fluid forms as a result of selective transportmechanisms across the membranes of the choroid plexuses. The composition of CSF differs from that of blood. Cerebrospinal fluid (CSF) surrounds and cushions the brainand spinal cord.
The CSF has about the same density as the brain itself, sothe brain essentially floats or is suspended in this special fluidenvironment. The major function of CSF is to serve as a shock-absorbingfluid to prevent the brain from bumping against the interior ofthe hard skull when the head is subjected to sudden, jarringmovements. In addition to protecting the delicate brain from mechanicaltrauma, the CSF plays an important role in the exchange ofmaterials between the neural cells and the interstitial fluidsurrounding the brain. Only the brain interstitial fluid but not the blood or CSF comesinto direct contact with the neurons and glial cells.
Because the brain interstitial fluid directly bathes the neuralcells, its composition is critical. The composition of the brain interstitial fluid is influencedmore by changes in the composition of the CSF than byalterations in the blood. Materials are exchanged fairly freely between the CSF andbrain interstitial fluid, whereas only limited exchange occursbetween the blood and brain interstitial fluid. Thus, the composition of the CSF must be carefullyregulated.
For example, CSF is lower in K and slightly higher in Na,making the brain interstitial fluid an ideal environment formovement of these ions down concentration gradients, a processessential for conduction of nerve impulses. The biggest difference is the presence of plasma proteins inthe blood but almost no proteins normally present in the CSF. Plasma proteins cannot exit the brain capillaries to leave theblood during formation of CSF. Once CSF is formed, it flows through the four interconnectedventricles of the brain and through the spinal cord’s narrowcentral canal, which is continuous with the last ventricle.
• Cerebrospinal fluid also escapes through small openings fromthe fourth ventricle at the base of the brain to enter thesubarachnoid space and subsequently flows between themeningeal layers over the entire surface of the brain and spinalcord.• When the CSF reaches the upper regions of the brain, it isreabsorbed from the subarachnoid space into the venous bloodthrough the arachnoid villi.• Flow of CSF through this system is facilitated by ciliary beatingalong with circulatory and postural factors that result in a CSFpressure of about 10 mm Hg.
Reduction of this pressure by removal of even a few milliliters(ml) of CSF during a spinal tap for laboratory analysis mayproduce severe headaches. Through the ongoing processes of formation, circulation, andreabsorption, the entire CSF volume of about 125 to 150 ml isreplaced more than three times a day. If any one of these processes is defective so that excessCSF accumulates causing hydrocephalus (“water on thebrain”) occurs. The resulting increase in CSF pressure can lead to braindamage and mental retardation if untreated. Treatment consistsof surgically shunting the excess CSF to veins elsewhere in thebody.
Blood Brain Barrier The brain is carefully shielded from harmful changes in theblood by a highly selective blood–brain barrier (BBB). Throughout the body, materials can be exchanged betweenthe blood and interstitial fluid only across the walls of capillaries,the smallest blood vessels. Unlike the rather free exchange across capillaries elsewhere,only selected, carefully regulated exchanges can be madeacross the BBB. For example, even if the K+ level in the blood is doubled, littlechange occurs in the K+ concentration of the fluid bathing thecentral neurons. This is beneficial because alterations in interstitial fluid K+would be detrimental to neuronal function.
The BBB has both anatomic and physiologic features. Capillary walls throughout the body are formed by a singlelayer of cells. Usually, all blood plasma components (except the largeplasma proteins) can be freely exchanged between the bloodand the interstitial fluid through holes or pores between the cellsof the capillary wall. In brain capillaries, however, the cells are joined by tightjunctions, which completely seal the capillary wall so thatnothing can be exchanged across the wall by passing betweenthe cells. The only possible exchanges are through the capillary cellsthemselves.
Lipid-soluble substances such as O2, CO2, alcohol, and steroidhormones penetrate these cells easily by dissolving in their lipidplasma membrane. Small water molecules also diff use through readily, by passingbetween the phospholipid molecules of the plasma membrane orthrough aquaporins (water channels). All other substances exchanged between the blood and braininterstitial fluid, including such essential materials as glucose,amino acids, and ions, are transported by highly selectivemembrane-bound carriers. Thus, transport across brain capillary walls between the wall-forming cells is prevented anatomically and transport through thecells is restricted physiologically. Together, these mechanisms constitute the BBB.
By strictly limiting exchange between the blood and brain,the BBB protects the delicate brain: from chemical fluctuations in the blood; minimizes the possibility that potentially harmful blood-borne substances might reach the central neural tissue; and it further prevents certain circulating hormones that could also act as neurotransmitters from reaching the brain, where they could produce uncontrolled nervous activity. On the negative side, the BBB limits the use of drugs for thetreatment of brain and spinal cord disorders because manydrugs are unable to penetrate this barrier.
Certain areas of the brain, most notably a portion of thehypothalamus, are not subject to the BBB. Functioning of the hypothalamus depends on its “sampling”the blood and adjusting its controlling output accordingly tomaintain homeostasis. Part of this output is in the form of water-soluble hormonesthat must enter hypothalamic capillaries to be transported totheir sites of action. Appropriately, these hypothalamic capillaries are not sealedby tight junctions.
Brain Oxygen and Glucose Delivery Even though many substances in the blood never actually comein contact with the brain tissue, the brain is more dependent thanany other tissue on a constant blood supply. Unlike most tissues, which can resort to anaerobic metabolismto produce ATP in the absence of O2 for at least short periods, thebrain cannot produce ATP without O2. Scientists recently discovered an O2-binding protein,neuroglobin, in the brain. This molecule, which is similar to hemoglobin, the O2-carryingprotein in red blood cells, is thought to play a key role in O2handling in the brain, although its exact function remains to bedetermined.
Also in contrast to most tissues, which can use other sourcesof fuel for energy production in lieu of glucose, the brain normallyuses only glucose but does not store any of this nutrient. Because of its high rate of demand for ATP, under restingconditions the brain uses 20% of the O2 and 50% of the glucoseconsumed in the body. Therefore, the brain depends on a continuous, adequate bloodsupply of O2 and glucose. Although it constitutes only 2% of body weight, the brainreceives 15% of the blood pumped out by the heart. Instead of using glucose during starvation, the brain can resortto using ketone bodies produced by the liver, but this alternatenutrient source also must be delivered by the blood to the brain.
Brain damage results if this organ is deprived of its critical O2supply for more than 4 to 5 minutes or if its glucose supply is cutoff for more than 10 to 15 minutes. The most common cause of inadequate blood supply to thebrain is a stroke.
INTRODUCTORY NOTES The term “autonomic” implies independent, self-controllingfunction without conscious effort. The ANS therefore helps to regulate our internal environment(visceral functions). The ANS is activated mainly by centers that are located in thespinal cord, brain stem and the hypothalamus. It comprises of the Sympathetic and parasympathetic nervoussystem but Enteric Nervous System (ENS) can also be consideredas part of the ANS. Portions of cerebral cortex, especially the limbic cortex cantransmit impulses to the lower centers thereby influencingautonomic control. The ANS also operates via visceral reflexes.
THE AUTONOMIC NERVOUS SYSTEMThe autonomic nervoussystem (ANS) regulatesphysiologic processes withoutconscious control.The ANS consists of twosets of nerve bodies:preganglionic andpostganglionic fibers.The two major divisions ofthe ANS are the sympatheticand parasympatheticsystems.
