Symptoms and signscaused byneural plasticity

AageR. Møller

Universityof Texas at Dallas, Callier Center for Communication Disorders, Dallas, TX, USA Plasticchanges in thecentral nervous system are associated with hyperactivity,hypersensitivity, and spread of activityincluding activation of brainregions that are not typicallyinvolved. Symptoms and signssuch as neuropathicpain and tinnitusand hyperactivedisorders such as muscle spasm and synkinesismay result from suchchanges in function. Plasticchanges that cause symptoms of diseasescan be initiated by novel stimulations,overstimulation, or deprivationof input and theinduced changesin thefunction of central nervoussystem structures may persist and aggravateafter these events have ceased if the condition isnot reversed.Disorders that are caused by neural plasticity are potentially reversible with treatment.However, theabsence of morphologic abnormalitiesmakes diagnosis of theseconditions difŽcult and theirtreatment hasbeen hampered by lack of understandingof theirpathophysiology. Here the role of neuralplasticity in thepathophysiology of severaldisorders is reviewed. [NeurolRes 2001; 23: 565–572]

Keywords:Neural plasticity, neuropathic pain; muscle spasm; synkinesis; tinnitus

INTRODUCTION structuresincluding re-routing of information to regions Ithas been known for manyyears that the developing ofthe brain that are not normallyinvolved in aparticular centralnervous system(CNS) isplastic, causing its function.Allodynia, i.e. pain evoked by somatic functionto change in different ways as a resultof stimulationthat normally does not evokepain, is an externaland internal factors. Only relatively recently has exampleof a symptomcaused by changes in the CNS. itbecome evident that the mature nervous systemis also Allodyniaand phonophobia aresigns of re-routing of plastic1–15.Neuralplasticity is an ability of the nerve informationin the central nervous systemevoked by cellsto change their function or structure.This isusually sensorystimulation. Synkinesis is asignof establishment considerednecessary for thedeveloping organism, and ofnew connections between motoneurons. Other beneŽcial to the mature organism because it canchange symptomssuch as hyperalgesia (increased sensitivity to thefunction of speciŽ c partsof the CNS tosuitchanging painfulstimuli) and hyperpathia (exaggerated subjective demandsor compensatefor theeffect of injuries and response topainful stimuli that continue after the diseases.It is neural plasticity that makes it possible for stimulationhas ceased), and muscle spasm that may strokevictims to regain functions after destruction of occurafter peripheral nerve injuries, are signs of plastic neuraltissue. Neural plasticity most likely also plays an changesresulting in hypersensitivity and hyperactivity. importantrole in making it possibleto adaptthe nervous Tinnitusand certain forms ofvertigo are examples of systemto the use of prostheses such ascochlear disorders thatmay be caused by plastic changes in the implantsand auditory brainstem implants. However, functionof speciŽ c CNSstructuresresulting in hyper- neuralplasticity can also cause symptoms and signs of activityor re-routingof information. diseases.The symptoms that arise from functional Theplastic changes that occur in themature nervous changesthat are expressions of neural plasticity are systemare different from thosethat occur in the not associatedwith detectable morphologic or chemical developingnervous system.The function of thedevelop- abnormalities.This isin signiŽ cant contrast to the ingnervous systemnormally changes during develop- symptomsand signs of disorders thatare associated mentand the abnormalities that occur are regarded as withtissue injuries and which usually can be identiŽ ed errors inthe normal development. The mature nervous byima gingtec hniques or byelec trophysiologic systemis normally stable, except for changesthat are methods. relatedto aging. Altered excitability of speciŽ c neural Symptomscaused by neural plasticity have been structures,changes in synaptic efŽ cacy or outgrowth of studiedmost extensively with regard to pain 4 ,15 –2 4, but newconnections (sprouting) are common changes neuralplasticity can also cause other symptoms and attributedto neural plasticity. Expression of neural signsabout which less is known. The symptoms of plasticitymay occur as a resultof external and internal neuralplasticity may be hypersensitivity, hyperactivity eventssuch asdeprivation of sensory input, over- and/or extendedactivation of central nervous system stimulation,or tissueinjury and in ammation. The same eventsmay cause long lasting modiŽ cations or altera- tionsin theexpression of receptors 1 9.Plasticchanges in thenervous systemmay be regarded as a form of Correspondenceand reprint requests to: Aage R. Møller, PhD, Universityof Texas at Dallas, Callier Center for Communication learning.Since plastic changes in function are not Disorders,1966 Inwood Rd., Dallas, TX 752 35-7298,USA. accompaniedby tissue damage they are potentially ,25–28 [[email protected]]Accepted for publication November 2000. reversible3 .

# 2001Forefront Publishing Group NeurologicalResearch, 2001, Volume 2 3, September 565 0161–6412/ 01/060565–08 Neuralplasticity: Aage R. Møller