Anatomy of the Autonomic Nervous SystemSympathetic:The preganglionic cell bodiesof the sympathetic system arelocated in the intermediolateralhorn of the spinal cord betweenT1 and L2 or L3.The sympathetic ganglia areadjacent to the spine andconsist of the vertebral(sympathetic chain) andprevertebral gangliaLong fibers run from theseganglia to effector organs,including the smooth muscle ofblood vessels, viscera, lungs,scalp (piloerector muscles), andpupils; the heart; and glands(sweat, salivary, and digestive).
ParasympatheticThe preganglionic cell bodies ofthe parasympathetic system arelocated in the nuclei of the brainstem and sacral portion of thespinal cord (S2-S4).These preganglionic fibers exitthe brain stem with the 3rd, 7th,9th, and 10th cranial nerves.Parasympathetic ganglia arelocated in the blood vessels of thehead, neck, and thoracoabdominalviscera; lacrimal and salivaryglands; smooth muscle of visceraand glands.Postganglionic parasympatheticfibers are relatively short (onlyabout 1 or 2 mm long) therebyproducing specific, localizedresponses in the effector organs.
Inputs to the Autonomic Nervous System The ANS receives input from parts of the CNS that process and integrate stimuli from the body and external environment. These parts include the hypothalamus, nucleus of the solitary tract, reticular formation, amygdala, hippocampus, and olfactory cortex.
Neurotransmitters of the ANS Two most common neurotransmitters released by neurons of the ANS are acetylcholine (cholinergic) and norepinephrine/noradrenaline (adrenergic). Acetylcholine: All preganglionic nerve fibers All postganglionic fibers of the parasympathetic system Sympathetic postganglionic fibers innervating sweat glands Adrenaline: In most sympathetic postganglionic fibers
Receptors of the ANS Neurotransmitters Cholinergic receptors: nicotinic or muscarinic. Adrenergic receptors: alpha (α) and beta (β), with α being more abundant. The adrenergic receptors are further divided into (α1, α2, β1 and β2) according to some factors.
Functions of the ANS The two divisions of the ANS are dominant under different conditions. The sympathetic system is activated during emergency “fight-or-flight” reactions and during exercise. The parasympathetic system is predominant during quiet conditions (“rest and digest”). As such, the physiological effects caused by each system are quite predictable. In other words, all of the changes in organ and tissue function induced by the sympathetic system work together to support strenuous physical activity and the changes induced by the parasympathetic system are appropriate for when the body is resting.
AUTONOMIC GANGLIA These are small swellings along the course of the autonomicnerves that contain a collection of nerve cells. Efferent autonomic fibers that arise from the lateral horn cellsare called the preganglionic fibers which are thick, white andmyelinated fibers. The preganglionic fibers enter the autonomic ganglia wherethey take either of two courses:i) terminate into several nerve terminals in the ganglion that relayimpulses into the ganglionic nerve cells. Postganlionic fibers emerge from these ganglionic fibers andproceed to supply the effector organs. These are thin, gray andunmyelinated fibers.
ii) Pass via the ganglion uninterrupted without relay andemerge on the other side still as preganglionic fibers toproceed to the adrenal medulla or to another ganglion wherethey terminate and relay The postganglionic nerve fibers emerge from the laterganglion to supply the effector organs.Types of the Autonomic Gangliaa) Lateral or Paravertebral Ganglia: Form sympatheticchain on both sides of the vertebral column with each chainforming 23 ganglia (3 cervical – superior, middle and inferiorganglia; 12 thoracic; 4 lumbar and 4 sacral) connected toeach other by nerve fibers.
b) Collateral or Prevertebral ganglia: These are celiac, thesuperior and inferior mesenteric ganglia. They are found along thecourse of sympathetic nerves, midway between the spinal cord andthe viscera. These are sympathetic ganglia i.e. sites of relay forsympathetic nerves only.c) Terminal Ganglia: These are present near or inside the effectororgan e.g. the eye, heart and the stomach. They are parasympatheticganglia i.e. sites of relay for parasympathetic nerves only. The Autonomic ganglia serve as: relay stations, expansion as wellas distribution centers.
REGULATORY SYSTEMS OF THE ANS Autonomic reflexes represent thesimplest level of ANS control The ANS involvement with thelimbic system, hypothalamus,solitary nucleus of the medulla andother brain stem nuclei hasexplained the ANS regulation. In fact, the limbic system has Stimulation of the limbicbeen termed the “cerebral cortex of system areas can evoke a broadthe ANS”. So the limbic system range of feelings and behaviors,represents one of the highest levels including rage, anger, fear, andof the hierarchy of normal control of aggression.the ANS.
In addition, stimulation of the limbic system, either directly or by inputfrom the senses, can evoke ANS-mediated physiological changes such asincreased heart rate, sexual arousal, and nausea.Autonomic Functions of the Hypothalamus Hypothalamus is known as the main ganglion of the ANS and theactivation of its different parts produces a variety of coordinated autonomicresponses: Activation of the dorsal hypothalamus, for e.g. increases blood pressure,intestinal motility, and intestinal blood supply but decreases supply to theskeletal muscles. These are associated with feeding behavior. However, activation of ventral hypothalamus increases blood pressureand the blood supply to the skeletal muscles but decreases intestinal motilityand blood flow to the intestines. These are associated with flight or flightresponses.
CHEMICAL TRANSMISSION• Chemical transmissions (synapses) enable cell-to-cell communication via the secretion of neurotransmitters by activating specific receptor molecules.•• A synapse is a junctional area between a neuronal terminal and another cell that could be another neuron, muscle cell or a gland.• If the second cell is a neuron, the synapse is called a neuronal synapse.• The neuron that conducts the signals is the presynaptic neuron having a presynaptic membrane at the synapse. However, the neuron that receives the signals and its membrane are postsynaptic neuron and postsynaptic membrane respectively.• The space between the presynaptic and postsynaptic membranes is called synaptic cleft and measures about 30-50 nm.
A key feature of all chemical synapses is the presence of small,membrane-bounded organelles called the synaptic vesicles within thepresynaptic terminalNeurotransmitters There are more than 100 types of neurotransmitters and theyvirtually undergo a similar cycle of use: synthesis and packaging into synaptic vesicles Release from the presynaptic cell Binding to postsynaptic receptor Rapid removal and degradation The secretion of the neurotransmitters is triggered by the influx of Ca2+ through the voltage-gated channels that give rise to transient increase in Ca2+ concentration within the presynaptic terminal.
Sequence of Events involved in Transmission at a Typical Chemical Synapse
The rise in the Ca2+ causes synaptic vesicles to fuse with presynapticplasma membrane and release their contents into the space between thepre- and postsynaptic cells. Neurotransmitters released therefore evoke postsynaptic electricalresponses by binding to members of a diverse group ofneurotransmitter receptors. There are two major classes of receptors: those in which the receptormolecule is also an ion channel and those in which the receptor and theion channel are two separate molecules. These receptors give rise to electrical signals by transmitter-inducedopening or closing of the ion channels.
CHEMICAL TRANSMISSION – Cont’d Whether the postsynaptic actions of a particular neurotransmitterare excitatory or inhibitory is determined by: The ionic permeability of the ion channel affected by the neurotransmitter and By the concentration of the permanent ions inside and outside thecellCriteria that Define NeurotransmittersThere are 3 primary criteria been used to confirm that a molecule actsas a neurotransmitter at a given chemical synapse:1) The substance must be present within the presynaptic neuron. Moreso,when enzymes and precursors required to synthesize the substance providemore evidence. However, presence of glutamate, glycine and aspartate is nota sufficient evidence.
(1) Neurotransmitter presence (2) Neurotransmitter release (3) Postsynaptic presence of specific receptors Requirements of identifying a neurotransmitter
2) The substance must be released in response to presynapticdepolarization, and the release must be Ca2+-dependent. This is quitechallenging not only because it may be difficult to selectively stimulate thepresynaptic neuron, but also because enzymes and transporters efficientlyremove the secreted neurotransmitters.3) Specific receptors for the substance must be present on the postsynapticcell/membrane. One way to demonstrate receptors is to show that applicationof exogenous transmitter mimics the postsynaptic effect of presynapticstimulation. A more rigorous demonstration is to show that agonists and antagonists thatalter the normal postsynaptic response have the same effect when the substancein question is applied exogenously. High resolution histological techniques canalso be used to show that specific receptors are present in the postsynapticmembrane (by detection of radioactively labeled receptor antibodies).
Categories of Neurotransmitters More than 100 different agents are known to serve asneurotransmitters that allow for diverse chemical signaling betweenneurons. These neurotransmitters are broadly divided into two based on size:i) Neuropeptides: These are relatively large transmitter moleculescomposed of 3 to 36 amino acids.ii) Small-molecule neurotransmitters: individual amino acids, such asGlutamate, GABA, Ach, serotonin and histamine are examples. Within this category, the biogenic amines such as dopamine,norepinephrine, epinephrine, serotonin and histamine are often discussedseparately because of their similar properties and postsynaptic actions.
NORADRENERGIC TRANSMISSIONSynthesis of Norepinephrine/Epinephrine The adrenal medulla that secretes epinephrine/adrenaline andnorepinephrine/noradrenaline, is an important component of thesympathetic nervous system. As a result, the sympathetic nervoussystem and adrenal medulla are often referred to as thesympathoadrenal system. Norepinephrine is one of the five well-established biogenic amineneurotransmitters: 3 catecholamines (dopamine, norepinephrineand epinephrine), histamine and serotonin. Noradrenaline like the other 2 catecholamines are derived fromtyrosine (which is a product of phenylalanine).
Synthesis of Norepinephrine/Epinephrine This reaction is catalyzed by phenylalanine hydroxylase in the liver) in a reaction catalyzed by tyrosine hydroxylase (in the neuron) requiring O2 as a co-substrate and tetrahydrobiopterin as a cofactor to form DihydrOxyPhenylAlanine (DOPA). Norepinephrine synthesis requires dopamine β-hydroxylase that catalyzes the production of noradrenaline from Dopamine. In the central adrenergic fibers (neurons of the thalamus, hypothalamus and midbrain) and in the adrenal medulla, noradrenaline is converted to adrenaline by Phenylethanolamine -N-methyl Transferase (PNMT). This enzyme is not found in the peripheral adrenergic fibers.
Fate / Degradation of Norepinephrine/epinephrine Noradrenaline is the loaded into synaptic vesicles via the Vesicular MonoAmine Transporter (VMAT) same as with dopamine. Norepinephrine is cleared from the synaptic cleft by Norepinephrine Transporter (NET) mainly in the nerve terminals which is also capable of taking up dopamine to be recirculated. Small amount of Noradrenaline like dopamine is oxidized by MonoAmine Oxidase (MAO) to inactive products. MAO is found in nerve terminals and other organs like liver and kidney. Some small amount is methylated to inactive products by Catechol O-Methyl-Transferase (COMT) enzymes found in the many tissues such as kidney and brain but not in the nerve terminals. Epinephrine is mainly methylated in various organs by COMT.
Adrenergic Receptors/Adrenoceptors Norepinephrine as well as epinephrine, acts on α- and β-adrenergicreceptors that are both G-protein coupled. There are two types of α-adrenergic receptors (α1 and α2) andthree β-adrenergic receptors (though 2 are the well known becauseof their expression in many types of neurons, β1 and β2). Norepinephrine for example excites mainly α receptors but excitesβ receptors to a slight extent; while epinephrine excites both types ofreceptors almost equally. Isoproterenol (a synthetic catecholamine) has strong action on β-receptors but essentially no action on α-receptors
AdrenergicDrugs/Agonists/Protagonists/Symphatomimietic Drugs These are drugs that mimic the actions of norepinephrine or epinephrinethrough the following mechanisms:i) Stimulating the release of the transmitter. Example of these include Amphetamineand Ephedrineii) Inhibiting the action of MAO enzyme. Example, Ephedrine and Hydrazineiii) Direct stimulation of receptors. Example norepinephrine and epinephrine (αand β), phenylephrine (α1), clonidine (α2), Dobutamine (β1), Salbutamol (β2) andisoproterenol (β1 and β2) Agonists and antagonists of adrenergic receptors, such as the β blockerpropanolol are used clinically for a variety of conditions ranging from cardiacarrhythmias to migraine headaches. However, most of the actions of these drugs are on smooth muscle receptorsparticularly on cardiovascular and respiratory systems.
Anti-Adrenergic Drugs/Adrenergic Blockers/Antagonists/Symphatolytic Drugs• These are drugs that block the actions of norepinephrine andepinephrine and they produce their actions via the followingmechanisms:i) Inhibiting the synthesis of norepinephrine. Example is Aldomet(that inhibits β-hydroxylase leading to the formation of a falsetransmitter).ii) Preventing the release of the transmitter. Example is Guanethidineiii) Direct blocking of the receptors. Examples are: Prazosin (α1),Yohimbine (α2), Phentolamine (α1 and α2), Atenolol (β1),Butaxamine (β2) and Propranolol (β1 and β2)
CHOLINERGIC TRANSMISSION Ach is synthesized in nerve terminals from the precursors acetyl coA and choline in the recation catalyzed by choline acetyl transferase (CAT) Choline is present in plasma at a high concentration (about 10 mM) and is taken up into cholinergic neurons by a high - affinity Na+/choline transporter. After synthesis in the neuroplasm a vesicular Ach transporter loads approx 10, 000 molecules of Ach into each cholinergic vesicle. In contrast to most other small-molecular neurotransmitters, the postsynaptic actions of Ach at many cholinergic synapses (the NMJ in particular) is not terminated by reuptake but by a powerful hydrolytic enzyme, Acetylcholinesterase (AchE)
Classification of Mammalian Nerve Fibers NB: A and B fibers are myelinated while the C fibers are unmyelinated
Relative susceptibility of mammalian A, B, and C nerve fibers to conduction block produced by various agents
Neurotrophins: Trophic Support of Neurons Proteins necessary for survival and growth of neurons arecalled neurotrophins. Many are products of the muscles or other structures that theneurons innervate, but others are produced by astrocytes. These proteins bind to receptors at the endings of a neuron. They are internalized and then transported by retrogradetransport to the neuronal cell body, where they foster theproduction of proteins associated with neuronal development,growth, and survival. Other neurotrophins are produced in neurons and transportedin an anterograde fashion to the nerve ending, where theymaintain the integrity of the postsynaptic neuron.