Mostof the knowledge about expression of neural NEURALPLASTICITY RELATED TO SPECIFICSYSTEMS plasticityin the mature nervous systemand how itcan Somatosensorysystem causesymptoms and signs of diseases has been gained Paresthesia,hyperesthesia, neuropathic pain and prur- from researchon pain.The results from painresearch itusare symptoms associated with disorders ofthe havebeen used in attempts to understand how plastic somatosensorynervous system.Disorders ofthe somato- changesmay occur in otherparts of the central nervous sensorysystem are also often associated with dysesthe- systemand which symptoms and signs may result 29 ,30. sia,i.e. an unpleasant sensation from stimulationsthat This reviewarticle provides an overviewof the role of arenormally innocuous. Someof these symptoms can neuralplasticity in causing symptoms and signs that becaused by peripheral neuropathies, hyperventilation resultfrom changesin the function of the nervous or metabolicdisturbances, but theycan also be caused system.SpeciŽ cally, the role of neural plasticity in byplastic changes of the CNS. The symptoms that are neuropathicpain, tinnitus, vestibular disorders, and causedby neural plasticity are not causedby neural synkinesisand muscle spasm is discussed. activitythat is generated at the location where the sensationis perceived, but ratherby activity generated intheCNS. Allodynia and hyperalgesia are examples of SIGNSOF CENTRALORIGIN OFSYMPTOMS symptomsthat are caused by changes in the CNS. Phantomsensations and phantom pain are perhaps the Pruritus (itching)is relatedto pain, and it canbe caused clearestdemonstrations of disorders wherethe neural byperipheral as well as central disturbances. Phantom activitythat causes the symptoms does not originateat limbsensations are examples of sensations that are thelocation of the symptoms 2 6,28, 31.Phantompain is generatedin the CNS but referredto a peripheral thereforea pure form ofcentral pain. Tinnitus that location.The plastic changes that cause these symptoms occursdespite a severedauditory nerve is also a clear maybe induced by deprivation or over-stimulation.That signof a centralorigin of the abnormal neural activity phantomlimb syndrome is relatedto over-stimulation is thatcauses the symptoms 30.Ithas been shown inanimal supported bythe Ž ndingthat avoiding over-stimulation experimentsthat the auditory 1,2,8,12,1 3, 32 and somato- during amputationby applying local anesthetics to the sensorysensory cortex 3,7,15 mayreorganize so that peripheralnerve can eliminate the occurrence of regionsthat are adjacent to the areas that are deprived of phantomlimb sensations 28. inputexpand to occupy the deprived cortical areas. Allodynia,where sensory stimulation that normally is innocuous isperceivedas beingpainful, is anindication Pain thatabnormal connections have been establishe d Neuropathicpain is an example of sensations that betweenthe somatosensory nervous systemand the maybe caused by neural activity generated in theCNS paincircuitry 4,1 6–18.Someindividuals with tinnitus after but referredto a peripherallocation. Neuropathic pain injuriesto the auditory nerve perceive sounds from canhave many causes but thecause is lessimportant for rubbing theskin, another example of abnormal connec- managementthan the mechanisms that produce the 2 1 19 tionsbetween sensory systems 30 .Synkinesisafter pain .Woolfand Salter deŽne three main types of peripheralnerve injuries 2 7 andin connection with pain:physiologic, in ammatory and neuropathic pain. hemifacialspasm 33– 36 isanother example of a condition Physiologicpain is caused by normal activation of thatis caused by establishment of new neural connec- nociceptors.In ammatory pain is caused by various tions.The vertigo and nausea from headmovements that forms ofin ammation and tissue damage. Neuropathic isexperienced by individuals with certain vestibular painis caused by lesions of the nervous system, disorders37 mayalso be caused by reorganization of the includinglesions of peripheral nerves or disorders of centralnervous system. theCNS suchas strokes,but itis not known whylesions 21 Centralneuropathic pain is often accompanied by tothe nervous systemcause pain .Neuropathicpain, depression16,whichindicates that new connections or stimulusindependent pain, may persist long after betweenpain circuits and structures belonging to the healingof the initial pathology and it is thus not adirect limbicsystem have been established. Phonophobia, reactionto the pathology. Neuropathic pain may thus whichoften accompanies auditory disorders such as representplastic changes in thefunction of the nervous tinnitus,is asignof abnormal connections between the system.Deafferentiation pain (including anesthesia auditorynervous systemand structures belonging to the dolorosa)is an example of central pain. The regions of limbicsystem 6 ,30 ,38.Abnormalconnections in the CNS thebody from wherepain is referred often extend with canbe established either by outgrowth of new connec- time,thus aform oflateral spread of activation and a tions(sprouting) or byincreasing the efŽ cacy of normally furthersign of involvement of the CNS. closedsynapses (unmasking of ordinarily ineffective Sensitizationof the CNS maycause the sensation of synapses).While outgrowth of new connections takes painfrom stimulationof nociceptors to increase when time,change in synaptic efŽ cacy can occur without delay. thestimulation is repeated.This isknown asthe ‘ wind- 20 ,4 0 Plasticchanges in the central nervous systemoften up’phenomenon ,andit is thus theopposite to resultin changesin processing of information. One sign adaptationin sensory systems. These changes are signs ofsuch change in information processing is altered ofcentral sensitization of excitatory synapses or by 19 temporalintegration of painful stimuli in individuals depressionof inhibition .Suchplastic changes may be withneuropathic pain 39. initiatedby stimulation of nociceptors, by in ammation