The first neurotrophin to be characterized was nerve growthfactor (NGF), a protein that is necessary for the growth andmaintenance of sympathetic neurons and some sensoryneuron. It is found in many different tissues. NGF is picked up byneurons and transported in retrograde fashion from the endingsof the neurons to their cell bodies. It is also present in the brain and appears to be responsiblefor the growth and maintenance of cholinergic neurons in thebasal forebrain and striatum.
NEUROTRANSMITTERS Mostly, neurons in the human brain communicate with oneanother by releasing chemical messengers called neurotransmitters. A large number of neurotransmitters are now known and moreremain to be discovered. Neurotransmitters evoke postsynaptic electrical responses bybinding to members of a diverse group of proteins calledneurotransmitter receptors. There are two major classes of receptors: those in which the receptor molecule is also an ion channel,which are called ionotropic receptors or ligand gated ionchannels, and give rise to fast postsynaptic responses thattypically last only a few milliseconds; and
those in which the receptor and ion channel are separatemolecules called metabotropic receptors, that produce slowerpostsynaptic effects that may endure much longer. Abnormalities in the function of neurotransmitter systemscontribute to a wide range of neurological and psychiatric disorders. As a result, many neuropharmacological therapies are based ondrugs that affect neurotransmitter release, binding, and/or removal.Categories of Neurotransmitters More than 100 different agents are known to serve asneurotransmitters. This large number of transmitters allows for tremendous diversityin chemical signaling between neurons and are divided into twobroad categories based on size.
i) neuropeptides are relatively large transmitter moleculescomposed of 3 to 36 amino acids.ii) small-molecule neurotransmitters are Individual aminoacids, such as glutamate, GABA, acetylcholine, serotonin,and histamine, are much smaller than neuropeptides Within the category of small-molecule neurotransmitters, thebiogenic amines (dopamine, norepinephrine, epinephrine,serotonin, and histamine) are often discussed separatelybecause of their similar chemical properties and postsynapticactions. The particulars of synthesis, packaging, release, andremoval differ for each neurotransmitter.
Acetylcholine Acetylcholine (ACh) was the firstsubstance identified as aneurotransmitter. Acetylcholine is synthesized innerve terminals from the precursorsacetyl coenzyme A (acetyl CoA,which is synthesized from glucose)and choline, in a reaction catalyzedby choline acetyltransferase(CAT). Choline is present in plasma at a After synthesis in the cytoplasmhigh concentration and is taken up of the neuron, a vesicular Achinto cholinergic neurons by a high- transporter loads approximatelyaffinity Na+/choline transporter. 10,000 molecules of ACh into each cholinergic vesicle.
In contrast to most other small-molecule neurotransmitters,the postsynaptic actions of ACh at many cholinergic synapses(the neuromuscular junction in particular) is not terminated byreuptake but by a powerful hydrolytic enzyme,acetylcholinesterase (AChE). This enzyme is concentrated in the synaptic cleft, ensuring arapid decrease in ACh concentration after its release from thepresynaptic terminal. The AChE has a very high catalytic activity (about 5000molecules of ACh per AChE molecule per second) andhydrolyzes Ach into acetate and choline. The choline produced by ACh hydrolysis is transported backinto nerve terminals and used to re-synthesize ACh.
Among the many interesting drugs that interact with cholinergicenzymes are the organophosphates that include some potentchemical warfare agents. One such compound is the nerve gas “Sarin,” which was madenotorious after a group of terrorists released this gas in Tokyo’sunderground rail system. Organophosphates can be lethal because they inhibit AChE,causing Ach to accumulate at cholinergic synapses. This build-up of ACh depolarizes the postsynaptic cell andrenders it refractory to subsequent ACh release, causingneuromuscular paralysis and other effects. The high sensitivity of insects to these AChE inhibitors hasmade organophosphates popular insecticides.
Acetylcholine Receptors There are two types of cholinergic receptors: Muscarinic Nicotinic
Glutamate• Glutamate is the most important transmitter in normal brainfunction.• Nearly all excitatory neurons in the central nervous system areglutamatergic, and it is estimated that over half of all brainsynapses release this agent.• Glutamate plays an especially important role in clinicalneurology because elevated concentrations of extracellularglutamate, released as a result of neural injury, are toxic toneurons.• Glutamate is a nonessential amino acid that does not cross theblood-brain barrier and therefore must be synthesized in neuronsfrom local precursors.
The most prevalent precursorfor glutamate synthesis isglutamine, which is released byglial cells. Once released, glutamine istaken up into presynaptic terminalsand metabolized to glutamate bythe mitochondrial enzymeglutaminase. Glutamate can also besynthesized by transaminationof 2-oxoglutarate, an intermediateof the tricarboxylic acid cycle. The glutamate synthesized in the presynaptic cytoplasm is Hence, some of the glucose packaged into synapticmetabolized by neurons can also vesicles by transporters,be used for glutamate synthesis. termed VGLUT.
The glutamate synthesized in the presynaptic cytoplasm ispackaged into synaptic vesicles by transporters, termedVGLUT. At least three different VGLUT genes have been identified. Once released, glutamate is removed from the synaptic cleftby the excitatory amino acid transporters (EAATs). Glutamate taken up by glial cells is converted into glutamineby the enzyme glutamine synthetase; glutamine is thentransported out of the glial cells and into nerve terminals.
In this way, synaptic terminals cooperate with glial cells tomaintain an adequate supply of the neurotransmitter. This overall sequence of events is referred to as theglutamate-glutamine cycle.Glutamate Receptors Several types of glutamate receptors have been identified. Three of these are ionotropic receptors and are called: NMDA (N-methyl-D-aspartate)receptors, AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate), receptors, and kainate receptors These glutamate receptors are named after the agonists thatactivate them.
All of the ionotropic glutamate receptors are nonselectivecation channels similar to the nAChR, allowing the passage ofNa+ and K+, and in some cases small amounts of Ca2+. Hence AMPA, kainate, and NMDA receptor activation alwaysproduces excitatory postsynaptic responses. Like other ionotropic receptors, AMPA/kainate and NMDAreceptors are also formed from the association of several proteinsubunits that can combine in many ways to produce a largenumber of receptor isoforms.
GABA and Glycine Most inhibitory synapses in the brain and spinal cord useeither γ-Aminobutyric acid (GABA) or glycine asneurotransmitters. Like glutamate, GABA was identified in brain tissue during the1950s. It is now known that as many as a third of the synapses in thebrain use GABA as their inhibitory neurotransmitter. GABA is most commonly found in local circuit interneurons,although cerebellar Purkinje cells provide an example of aGABAergic projection neuron. The predominant precursor for GABA synthesis is glucose,which is metabolized to glutamate by the tricarboxylic acid cycleenzymes (pyruvate and glutamine can also act as precursors).
The predominant precursor forGABA synthesis is glucose, whichis metabolized to glutamate by thetricarboxylic acid cycle enzymes(pyruvate and glutamine can alsoact as precursors). The enzyme glutamic aciddecarboxylase (GAD), which isfound almost exclusively inGABAergic neurons, catalyzes theconversion of glutamate to GABA. Because pyridoxal phosphate is derived from GAD requires a cofactor, vitamin B6, a B6 deficiencypyridoxal phosphate, for activity. can lead to diminished GABA synthesis.
The significance of thisbecame clear after a disastrousseries of infant deaths was linkedto the omission of vitamin B6from infant formula. This lack of B6 resulted in alarge reduction in the GABAcontent of the brain, and thesubsequent loss of synapticinhibition caused seizures that insome cases were fatal. Once GABA is synthesized, itis transported into synapticvesicles via a vesicularinhibitory amino acidtransporter (VIATT).
The mechanism of GABA removal is similar to that forglutamate: Both neurons and glia contain high-affinitytransporters for GABA, termed GATs (several forms of GAThave been identified). Most GABA is eventually converted to succinate, which ismetabolized further in the tricarboxylic acid cycle that mediatescellular ATP synthesis. The enzymes required for this degradation, GABAtransaminase and succinic semialdehyde dehydrogenase,are mitochondrial enzymes. Inhibition of GABA breakdown causes a rise in tissue GABAcontent and an increase in the activity of inhibitory neurons. There are also other pathways for degradation of GABA.
The most noteworthy of these results in the production of γ-hydroxybutyrate, a GABA derivitive that has been abused as a“date rape” drug. Oral adminis-tration of γ-hydroxybutyrate can causeeuphoria, memory deficits, and unconsciousness. Presumably these effects arise from actions on GABAergicsynapses in the CNS. Inhibitory synapses employing GABA as their transmitter canexhibit three types of postsynaptic receptors, called GABAA,GABAB, and GABAC. GABAA and GABAC receptors are ionotropic receptors,while GABAB receptors are metabotropic.
Drugs that act as agonists or modulators of postsynapticGABA receptors, such as benzodiazepines and barbiturates,are used clinically to treat epilepsy and are effective sedativesand anesthetics.
SENSORY SYSTEMS: TOUCH, PAIN, AND TEMPERATURELearning ObjectivesAt the end of this lesson, the students are expected to: List common senses and their receptors; Explain the terms hyperalgesia and allodynia; Explain sensory coding; Compare the pathway that mediates sensory input from touch,proprioceptive, and vibratory senses to that mediating informationfrom pain and thermoreceptors; and Describe mechanisms to modulate transmission in painpathways.
Information about the internal and external environmentactivates the central nervous system (CNS) via sensoryreceptors. These receptors are transducers that convert various formsof energy into action potentials in neurons. The somatic sensory system has two major components: a subsystem for the detection of mechanical stimuli (e.g.,light touch, vibration, pressure and cutaneous tension); and a subsystem for the detection of painful stimuli andtemperature. Together, these two subsystems give humans and otheranimals the ability to:
identify the shapes and textures of objects; monitor the internal and external forces acting on the body atany moment; and Detect potentially harmful circumstances.Types of Somatic Sensory Receptors Cutaneous (superficial) receptors for touch and pressure aremechanoreceptors. Potentially harmful stimuli such as pain, extreme heat, andextreme cold are mediated by nociceptors. Chemoreceptors are stimulated by a change in the chemicalcomposition of the environment in which they are located.
These include receptors for taste and smell as well asvisceral receptors such as those sensitive to changes in theplasma level of O2, pH, and osmolality. Photoreceptors are those in the rods and cones in the retinathat respond to light.Cutaneous Mechanoreceptors Sensory receptors can be specialized dendritic endings ofafferent nerve fibers and are often associated with non-neuralcells that surround them, forming a sense organ. Touch and pressure are sensed by four types of mechanoreceptors:
i. Meissner’s corpuscles respond to changes in texture andslow vibrations.ii. Merkel cells respond to sustained pressure and touch.iii. Ruffini corpuscles respond to sustained pressure.iv. Pacinian corpuscles respond to deep pressure and fastvibration.Nociceptors and Thermoreceptors Pain and temperature sensations arise from unmyelinateddendrites of sensory neurons located around hair folliclesthroughout the smooth and hairy skin, as well as in deep tissue.
Impulses from nociceptors (pain) are transmitted via two fibertypes:i. One system comprises thinly myelinated Aδ fibers thatconduct at rates of 12–30 m/s.ii. The other is unmyelinated C fibers that conduct at low rates of0.5–2 m/s. Thermoreceptors also span the following two fiber types:i. cold receptors are on dendritic endings of Aδ fibers and Cfibers; andii. warm receptors are on C fibers.
On the other hand, the nociceptors could be categorizedbased on stimuli they respond to into: Mechanical nociceptors respond to strong pressure. Thermal nociceptors are activated by skin temperaturesabove 45°C or by severe cold. Chemically sensitive nociceptors respond to various agentssuch as bradykinin, histamine, high acidity, andenvironmental irritants. Polymodal nociceptors respond to combinations of thesestimuli.
The Major Classes of Somatic Sensory Receptors
The Major Afferent Pathway for MechanosensoryInformation: The Dorsal Column–Medial Lemniscus System The action potentials generated by tactile and othermechanosensory stimuli are transmitted to the spinal cord byafferent sensory axons traveling in the peripheral nerves. The neuronal cell bodies that give rise to these first-orderaxons are located in the dorsal root (or sensory) gangliaassociated with each segmental spinal nerve. The dorsal horn in the spinal cord is divided on the basis ofhistologic characteristics into laminae I–VII, with lamina I beingthe most superficial and lamina VII the deepest. Lamina II and part of lamina III make up the substantiagelatinosa, the area near the top of each dorsal horn.
Schematic representation of the terminations of the three types of primary afferent neurons in the various layers of the dorsal horn of the spinal cord
Dorsal root ganglion cells are also known as first-orderneurons because they initiate the sensory process. Depending on whether they belong to the mechanosensorysystem or to the pain and temperature system, the first-orderaxons carrying information from somatic receptors have: different patterns of termination in the spinal cord; and define distinct somatic sensory pathways within the centralnervous. These differences provide for different pathways as follows:
the dorsal column–medial lemniscus pathway that carriesthe majority of information from the mechanoreceptors thatmediate tactile discrimination and proprioception; and the spinothalamic (anterolateral) pathway mediates painand temperature sensation. The difference(s) in the afferent pathways of these modalitiesis one of the reasons of treating the sensations separately.
DORSAL COLUMN (MEDIAL LEMNISCAL) PATHWAY This is the principal directpathway to the cerebralcortex for touch, vibratorysense, and proprioception(position sense). Upon entering the spinalcord, the major branch of theincoming axons called thefirst-order axons carryinginformation from peripheralmechanoreceptors ascendsipsilaterally through thedorsal columns (posteriorfuniculi) of the cord.
In this column, it goes allthe way to the lower medulla,where it terminates bysynapsing with the second-order neurons in the gracileand cuneate nuclei (togetherreferred to as the dorsalcolumn nuclei). Axons in the dorsal columnsare topographically organizedsuch that:
the fibers that conveyinformation from lower limbsthat are in the medialsubdivision of the dorsalcolumns, called the graciletract; and The lateral subdivision,called the cuneate tract,which contains axonsconveying information fromthe upper limbs, trunk, andneck.
In a cross-section through themedulla, the medial lemniscalaxons carrying information fromthe lower limbs are locatedventrally, whereas the axonsrelated to the upper limbs arelocated dorsally (again, a fact ofsome clinical importance). The second-order neuronsfrom these nuclei ascendcontralaterally ascend in themedial lemniscus to end in thecontralateral ventral posteriorlateral (VPL) nucleus andrelated specific sensory relaynuclei of the thalamus.