566 NeurologicalResearch, 2001, Volume 2 3, September Neuralplasticity: Aage R. Møller

temporalintegration is a signof involvement of the centralnervous systemin pain and testing of temporal integrationcould serve as a valuablediagnostic tool to differentiatebetween neuropathic pain of central origin andpain caused by stimulation of nociceptors (physio- logicor inammatory pain). Recently,the administration of Botulinum toxin has beenintroduced for treatmentof myofacial pain and otherintractable headaches 4 3.Botulinumtoxin that blockmuscle endplates is injected in muscles of the head.The efŽ cacy of that treatment may be explained by neuralplasticity that causes the output ofproprioceptors toactivate pain circuits, thus similarto ‘ allodynia’in neuropathicpain. The proprioceptors would beacti- vatedby muscle contractions. This mayalso be at least a partialexplanation of other forms ofpain from muscle A spasm.The effect increased gradually over a 60-day observationperiod, which supports thehypothesis that neuralplasticity of proprioceptionis involved.Naturally, musclespasm may cause pain in muscles from exhaustion. Theabnormal connections between the somato- sensorysystem and pain circuits in the spinal cord or brainstemthat result in symptoms, such as allodynia, maybe established either by unmasking of inefŽ cient synapses44 or byestablishment of anatomically new connectionsthrough sproutingof axons 4 ,2 2,45. There is recentevidence that A-beta Ž bers maysprout from inthe dorsalhorn ofthe spinal cord intoparts where C-Ž bers normallyterminate 4 ,2 2,4 5.Suchnew connections betweensensory Ž bers andneurons thatnormally receiveinput from nociceptorsrepresenting functional connectionsbetween the somatosensory system and paincircuits in the spinal cord mayexplain allodynia. Anotherpossibility is a changein the function of the B widedynamic range (WDR) neurons insuch awaythat Figure 1 A: Typicalthreshold curves for sensation (solid squares) and theseneurons mayincrease their maximal Ž ringrate to pain(open circles), shown as a functionof stimulusrepetition rate in levelsthat can open normallyinefŽ cient synapses that twoindividuals without pain. The threshold functions for sensation and connectthese neurons topain circuits 17 .Suchchanges painwere Ž ttedto exponential functions (solid lines). B: Typical mayoccur by reduction of inhibitory input to (WDR) thresholdcurves for sensation (solid squares) and pain (open circles), in anindividual with neuropathic pain. (From Mø ller and Pinkerton, neurons or byan increase in excitatory input to these 1997)39 neurons. Thesympathetic nervous systemmay also be involvedand produce apositivefeedback of pain- evokedneural activity. The extreme expression of sympatheticinvolvement is reex sympatheticdystrophy or peripheralnerve injuries. Hyperpathia represents a (RSD)41. modiŽcation of pain activation that may be caused by Establishmentof new connections in the brain or increasedsensitivity of nociceptors caused by repeated spinalcord mayalso explain the affective components stimulation(autosensitization), i.e., an exaggerated ofpain. At least some of the affective attributes to pain response topainful stimuli. Thus, morethan transient mayresult from establishmentof connections to the activationof C-Ž ber nociceptorscan induce central medialportion ofthe thalamus and to limbicstructures. sensitizationinvolving NMDA receptors 41,42. However,the pathways for nociceptiveinput ( Figure Changesin temporalintegration can be demonstrated 2)16,arecomplex and the pathways for neuropathicpain bydetermining the threshold to pain from electrical arelikely to be even more complex with a highdegree stimulationwith impulses presented at differentfrequen- ofparallel processing including connections with cies39.Normally,the pain threshold to stimulation with autonomicsystems. trainsof impulses decreases when theinterval between theimpulses is decreased as an expression of temporal integration.The pain threshold is lowered in individuals Tinnitus withneuropathic pain and it does not decreasewhen the Tinnitusis a commondisorder ofhearing that has stimulusinterval is decreased ( Figure 1). Abnormal many forms46 –48.Mostpeople who havetinnitus are

NeurologicalResearch, 2001, Volume 2 3, September 567 Neuralplasticity: Aage R. Møller