These axons of the medial lemniscus that reach the ventralposterior lateral (VPL) nucleus of the thalamus are the third-order neurons of the dorsal column–medial lemniscus system.The Trigeminal Portion of the Mechanosensory System As noted, the dorsal column–medial lemniscus pathwaydescribed in the preceding section carries somatic informationfrom only the upper and lower body and from the posterior thirdof the head. Tactile and proprioceptive information from the face isconveyed from the periphery to the thalamus by a different routecalled trigeminal somatic sensory system. Low-threshold mechanoreception in the face is mediated byfirst order neurons in the trigeminal (cranial nerve V) ganglion.
The peripheral processes ofthese neurons form the threemain subdivisions of the 10 Somatic Sensory Cortextrigeminal nerve: the ophthalmic; Maxillary; and mandibular branches,• Each of these innervates awell-defined territory on theface and head, including theteeth and the mucosa of theoral and nasal cavities.
The central processes oftrigeminal ganglion cells formthe sensory roots of the 10 Somatic Sensory Cortextrigeminal nerve. They enter the brainstem atthe level of the pons toterminate on neurons in thesubdivisions of the trigeminalbrainstem complex. The trigeminal complex hastwo major components: the principal nucleus the spinal nucleus(responsible for processing (responsible for processingmechanosensory stimuli); and painful and thermal stimuli).
Thus, most of the axonscarrying information from low- 0 1 Somaticthreshold cutaneous Sensory Cortexmechanoreceptors in the faceterminate in the principal nucleus. In effect, this nucleuscorresponds to the dorsal columnnuclei that relay mechanosensoryinformation from the rest of thebody. The spinal nucleus corresponds The second order neurons of theto a portion of the spinal cord that trigeminal brainstem nuclei give off axons that cross the midline andcontains the second-order neurons ascend to the ventral posterior medialin the pain and temperature system (VPM) nucleus of the thalamus via thefor the rest of the body. trigeminothalamic tract (also called the trigeminal lemniscus).
The Somatic Sensory Components of the Thalamus Each of the several ascendingsomatic sensory pathwaysoriginating in the spinal cord andbrainstem converge on the thalamus. The ventral posterior complex(VPL and VPM) of the thalamus,which comprises a lateral and amedial nucleus, is the main target ofthese ascending pathways. The VPL nucleus receivesprojections from the medial The VPM nucleus receiveslemniscuscarrying all somatosensory axons from the trigeminalinformation from the body and lemniscus (that is, mechanosensory and nociceptiveposterior head. information from the face).
The Somatic Sensory Cortex The axons arising fromneurons in the ventral posteriorcomplex of the thalamus projectto cortical neurons locatedprimarily in layer IV of thesomatic sensory cortex. The primary somatic sensorycortex in humans (also called SI),which is located in thepostcentral gyrus of the Experiments carried out inparietal lobe, comprises four non-human primates indicatedistinct regions, or fields, known that neurons in areas 3b and 1as Brodmann’s areas 3a, 3b, 1, respond primarily to cutaneousand 2. stimuli.
The axons arising fromneurons in the ventral posteriorcomplex of the thalamus projectto cortical neurons locatedprimarily in layer IV of thesomatic sensory cortex. The primary somatic sensorycortex in humans (also called SI),which is located in thepostcentral gyrus of theparietal lobe, comprises four Experiments carried out indistinct regions, or fields, known non-human primates indicateas Brodmann’s areas 3a, 3b, 1, that neurons in areas 3b and 1and 2. respond primarily to cutaneous stimuli.
Neurons in 3a respond mainlyto stimulation of proprioceptors;area 2 neurons process bothtactile and proprioceptive stimuli. Mapping studies in humansand other primates show furtherthat each of these four corticalareas contains a separate andcomplete representation of thebody. In these somatotopic maps,the foot, leg, trunk, forelimbs, andface are represented in a medialto lateral arrangement.
Ventrolateralspinothalamic Tract Fibers from nociceptors andthermoreceptors synapse onneurons in the dorsal horn. The axons from these neuronscross the midline and ascend in theventrolateral quadrant of the spinalcord, where they form the lateralspinothalamic tract. Fibers within this tract synapse inthe VPL nuclei. Other dorsal horn neurons that From this pathway,receive nociceptive input synapse in fibers then project to thethe reticular formation of the brain centrolateral nucleus ofstem (spinoreticular pathway). the thalamus.
Positron emission tomographic (PET) and functionalmagnetic resonance imaging (fMRI) studies in normalhumans indicate that pain activates cortical areas SI, SII, andthe cingulate gyrus on the side opposite the stimulus. Also,the mediofrontal cortex and insular cortex are activated.These technologies were important in distinguishingtwo components of pain pathways. From VPL nuclei in the thalamus, fibers project to SI and SII. This is called the neospinothalamic tract, and it isresponsible for the immediate awareness of the painfulsensation and the awareness of the location of the noxiousstimulus.
The pathway that includes synapses in the brain stem reticularformation and centrolateral thalamic nucleus projects to thefrontal lobe, limbic system, and insula. This is called the paleospinothalamic tract, and it mediatesthe emotional response to pain. In the CNS, visceral sensation travels along the samepathways as somatic sensation in the spinothalamic tracts andthalamic radiations, and the cortical receiving areas for visceralsensation are intermixed with the somatic receiving areas. This likely contributes to the phenomenon called referredpain.
PHYSIOLOGY OF PAIN Pain is defined by the International Association for theStudy of Pain (IASP) as “an unpleasant sensory and emotionalexperience associated with actual or potential tissue damage….” This is different from nociception, which the IASP defines asthe unconscious activity induced by a harmful stimulus applied tosense receptors. Pain can be classified mainly into two as:A) Physiological (or acute) pain Acute pain typically has a sudden onset and recedes duringthe healing process. It can be considered “good pain” because it serves animportant protective mechanism.
The withdrawal reflex is an example of this protective roleof pain.B) Pathological (Chronic) Pain Chronic pain can be considered “bad pain” because itpersists long after recovery from an injury and is often refractoryto common analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates. It can result from nerve injury including diabeticneuropathy, toxin-induced nerve damage, and ischemia. Pathological pain can be subdivided into:i) Inflammatory pain; andii) neuropathic pain
Hyperalgesia and Allodynia Pain that is often accompanied by, an exaggerated responseto a noxious stimulus is called hyperalgesia. Allodynia is a sensation of pain in response to an innocuousstimulus. An example of allodynia is the painful sensation from a warmshower when the skin is damaged by sunburn. Hyperalgesia and allodynia signify increased sensitivity ofnociceptive afferent fibers.
In response to tissue injury Injured cells releasechemical mediators can chemicals such as K+ thatsensitize and activate depolarize nerve terminals,nociceptors thereby making nociceptors morecontributing to hyperalgesia responsive.and allodynia. Injured cells also release bradykinin and substance P, which can further sensitize nociceptive terminals. Other Chemicals include: histamine is released from mast cells; serotonin (5-HT) from platelets;Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.
calcitonin gene-related peptide All these chemicals(CGRP) from nerve terminals; and contribute to the inflammatory process andprostaglandins from cell activating or sensitizing themembranes. nociceptors. Substance P acts on mast cells to cause degranulation and release of histamine, which activates nociceptors and plasma extravasation CGRP dilates blood vessels that together with the plasma extravasation result in edema formation.Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.
The resulting edema causes Some releasedadditional release of bradykinin. substances act by releasing another one (e.g., bradykinin activates both Aδ and C fibers and increases synthesis and release of prostaglandins). Prostaglandin E2 (a cyclooxygenase metabolite of arachidonic acid) is released from damaged cells and produces hyperalgesia. This is why aspirin and other NSAIDs (inhibitors of cyclooxygenase) alleviateAdopted from Kandel ER, Schwartz JH, Jessell TM [editors]: Pain.Principles of Neural Science. McGraw-Hill, 2000.
Sensory Coding Converting a receptor stimulus to a recognizable sensation istermed sensory coding. All sensory systems code for four elementary attributes of astimulus: modality, location, intensity, and duration. Modality is the type of energy transmitted by the stimulus. The particular form of energy to which a receptor is mostsensitive is called its adequate stimulus. Location is the site on the body or space where the stimulusoriginated. A sensory unit is a single sensory axon and all its peripheralbranches while the receptive field of a sensory unit is the spatialdistribution from which a stimulus produces a response in thatunit.
One of the most important mechanisms that enablelocalization of a stimulus site is lateral inhibition. Activity arising from sensory neurons whose receptors are atthe peripheral edge of the stimulus is inhibited compared to thatfrom the sensory neurons at the center of the stimulus. Thus, lateral inhibition enhances the contrast between thecenter and periphery of a stimulated area and increases theability of the brain to localize a sensory input. Lateral inhibition underlies the neurological assessmentcalled the two-point discrimination test, which is used to testthe integrity of the dorsal column (medial lemniscus) system.
Intensity is signaled by the response amplitude or frequencyof action potential generation. Duration refers to the time from start to end of a response inthe receptor. If a stimulus of constant strength is applied to a receptor, thefrequency of the action potentials in its sensory nerve declinesover time. This phenomenon is known as adaptation or desensitization;the degree to which it occurs varies from one sense to another. Based on this phenomenon, receptors can be classified into: rapidly adapting (phasic) receptors; and slowly adapting (tonic) receptors.
Central Pain Pathways The pathways that carry information about noxious stimuli tothe brain, as might be expected for such an important andmultifaceted system, are also complex. It helps in understanding this complexity to distinguish twocomponents of pain: the sensory discriminative component, which signals the location, intensity, and quality of the noxious stimululation, the affective-motivational component of pain—which signals the unpleasant quality of the experience, and enables the autonomic activation that follows a noxious stimulus. The discriminative component is thought to depend onpathways that target the traditional somatosensory areas ofcortex, while the affective- motivational component is thought todepend on additional cortical and brainstem pathways.
Pathways responsible for the discriminative component of painoriginate with other sensory neurons, in dorsal root ganglia and,like other sensory nerve cells the central axons of nociceptivenerve cells enter the spinal cord via the dorsal roots. When these centrally projecting axons reach the dorsal horn ofthe spinal cord, they branch into ascending and descendingcollaterals, forming the dorsolateral tract of Lissauer. Axons in Lissauer’s tract typically run up and down for one ortwo spinal cord segments before they penetrate the gray matterof the dorsal horn. Once within the dorsal horn, the axons give off branches thatcontact neurons located in several of Rexed’s laminae (theselaminae are the descriptive divisions of the spinal gray matter incross section).
The axons of these second-order neurons in the dorsal horn ofthe spinal cord cross the midline and ascend all the way to thebrainstem and thalamus in the anterolateral (also calledventrolateral) quadrant of the contralateral half of the spinal cord. These fibers form the spinothalamic tract, the majorascending pathway for information about pain and temperature. This overall pathway is also referred to as the anterolateralsystem, much as the mechanosensory pathway is referred to asthe dorsal column–medial lemniscus system. The location of the spinothalamic tract is particularly importantclinically because of the characteristic sensory deficits that followcertain spinal cord injuries.
Since the mechanosensory pathway ascends ipsilaterally in thecord, a unilateral spinal lesion will produce sensory loss of touch,pressure, vibration, and proprioception below the lesion on thesame side. The pathways for pain and temperature, however, cross themidline to ascend on the opposite side of the cord. Therefore, diminished sensation of pain below the lesion will beobserved on the side opposite the mechanosensory loss (and thelesion). This pattern is referred to as a dissociated sensory loss and(together with local dermatomal signs) helps define the level of thelesion.
As is the case of the mechanosensory pathway, informationabout noxious and thermal stimulation of the face follows a separateroute to the thalamus. First-order axons originating from the trigeminal ganglion cellsand from ganglia associated with nerves VII, IX, and X carryinformation from facial nociceptors and thermoreceptors into thebrainstem. After entering the pons, these small myelinated and unmyelinatedtrigeminal fibers descend to the medulla, forming the spinaltrigeminal tract (or spinal tract of cranial nerve V), and terminate intwo subdivisions of the spinal trigeminal complex: the pars interpolari; and pars caudalis.
Axons from the second-order neurons in these two trigeminalnuclei, like their counterparts in the spinal cord, cross the midlineand ascend to the contralateral thalamus in the trigeminothalamictract. The principal target of the spinothalamic and trigeminothalamicpathway is the ventral posterior nucleus of the thalamus. Similar to the organization of the mechanosensory pathways,information from the body terminates in the VPL, while informationfrom the face terminate in the VPM. These nuclei send their axons to primary and secondarysomatosensory cortex. The nociceptive information transmitted to these cortical areasis thought to be responsible for the discriminative component of pain:
identifying the location; the intensity; and quality of the stimulation. Consistent with this interpretation, electrophysiologicalrecordings from nociceptive neurons in S1, show that theseneurons have small localized receptive fields, propertiescommensurate with behavioral measures of pain localization. The affective–motivational aspect of pain is evidently mediatedby separate projections of the anterolateral system to thereticular formation of the midbrain (in particular the parabrachialnucleus), and to thalamic nuclei that lie medial to the ventralposterior nucleus (including the so-called intralaminar nuclei).
Studies in rodents show that neurons in the parabrachialnucleus respond to most types of noxious stimuli, and have largereceptive fields that can include the whole surface of the body. Neurons in the parabrachial nucleus project in turn to thehypothalamus and the amygdala, thus providing nociceptiveinformation to circuits known to be concerned with motivation andaffect. These parabrachial targets are also the source of projections tothe periaqueductal grey of the midbrain, a structure that plays animportant role in the descending control of activity in the painpathway.
Nociceptive inputs to the parabrachial nucleus and to theventral posterior nucleus arise from separate populations ofneurons in the dorsal horn of the spinal cord. Parabrachial inputs arise from neurons in the most superficialpart of the dorsal horn (lamina I), while ventral posterior inputsarise from deeper parts of the dorsal horn (e.g., lamina V). By taking advantage of the unique molecular signature of thesetwo sets of neurons, it has been possible to selectively eliminatethe nociceptive inputs to the parabrachial nucleus in rodents. In these animals, the behavioral responses to the presentationof noxious stimulation (capsaicin, for example) are substantiallyattenuated.
Projections from the anterolateral system to the medial thalamicnuclei provide nociceptive signals to areas in the frontal lobe, theinsula and the cingulate cortex. In accord with this anatomy, functional imaging studies inhumans have shown a strong correlation between activity in theanterior cingulate cortex and the experience of a painful stimulus. Moreover, experiments using hypnosis have been able to teaseapart the neural response to changes in the intensity of a painfulstimulus from changes in its unpleasantness. Changes in intensity are accompanied by changes in theactivity of neurons in somatosensory cortex, with little change inthe activity of cingulate cortex, whereas changes inunpleasantness are correlated with changes in the activity ofneurons in cingulate cortex.