conjunctionwith acoustic tumors andother injuries or irritationof the auditory nerve such as from closecontact witha blood vessel 5 3.Someindividuals acquire tinnitus withoutany known cause.There is evidence that deprivationof input can cause temporary tinnitus and thatpermanent deprivation such asmay occur in individualswith hearing loss can cause chronic tinnitus2 6,47. Sound deprivationcan cause changes in processingof informationin the auditory system in animals that resemblesthat seen in patients with severe tinnitus. Thus, Gerken et al.54 found thatdeprivation of auditory inputinduces hypersensitivity of auditory nuclei and changesin temporal integration. Other animal experi- mentshave shown thatexcessive stimulation of the auditorysystem can cause signs of hyperactivity and alteredtemporal integration in the inferior colliculus 52. Thesechanges were shown toberelatedto reductionin GABAergicinhibition 52 ,55. Thefact that many individuals with tinnitus perceive sounds asbeing distorted and Ž nd itdifŽ cult to match theirtinnitus to physicalsounds maybe explained by a Figure 2: Schematicdrawing of ascending subcortical and cerebral changein processing of auditory information. This corticalstructures involved in processing of pain. PAG, periaqueductal hypothesisis supported bythe Ž ndingthat the non- gray;PB, parabrachial nucleus of the dorsolateral pons; Vmpo, ventromedialpart of the posterior nuclear complex; MDvc, ventro- classicalascending auditory pathways are activated in caudalpart of the medial dorsal nucleus; VPL, ventroposterior lateral someindividuals with severe forms oftinnitus, which nucleus;ACC, anterior cingulated cortex; HT, hypothalamus; S-1 and does not occurin individuals who do not have S-2,Ž rst andsecond somatosensory cortical areas; PPC, posterior tinnitus38.This isa signthat neural activity has spread parietalcomplex; SMA, supplementarymotor area; AMYG, amygdala; toother parts of the CNS beyondthose normally PF,prefrontalcortex. [Reprinted with permission from Price DD. Psychologicaland neural mechanisms of the affective dimension of activatedby sound. Thenonclassical auditory pathways pain. Science 2000; 288:176–1772. American Association for the projectto themedial and dorsal portions ofthethalamic Advancementof Science] relay(medial geniculate body) and the association cortices15,47,whichin turn haveconnections to the amygdalaand other limbic structures. Activation of structuresbelonging to thelimbic system can explain the littlebothered by their condition, but severeforms of emotionalcomponents of tinnitus. Activation of the tinnitusmay affect the quality of life in aserious manner nonclassicalauditory pathway may thus explainwhy bypreventing sleep and the ability to do intellectual patientswith severe tinnitus often have emotional work.Some forms oftinnitus are accompanied by reactionsto sound (hyperacusisand phonophobia). hyperacusisand distortion of sounds. Phonophobia Studiesby Lockwood et al.6 usingfunctional MRI in anddepression with high risk of suicide may also be individualswho couldcontrol their tinnitus have presentin patients with severe tinnitus 30,48 ,4 9. Severe conŽrmed that limbic structures such asthe hippo- tinnitushas many similarities with neuropathic pain, campusare activated in some patients with tinnitus. both inthe way it affects a person’s lifeand in its Thenonclassical auditory pathways receive input pathology2 9,30.However,tinnitus is rarely taken as from thesomatosensory system, a factthat was used to serious aschronicsevere pain, although it can be just as show theinvolvement of the nonclassical pathway in debilitating. patientswith tinnitus 38.Thatmay explain why some Sincetinnitus is perceived as a sound itis often individualscan change their tinnitus by skin stimula- associatedwith disorders ofthe ear. The fact that deaf tion49,56 ,5 7,or bycontracting speciŽ c muscles 5 8. It may peoplecan have tinnitus and that tinnitus may occur in alsoexplain why a fewindividuals have auditory individualswhose auditorynerve has been severed are sensationsfrom skinstimulation. That some individuals strongindications that at least some forms ofsevere canchange their tinnitus voluntarily by changing their tinnitusare not generatedin theear. The hypothesis that gaze59,indicatesthat control of eye muscles modulates tinnitusis a phantomsensation 5 0 thatis caused by auditorypathways in some tinnitus patients. Such ability hypersensitivityand hyperactivity in speciŽ c central tomodulate the intensity and the character of tinnitus nervous systemcircuitry has been supported bymany seemsto bemost common in patients whose tinnitusis studies51,52. causedby surgically induced injuries to the auditory Tinnitusmay appear gradually over many years of nerve,e.g. during removalof acoustic tumors, and it is exposureto loud sounds, or itmayappear after a single furtherevidence of involvement of parts of the CNS or afewinstances of exposure to very loud sounds, otherthan those normally activated by sound, most especiallyimpulsive noise. Tinnitus may also occur in likelythe nonclassical auditory pathways.

568 NeurologicalResearch, 2001, Volume 2 3, September Neuralplasticity: Aage R. Møller

Involvementof the nonclassical auditory pathway targetmuscles. Post-traumatic synkinesis has often been mayalso explain why tinnitus patients often Ž nd it interpretedas a failureof regenerating axons to reach difŽcult to match physical sounds totheir tinnitus and theirproper targets.This hypothesishas prevailed when theyŽ nd anacceptable match it is usually to despitethe lack of factual support. On theother hand, sounds ofverylow intensity. This hasbeen regarded as a thereis considerable evidence that plastic changes in contradictionto the severe discomfort these patients theCNS cancause synkinesis and muscle spasm, by report andit can set a patient’s descriptionof his/ her openingabnormal connections between motoneurons. situationin doubt. This mayoccur, either by unmasking of inefŽ cient synapsesor byoutgrowth ofaxons (sprouting). Symptomsof spasticity and muscle spasm may be Vestibulardisorders causednot onlyby hyperactivity of motor systemsbut Normally,we are not consciousof the activation of alsoby altered proprioceptions. Thus, recentstudies of thevestibular inner ear apparatus. The nausea that facialmotor controlhave shown evidencethat post- resultsfrom headmovements is a signthat information traumaticsynkinesis is aresultof changes in thefunction from thevestibular system has reached consciousness. ofthe facial motonucleus caused by injuries to thefacial Nauseaand dizziness are not normalresponses to nerve62 andthus, is not aresultof outgrowing axons activationof the vestibular system and must thus be havingmissed their target. This evidencecombined with causedby establishment of connections between the theevidence that facial exercise can reduce the vestibularsystem and the conscious brain and the areas synkinesis27 ,6 3 suggeststhat post-traumatic synkinesis is ofthe brain that cause vomiting. Disorders ofthe anexpression of increased synaptic efŽ cacy between vestibularsystem, such as benign paroxysmal positional motoneurons inducedby injury to theiraxons. nystagmus(BPPN) characterized by nystagmus and Synkinesisoften occurs together with muscle spasm in dizzinessfrom headmovements, are most likely caused patientswith hemifacial spasm (HFS) 35, 36.HFSisa rare byan anomaly in the peripheral vestibular organ 60 that disorder6 4 thatis characterized by attacks of spasm in maysend novel information to higher centers that cause themuscles of one side of the face. It canbe effectively are-routingof information. Some of the abnormal curedby moving a blood vesseloff the intracranial sensationsfrom headmovement could be explained portion ofthe facial nerve, near its exit from the bymalfunction of the vestibular system resulting in brainstem33,65.Thesynkinesis can be demonstrated by excessivemuscle activity, which might be what the testingthe blink re ex 36,66,67,whichcan be elicited by patientperceives. However, nausea and the feeling of electricalstimulation of the supraorbital branch ofthe dizzinessseems to be a resultof re-routing of informa- trigeminalnerve. The blink re ex response isnormally tionfrom thevestibular apparatus to regionsof the CNS limitedto the orbicularis oculi muscles but inpatients thatusually do not receivesuch information. withHFS itmay also include contractions of other face Individualswith a raredisorder ofthe vestibular muscles. system,such as disabling positional vertigo (DPV) 37 ,61, Oneof the two hypotheses about the cause of these experiencenausea and discomfort from anyhead signspostulates that the symptoms and signs of HFS are movementto an extentthat it often forces such patients causedby crosstalk between axons at thelocation of the tospend mostof theirtime in bed. This meansthat new vascularcontact with the intracranial portion ofthe connectionsfrom thevestibular system to brain regions facialnerve 34,whilethe other hypothesis claims that not usuallyinvolved in processinginformation from the hyperactivityof the facial motonucleus causes these vestibularapparatus must have been established. The symptoms68.Studiesin patients undergoing MVD factthat these conditions may appear, and disappear, operationsfor HFShavesupported thehypothesis that withoutnoticeable delay indicates that these new thesigns of HFS (spasmand synkinesis) are caused by connectionsare opened by functional changes (e.g. hyperactivityof the facial motonucleus 36,67,69 and unmaskingof ineffective synapses) that connect the suggestthat the synkinesis is a resultof increased vestibularsystem with regions of the conscious brain efŽcacy of synapses that connect facial motoneurons thatare not normallyactivated by vestibular input. The thatinnervate different muscle groups ofthe face 36 ,6 9. factthat DPV canbe successfully cured by MVD ofthe Thesesynapses are assumed to be dormant under vestibularnerve root 37,61 suggeststhat abnormal input normalcircumstances. The hyperactivity has similarities from thevestibular nerve causes and maintains these withthe kindling phenomenon Žrst describedby God- abnormalconnections (e.g. the abnormal neural activity dard7 0 who showed thatnovel stimulation of a nucleus maybe caused by irritation of the vestibular nerve by a couldlead to spontaneous activity. The novel stimula- blood vessel(DPV) or asa resultof malfunction of the tionthat causes the facial motonucleus to become vestibularorgan (BPPN)). hyperactivemay be generated by the irritation of the facialnerve from closecontact with a blood vessel.This hypothesiswas supported bystudies of animal models of Synkinesisand muscle spasm HFS1,5,11 inwhich similar signs, as in HFS (spasmand Synkinesisand spasm are common sequelae of synkinesis),were created by electrical stimulation of the regenerationof injured peripheral motor nervessuch facialnerve according to a typicalkindling para- asthe facial nerve, indicating that abnormal connections digm5,10,11.Thesestudies thus indicatethat the synkin- havebeen established between motoneurons andthe esisin HFS isnot adirectresult of the close contact