The cortical representation of pain is the least well documentedaspect of the central pathways for nociception, and further studieswill be needed to elucidate the contribution of regions outside thesomatosensory areas of the parietal lobe. Nevertheless, a prominent role for these areas in the perceptionof pain is suggested by the fact that ablations of the relevantregions of the parietal cortex do not generally alleviate chronicpain (although they impair contralateral mechanosensoryperception, as expected).
Some Disorders of Sensory System1. Referred Pain• There are few, if any, neurons in the dorsal horn of the spinalcord that are specialized solely for the transmission of visceralpain.• The visceral pain is conveyed centrally via dorsal hornneurons that are also concerned with cutaneous pain.• As a result of this arrangement, disorder of an internal organis sometimes perceived as cutaneous pain.• This phenomenon is called referred pain.• The most common clinical example is anginal pain which isreferred to the upper chest wall, with radiation into the left armand hand.
Other important examples are: gallbladder pain referred to the scapular region; esophogeal pain referred to the chest wall; ureteral pain (e.g., from passing a kidney stone) referred to the lower abdominal wall; bladder pain referred to the perineum; and the pain from an inflamed appendix referred to the anterior abdominal wall around the umbilicus. Understanding referred pain can lead to an astute diagnosisthat might otherwise be missed.
2. Phantom Limbs and Phantom Pain Following the amputation of an extremity, nearly all patientshave an illusion that the missing limb is still present. Although this illusion usually diminishes over time, it persists insome degree throughout the amputee’s life and can often bereactivated by injury to the stump or other perturbations. Such phantom sensations are not limited to amputated limbsbut there could also be: phantom breasts following mastectomy; phantom genitalia following castration; and phantoms of the entire lower body following spinal cord transection.
Phantoms are also common after local nerve block forsurgery and sometimes during recovery from brachial plexusanesthesia. These sensory phantoms demonstrate that the centralmachinery for processing somatic sensory information is not idlein the absence of peripheral stimuli. Apparently, the central sensory processing apparatuscontinues to operate independently of the periphery, giving riseto these bizarre sensations. The resulting condition is refered to as, a chronic, intenselypainful experience that is difficult to treat with conventionalanalgesic medications.
Neurogenic Quote……..from this description, it should be evident thatthe full experience of sensory sensations (includingmechanosensation, pain and temperature) involve thecooperative action of an extensive network of brainregions whose properties are only beginning to beunderstood…….
MOVEMENT AND ITS CENTRAL CONTROL Movements, whether voluntary or involuntary, are producedby muscular contractions orchestrated by the brain and spinalcord. Analysis of these circuits is fundamental to an understandingof both normal behavior and the etiology of a variety ofneurological disorders. Ultimately, all movements produced by the skeletalmusculature are initiated by “lower” motor neurons in the spinalcord and brainstem that directly innervate skeletal muscles. The innervation of visceral smooth muscles is separatelyorganized by the autonomic divisions of the visceral motorsystem.
The lower motor neurons are controlled: directly by local circuits within the spinal cord and brainstem that coordinate individual muscle groups; and indirectly by “upper” motor neurons in higher centers that regulate those local circuits, thus enabling and coordinating complex sequences of movements. Especially important of the circuits are in the basal gangliaand cerebellum that regulate the upper motor neurons, ensuringthat movements are performed with spatial and temporalprecision. Specific disorders of movement often signify damage to aparticular brain region.
Some clinically important and intensively studiedneurodegenerative disorders such as Parkinson’s disease,Huntington’s disease, and amyotrophic lateral sclerosisresult from pathological changes in different parts of the motorsystem. Knowledge of the various levels of motor control is essentialfor understanding, diagnosing, and treating these diseases.
Overall organization of neural structures involved in the control of movement
Lower and Upper Motor Neurons• Skeletal (striated) muscle contraction is initiated by “lower”motor neurons in the spinal cord and brainstem.• The cell bodies of the lower neurons are located in theventral horn of the spinal cord gray matter and in the motornuclei of the cranial nerves in the brainstem.• The cell bodies of upper motor neurons are located either inthe cortex or in brainstem centers, such as the vestibularnucleus, the superior colliculus, and the reticular formation.• The axons of the upper motor neurons typically contact thelocal circuit neurons in the brainstem and spinal cord, which,via relatively short axons, contact in turn the appropriatecombinations of lower motor neurons.
These neurons (also called α motor neurons) send axonsdirectly to skeletal muscles via the ventral roots and spinalperipheral nerves, or via cranial nerves in the case of thebrainstem nuclei. The spatial and temporal patterns of activation of lower motorneurons are determined primarily by local circuits locatedwithin the spinal cord and brainstem. Descending pathways from higher centers comprise theaxons of “upper” motor neurons and modulate the activity oflower motor neurons by influencing this local circuitry.
The local circuit neurons also receive direct input fromsensory neurons, thus mediating important sensory motorreflexes that operate at the level of the brainstem and spinalcord. Lower motor neurons, therefore, are the final commonpathway for transmitting neural information from a variety ofsources to the skeletal muscles.Neural Centers Responsible for Movement The neural circuits responsible for the control of movementcan be divided into four distinct but highly interactivesubsystems, each of which makes a unique contribution tomotor control.
The first of these subsystems is the local circuitry within thegray matter of the spinal cord and the analogous circuitry in thebrainstem. The relevant cells of this subsystem include: the lower motor neurons (which send their axons out of the brainstem and spinal cord to innervate the skeletal muscles of the head and body, respectively); and the local circuit neurons (which are the major source of synaptic input to the lower motor neurons). All commands for movement, whether reflexive or voluntary,are ultimately conveyed to the muscles by the activity of the lowermotor neurons. Thus these neurons comprise, the “final common path” formovement.
The second motor subsystem consists of the upper motorneurons whose cell bodies lie in the brainstem or cerebral cortex Axons of the upper motor neurons descend to synapse with the localcircuit neurons or, more rarely, with the lower motor neurons directly. The upper motor neuron pathways that arise in the cortex areessential for the initiation of voluntary movements and for complexspatiotemporal sequences of skilled movements. In particular, descending projections from cortical areas in the frontallobe, including: Brodmann’s area 4 (the primary motor cortex); the lateral part of area 6 (the lateral premotor cortex); and the medial part of area 6 (the medial premotor cortex)• Are essential for planning, initiating, and directing sequences ofvoluntary movements.
Upper motor neurons originating in the brainstem areresponsible for regulating muscle tone and for orienting the eyes,head, and body with respect to vestibular, somatic, auditory, andvisual sensory information. Their contributions are thus critical for basic navigationalmovements, and for the control of posture. The third and larger of these subsystems, the cerebellum, islocated on the dorsal surface of the pons. The cerebellum acts via its efferent pathways to the uppermotor neurons as a servomechanism, detecting the difference,or “motor error,” between an intended movement and themovement actually performed.
The cerebellum uses this information about discrepancies tomediate both real-time and long-term reductions in these motorerrors (the latter being a form of motor learning). As might be expected from this account, patients withcerebellar damage exhibit persistent errors in movement. The fourth subsystem, embedded in the depths of theforebrain, consists of a group of structures collectively referred toas the basal ganglia. The basal ganglia suppress unwanted movements andprepare (or “prime”) upper motor neuron circuits for the initiationof movements.