NeurologicalResearch, 2001, Volume 2 3, September 569 Neuralplasticity: Aage R. Møller betweena blood vesseland the facial nerve but caused form newconnections. However, many of these byabnormal connections between motoneurons, prob- changesoccur with a veryshort delay,which preclude ablyby the unmasking dormant synapses, which is formationof new connections by sprouting. Morpho- initiatedand maintained by the irritation of the facial logicchanges have been shown tooccur after over- nerveby a blood vessel. stimulationin the auditory system 71–7 3.Somestudies Ifit is acceptedthat the function of sensorypathways indicatethat outgrowth ofnew connections may be maychange as aresultof neural plasticity, then it seems involvedin chronic pain, where A-Ž bers inthe spinal reasonableto assume that the processing of proprio- cord sprout from alocationdeep in the dorsal horn of ceptiveinformation can be modiŽ ed or modulated.This thespinal cord intoparts where C-Ž bers normally meansthat abnormal motor functionmay not onlybe terminateand make synaptic contacts 4 ,2 2,47. This is causedby abnormalities in the (descending) motor assumedto be the cause of allodynia after peripheral pathwaysbut alsoby changes in proprioceptive feed- nerveinjuries. back. Ifnew connections are made by sprouting of axons, theeffect takes some time to develop while unmasking ofdormant synapses can occur instantly. In theiroriginal MECHANISMSOF NEURALPLASTICITY studyof the establishment of new connections Wall and Oneof the Ž rst demonstrationsof plastic changes in coworkersfound thatthe new connections to derma- synapticefŽ cacy was made by Wall 4 4 who showed that tomesthat they observed were made without delay. This deprivationof input can change the response areasof meansthat it could not bea resultof sprouting but could neurons. Heshowed thatsevering dorsal roots caused havebeen caused by an increase in synaptic strength. cellsin thedorsal horn ofthe spinal cord torespond to Walland co-workers alsoshowed thatelectrical inputfrom dermatomesfrom whichthey normally did estimationwas more efŽ cient in activating dorsal horn not respond. On thebasis of these Ž ndingsWall 44 neurons from distantdermatomes than natural stimula- coinedthe term ‘ dormantsynapses’ to describesynaptic tions,which indicates that synapses may conduct when connectionsthat exist anatomically but thefunction of stimulatedby high frequency stimulation while being whichare blocked because they have high synaptic unresponsiveto low frequency stimulation. This means thresholds.Wall 44 explainedhow unmaskingof such thatpathways in the brain may become activated in normallyineffective synapses can occur under abnormal response tonovelinput if the discharges have a shorter conditions,such asdeprivation of input. Synapses may intervalthan the normal neural activity. beineffective because the rate of the input is too low. Thefact that dizziness may develop suddenly Increasingthe rate such asmayoccur as aresultof novel excludessprouting as a causeand indicates that the neuralactivity can then open suchsynapses. anomalyis the result of opening of dormant synapses in Theunmasking of inefŽ cient (dormant) synapses may analready anatomically established pathway. Reversal extendsensory activation areas (‘ lateralspread’ ) by ofopening of ineffective connections may consequently openingconnections to adjacent neurons. Suchun- bepossible and there are examples of how trainingcan maskingof dormant synapses can also open connections alleviatesome symptoms of such lateralspread. Thus, toregions of the brain that are not normallyactivated. paincan be treated by TENS 25,tinnitusby the Tinnitus Sproutingof axons may create anatomically new RetrainingTherapy (TRT) 5 0,andsynkinesis can be connectionsthat have a similareffect of widening successfullytreated by exercise as shown for thefacial response areas.One of the earliest experimental nerve27 . demonstrationsof that widening of the response areas Hyperactivityand hypersensitivity that may cause asa resultof changes (deprivation) of input was that of phantomsensations such astinnitus, tingling and muscle Merzenichand colleagues 3,7 who showed thatamputa- spasmmay be caused by strengthening of synaptic tionof a Žngercauses the cortical representation of that efŽcacy (long-term potentiation, LTP) or increased skinarea to be given to the adjacent Ž ngers.Jenkins et excitabilityof sensory receptors or centrallylocated al.3 showed thatstimulation of the somatosensory neurons or bydecreased inhibition. Studies of LTP in systemcould also change the representation of body slicesof hippocampus in rats or guineapigs shows thatit partson thesomatosensory cortex. These now classical isbest invoked by stimulation at a highrate. The effect experimentswere followed by studies of other sensory maylast from minutesto days and glutamate and the systemswhere similar plasticity was demonstrated 8,9, 32 NMDAreceptor(N-methyl-D-aspartate) have been andshowed thatsimilar changes may occur because of implicatedin LTP. Unmasking of ineffective synapses othernovel manipulations, such as overstimulation 9. mayoccur because of increased synaptic efŽ cacy or Such‘ lateralspread’ of activation is a generalsign of becauseof a decreaseof inhibitory input that normally plasticchanges and the widening of the response areas hasblocked synaptic transmission 1 ,2 ,8. maybe regarded as an‘un-sharpening’of response areas andmotor projections,thus theopposite to what occurs inontogeny where sensory receptive areas are narrowed CONCLUSION byreduction in synapticefŽ cacy, pruning ofaxons and Thedisorders thatare caused by plastic changes in the dendritesand apoptosis. functionof CNS structuresare characterized by distinct Thephenomenon of‘ lateralspread’ may equally well andprominent symptoms and signs but fewobjective beexplained by sprouting of axons and dendrites to signs,which complicates the diagnosis. The descriptions

570 NeurologicalResearch, 2001, Volume 2 3, September Neuralplasticity: Aage R. Møller ofsymptoms that patients present can be confusing auditorycortex of guinea pigs with partial unilateral deafness. becausethey often involve the events that were assumed JComparativeNeurol 1989; 282: 456–471 10Saito S, Møller AR. Chronic electrical stimulation of the facial nerve tohave precipitated the symptoms, e.g. trauma to a causessigns of facialnucleus hyperactivity. Neurol Res 1993; 15: peripheralnerve, yet the symptoms of the patient often 225–231 seemunrelated to these events. Lack of familiarity with 11Sen CN, Møller AR. Signs of hemifacialspasm created by chronic neuralplasticity as a causeof symptoms and signs may periodicstimulation of the facial nerve in therat. Exp Neurol 1987; 98: 336–349 leadto erroneous diagnosisand ineffective treatment. 12Syka J, PopelarJ. Noiseimpairment in theguinea pig. I. Changesin Theuncertainty about which medical specialty is best electricalevoked activity along the auditory pathway. Hear Res suitedto care for patientswith such disorders further 1982; 8: 263–272 hamperscorrect diagnosis and development of effective 13 SykaJ, RybalkoN, PopelarJ. Enhancementof the auditory cortex treatments. evokedresponses in awake guinea pigs after noise exposure. Hear Res 1994; 78: 158–168 Thehypothesis that plastic changes in the nervous 14Szczepaniak WS, Mø ller AR. Evidenceof neuronalplasticity within systemmay be the cause of symptoms and signs of theinferior colliculus after noise exposure. A studyof evoked certaindisorders isattractive because it suggests that potentialsin the rat. ElectroencephClin Neurophysiol 1996; 100: suchdisorders arepotentially treatable, and under- 158–164 standingthe cause of the plastic changes may make the 15Wall JT, KaasJH, Sur M, NelsonRJ, Felleman DJ, Merzenich MM. Functionalreorganization in somatosensory cortical areas 3b and 1 disorders preventable.That the risk of acquiring some of ofadultmonkeys after median nerve repair: Possible relationships thesedisorders canbe reduced has been demonstrated. tosensory recovery in humans. J Neurosci 1986; 6: 218–233 Yetthe risk of many other disorders canprobably also be 16Price DD. Psychologicaland neural mechanisms of the affective reducedby appropriate intervention. dimensionof pain. Science 2000; 288: 1769–1772 17Coderre TJ, Katz J, VaccarinoAL, MelzackR. Contributionto Manyforms ofchronic pain can be cured by electrical centralneuroplasticity to pathological pain: Review of clinicaland stimulation(TENS) but itrequires proper diagnosis. experimentalevidence. Pain 1993; 52: 259–285 Attemptsto treat conditions that were initially triggered 18Price DD, LongS, HuittC. Sensorytesting of pathophysiological byperipheral events, which then progressed, by surgical mechanismsof pain in patients with re ex sympatheticdystrophy. Pain 1992; 49: 163–173 interventionat thesite of thepain is usuallyunsuccessful 19Woolf CJ, SalterMW. Neuronalplasticity: Increasing the gain of inalleviating the pain. This ismost likely due to the pain. Science 2000; 288: 1765–1768 resultantchanges in the CNS. Equally unsuccessful are 20Woolf CJ, ThompsonSWN. The induction and maintenance of treatmentsof the ear in attempts to treat tinnitus that is centralsensitization is dependenton N-methyl-D-aspartic acid causedby activity generated in the CNS. receptoractivation: Implications for the treatment of post-injury painhypersensitivity states. Pain 1991; 44: 293–299 Thesymptoms and signs that are discussed in this 21Woolf CJ, Mannion RJ. Neuropathicpain: Aetiology, symptoms, paperrepresent only a smallfraction of the disorders that mechanisms,and management. Lancet 1999; 353: 1959–1964 arecaused by plastic changes in the central nervous 22Woolf CJ, ShortlandP, CoggeshallRE. Peripheralnerve injury systemand many patients have received inadequate triggerscentral sprouting of myelinated afferents. Nature 1992; treatmentbecause of failure to correctly diagnose their 355: 75–78 23 MelzackR, WallPD. Pain mechanisms: A newtheory. Science disorder. 1965; 150: 971–979 24Mendell LM. ModiŽability of spinal synapses. Physiol Rev 1984; 64: 260–324 REFERENCES 25Willer JC. Relievingeffect of TENSon painful muscle contraction 1IrvineDR, RajanR. Injury-and use-related plasticity in the primary producedby an impairment of reciprocal innervation :An sensorycortex of adult mammals: Possible relationship to electrophysiologicalanalysis. Pain 1988; 32: 271–274 perceptuallearning. ClinExper Pharmacol Physiol 1996; 23: 26Jastreboff PJ. Tinnitusas a phantomperception: Theories and 939–947 clinicalimplications. In: Vernon JA, Mø ller AR, eds. Mechanismsof 2IrvineDR, RajanR. Injury-inducedreorganization of frequency Tinnitus, Boston:Allyn & Bacon,1995: pp. 7 3–93 mapsin adult auditory cortex: The role of unmaskingof normally- 27Brach JS, VanSwearingenJM, LenertJ, JohnsonPC. Facial inhibitedinputs. ActaOto-Laryngoligica 1997; 532 (Suppl.): 39–45 neuromuscularretraining for oral synkinesis. PlastRecon Surg 3 JenkinsWM, Merzenich MM, OchsMT, Allard T, Guic-RoblesE. 1997; 99: 1922–1931 Functionalreorganization of primary somatosensory cortex in adult 28Bach S, NorengMF, ThelldenNU. Phantomlimb pain in amputees owlmonkeys after behaviorally controlled tactile stimulation. duringthe Ž rst 12months following limb amputation, after JNeurophysiol 1990; 63: 82–104 preoperativelumbar epidural blockade. Pain 1988; 33: 297–301 4KohamaI, IshikawaK, KocsisJD. Synapticreorganization in the 29Mø ller AR. Similaritiesbetween chronic pain and tinnitus. Am J substantiagelatinosa after peripheral nerve neuroma formation: Otol 1997; 18: 577–585 Aberrantinnervation of lamina II neuronsby beta afferents. 30Møller AR. Similaritiesbetween severe tinnitus and chronic pain. J Neurosci 2000; 20: 1538–1549 JAmAcad Audiology 2000; 11: 115–124 5KurokiA, Møller AR. Chronic vascular irritation of the facial nerve 31MelzackR. Phantomlimbs. ScientiŽc Am 1992; 266: 120–126 causesfacial spasm in rats. Neurol Res 1994; 16: 284–288 32RobertsonD, IrvineDRF. Plasticity of frequency organization in 6LockwoodAH, SalviRJ, CoadML, TowsleyML, WackDS, Murphy auditorycortex of guinea pigs with partial unilateral deafness. BW.Thefunctional neuroanatomy of tinnitus. Evidence for limbic JCompNeurol 1989; 282: 456–471 systemlinks and neural plasticity. Neurology 1998; 50: 114–120 33 GardnerWJ, SavaGA. Hemifacialspasm – areversiblepatho- 7MerzenichMM, KaasJH, WallJ, NelsonRJ, SurM, FellemanD. physiologicstate. J Neurosurg 1962; 19: 240–247 Topographicreorganization of somatosensorycortical areas 3b and 34GardnerWJ. Crosstalk – Theparadoxical transmission of a nerve 1inadult monkeys following restricted deafferentation. Neuro- impulse. Arch Neurol 1966; 14: 149–156 science 1983; 8: 3–55 35EstebanA, Molina-NegroP. Primaryhemifacia lspasm:A 8RajanR, IrvineDR. Neuronalresponses across cortical Ž eldA1 in neurophysiologicalstudy. JNeurol,Neurosurg Psychiatry 1986; plasticityinduced by peripheral auditory organ damage. Audiol 49: 58–63 Neurootol 1998; 3: 123–144 36Møller AR. Cranial nerve dysfunction syndromes: Pathophysiology 9RobertsonD, IrvineDR. Plasticityof frequency organization in ofmicrovascular compression. In: Barrow DL, ed. Neurosurgical

NeurologicalResearch, 2001, Volume 2 3, September 571 Neuralplasticity: Aage R. Møller

TopicsBook 1 3,Surgeryof Cranial Nerves of thePosterior Fossa, 55Szczepaniak WS, Møller AR. Evidenceof decreased GABAergic AmericanAssociation of Neurological Surgeons: Park Ridge, IL, inuence on temporal integration in the inferior colliculus 1993:pp.105– 129 followingacute noise exposure: A studyof evoked potentials in 37Møller MB, Møller AR, Jannetta PJ, SekharLN. Diagnosisand the rat. NeurosciLett 1995; 196: 77–80 surgicaltreatment of disablingpositional vertigo. J Neurosurg 1986; 56Cacace AT, Cousins JP, Parnes SM, McFarlandDJ, Semenoff D, 64: 21–28 HolmesT, DavenportC, StegbauerK, LovelyTJ. Cutaneous-evoked 38Møller AR, Mø ller MB, YokotaM. Someforms of tinnitus may tinnitus.II. Reviewof neuroanatomical, physiological and func- involvethe extralemniscal auditory pathway. Laryngoscope 1992; tionalimaging studies. AudiolNeuro-Otol 1999; 4: 258–268 102: 1165–1171 57Cacace AT, CousinsJP, ParnesSM, SemenoffD, HolmesT, 39Møller AR, PinkertonT. Temporalintegration of pain from McFarlandDJ, Davenport C, StegbauerK, LovelyTJ. Cutaneous- electricalstimulation of theskin. Neurol Res 1997; 19: 481–488 evokedtinnitus. I. Phenomenology,psychophysics and functional 40Thompson SWN, King AE, Woolf CJ. Activity-dependentchanges imaging. AudiolNeuro-Otol 1999; 4: 247–257 inrat ventral horn neurons in vitro:Summationof prolonged 58Levine RA. Somatic(craniocervical) tinnitus and the dorsal afferentevoked post-synaptic depolarization produce a d-APV cochlearnucleus hypothesis. AmJOtolaryngol 1999; 20: 351–362 sensitivewind-up. EurJ Neurosci 1990; 2: 638–649 59Cacace AT, Lovely TJ, McFarland DJ, Parnes SM, WinterDF. 41Campbell JN, Raja SN, Meyer RA, Mackinnon SE. Myelinated Anomalouscross-modal plasticity following posterior fossa surgery: afferentssignal the hyperalgesia associated with nerve injury. Pain Somespeculations on gaze-evoked tinnitus. Hear Res 1994; 81: 1988; 32: 89–94 22–32 42Stubhaug A, BreivikH, EidePK, Kreunen M, FossA. Mappingof 60Parnes LS, Price-JonesRG. Particlerepositioning maneuver for punctuatehyperalgesia around a surgicalincision demonstrates benignparoxysmal positional vertigo. AnnOtol Rhinol Laryngol thatketamine is apowerfulsuppressor of central sensitization to 1993; 102: 325–331 painfollowing surgery. ActaAnaesthesiologica Scandinavica 61Jannetta PJ, Møller MB, Møller AR. Disablingpositional vertigo. 1997; 41: 1124–1132 New EnglJ Med 1984; 310: 1700–1705 43 PortaM. Acomparativetrial of botulinum toxin type A and 62Kreutzberg GW. Neurobiologyof Regenerationand Degeneration methylprednisolonefor the treatment of myofascialpain syndrome theFacial Nerve, New York:Thieme, 1986: pp. 75– 8 3 andpain from chronic muscle spasm. Pain 2000; 85: 101–105 63 JohnsonPC, BrownH, KuzonWM, BallietR, GarrisonJL, Campbel 44Wall PD. Thepresence of ineffective synapses and circumstances J.Simultaneousquantitation of facial movem ents:The maximal whichunmask them. PhilTrans Roy Soc Lond 1977; 278: 361–372 staticresponse assay of facial nerve function. AnnPlast Surg 1994; 45Koerber HR, MirnicsK, KavookjianAM, Light AR. Ultrastructural 32: 171–179 analysisof ectopic synaptic boutons arising from peripherally 64Auger RG, WhisnantJP. Hemifacialspasm in Rochester and regeneratedprimary afferent Ž bers. JNeurophysiol 1999; 81: OlmstedCounty, Minnesota, 1960 to 1984. Arch Neurol 1990; 47: 1636 1233–1234 46Vernon JA, Møller AR, eds. Mechanismsof Tinnitus, Boston, MA: 65Barker FG, Jannetta PJ, BissonetteDJ, Shields PT, LarkinsMV. Allyn& Bacon,1995 Microvasculardecompression for hemifacial spasm. J Neurosurg 47Mø ller AR. Tinnitus.In: Jackler RK, Brackmann D, eds. Neuro- 1995; 82: 201–210 tology, St.Louis, MO: MosbyYear Book, Inc., 1994: pp. 15 3–165 66Nielsen VK. Pathophysiologyof hemifacial spasm: II. Lateral 48Mø ller AR. Hearing:Its Physiology and Pathophysiology, San spreadof the supraorbital nerve re ex. Neurology 1984; 34: Diego,CA: AcademicPress, 2000 427–431 49Mø ller AR. Pathophysiologyof tinnitus. In: Vernon JA, Møller AR, 67Mø ller AR, Jannetta PJ. Blink re ex in patients with hemifacial eds. Mechanismsof Tinnitus, Boston,MA: Allyn& Bacon,1995: spasm:Observations during microvascular decompression opera- pp. 207–217 tions. J Neurol Sci 1986; 72: 171–182 50Jastreboff PJ. Phantomauditory perception (tinnitus): Mechanisms 68Ferguson JH. Hemifacial spasm and the facial nucleus. Ann Neurol ofgenerationand perception. NeurosciRes 1990; 8: 221–254 1978; 4: 97–103 51Gerken GM, Saunders SS, PaulRE. Hypersensitivityto electrical 69Mø ller AR, Jannetta PJ. Onthe origin of synkinesis in hemifacial stimulationof auditory nuclei follows hearing loss in cats. Hear Res spasm:Results of intracranial recordings. J Neurosurg 1984; 61: 1984; 13: 249–260 569–576 52Szczepaniak WS, Mø ller AR. Effects of (– )-baclofen,clonazepam, 70Goddard GV. Amygdaloidstimulation and learning in the rat. anddiazepam on tone exposure-induced hyperexcitability of the JCompPhysiol Psychol 1964; 58: 23–30 inferiorcolliculus in the rat: Possible therapeutic implications for 71Morest DK, Ard MD, Yurgelun-Todd D. Degenerationin the central pharmacologicalmanagement of tinnitus and hyperacusis. Hear auditorypathways after acoustic deprivation or over-stimulation in Res 1996; 97: 46–53 the cat. Anat Rec 1979; 193: 750 53 Møller MB, Møller AR, Jannetta PJ, JhoHD. Vasculardecompres- 72Morest DK, Bohne BA. Noise-induced degeneration in the brain sionsurgery for severe tinnitus: Selection criteria and results. andrepresentation of innerand outer hair cells. Hear Res 1983; 9: Laryngoscope 1993; 103: 421–427 145–152 54Gerken GM, Solecki JM, BoettcherFA. Temporal integration of 73 WillottJF, Lu SM. Noise-inducedhearing loss can alter neural electricalstimulation of auditory nuclei in normal hearing and codingand increase excitability in the central nervous system. hearing-impairedcat. Hear Res 1991; 53: 101–112 Science 1981; 16: 1331–1332

572 NeurologicalResearch, 2001, Volume 2 3, September