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1、神经病理学第1页，共89页，编辑于2022年，星期二第2页，共89页，编辑于2022年，星期二Schizophrenial lEmil Kraepelin“Dementia Praecox(1896)Emil Kraepelin“Dementia Praecox(1896)l lBlueler“Schizophrenia”Blueler“Schizophrenia”l lOnset:adolescence or young adulthoodOnset:adolescence or young adulthoodl lDSM-IV review:DSM-IV review:Positive s
2、ymptoms(delusions,hallucinations,disorganized Positive symptoms(delusions,hallucinations,disorganized speech or behavior)speech or behavior)Negative symptoms(catatonia,affective flattening,withdrawal,Negative symptoms(catatonia,affective flattening,withdrawal,or avolition)or avolition)Social-occupat
3、ional disturbanceSocial-occupational disturbance 6+months6+months第3页，共89页，编辑于2022年，星期二Associated FeatureslCognitive DisturbancesMemorySensory filteringAttentionEmotion recognitionEye-trackinglInterpersonal Dysfunction第4页，共89页，编辑于2022年，星期二SubtypeslCatatoniclParanoidlDisorganizedlUnlikely to be a rela
4、ted to a single physiopathology第5页，共89页，编辑于2022年，星期二NeuropathologylNeurodevelopmental hypothesislNeurodegenerative hypothesislDopamine hypothessislGlutamatergic hypothesis*These are not exclusive第6页，共89页，编辑于2022年，星期二What causes schizophrenia?l lHeritable Heritable(Shastry,2002)(Shastry,2002)l lEnvir
5、onmental factorsEnvironmental factors Epidemiological studiesEpidemiological studiesl lBirth complicationsBirth complicationsl lMaternal stressMaternal stressl lSeasonality effectSeasonality effectl lViral epidemicsViral epidemicsl lLatitude effectLatitude effectl lRh incompatibilityRh incompatibili
6、ty第7页，共89页，编辑于2022年，星期二NeuropathologyStructural alterationslBehavioral symptoms indicative of brain damage(unusual rates of blinking,poor control of eye movements,unusual facial expressions)lEnlarged ventricles(Weinberger&Wyatt,1982;Andreason)(Weinberger&Wyatt,1982;Andreason)第8页，共89页，编辑于2022年，星期二Ven
7、tricular enlargement in monozygotic twin with schizophreniaBarondes,1993第9页，共89页，编辑于2022年，星期二Hippocampal volume loss and enlarged ventriclesVan Heron et al.,2005第10页，共89页，编辑于2022年，星期二NeuropathologyStructural alterations(cont)l lAlterations in numerous areas,including frontal Alterations in numerous
8、areas,including frontal lobes,medial temporal lobes,lateral temporal lobes,medial temporal lobes,lateral temporal lobes,parietal lobe,basal ganglia,corpus lobes,parietal lobe,basal ganglia,corpus callosum,thalamus and even the cerebellumcallosum,thalamus and even the cerebelluml lWhite matter defici
9、tsWhite matter deficitsl lEvidence of disorganized neurons and failures of Evidence of disorganized neurons and failures of migrationmigration Altered density and disorganization of neurons found in the Altered density and disorganization of neurons found in the white matter below layer VI in the co
10、rtexwhite matter below layer VI in the cortex Disorganized pyramidal cells in the hippocampusDisorganized pyramidal cells in the hippocampus第11页，共89页，编辑于2022年，星期二Altered development of hippocampal pyramidal neurons第12页，共89页，编辑于2022年，星期二第13页，共89页，编辑于2022年，星期二Neurodevelopmental Hypothesisl lHome movie
11、s from families with schizophrenic child Home movies from families with schizophrenic child displayed abnormal behavior displayed abnormal behavior(Walker et al,1994;1996)(Walker et al,1994;1996)l lChildren who later become schizophrenic exhibit Children who later become schizophrenic exhibit poor s
12、ocial adjustment and school performancepoor social adjustment and school performancel lDevelopmental delaysDevelopmental delaysl lPremorbid psychopathology(anxiety,depression,Premorbid psychopathology(anxiety,depression,conduct disorders,ADHD)conduct disorders,ADHD)(Kim-Cohen et al,2003)(Kim-Cohen e
13、t al,2003)l lPhysical abnormalities Physical abnormalities(Schiffman,et al.2002)(Schiffman,et al.2002)l lRates of concordance are higher in monochorionic Rates of concordance are higher in monochorionic twins compared dichorionic twins(60%vs.11%)twins compared dichorionic twins(60%vs.11%)(Davis,et a
14、l,1995)(Davis,et al,1995)第14页，共89页，编辑于2022年，星期二But why are symptoms not observed until adolescence?lSomething must trigger the degenerative process at the period of adolescencelLoss and disorganization of neurons become unmasked with pruning and synaptic reorganization第15页，共89页，编辑于2022年，星期二Rapid los
15、s of brain volume during adolescence in schizophrenicsThompson et al,2001第16页，共89页，编辑于2022年，星期二Thompson et al,2001第17页，共89页，编辑于2022年，星期二第18页，共89页，编辑于2022年，星期二Twin studyloss of dlPFC and temporal cortical tissueCannon et al 2002第19页，共89页，编辑于2022年，星期二HypofrontalitylReduced activation of the dorsolater
16、al prefrontal cortex contributes to negative symptoms and cognitive deficitsFunctional imaging studies report reduced activationEvidence of executive functioning deficits第20页，共89页，编辑于2022年，星期二Reduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first
17、 episode/drug nave schizophrenicsMacDonald et al.,2005第21页，共89页，编辑于2022年，星期二poorly innervatedtoxic or genetic insultdysfunctiondeathpoor neuronal migrationinadequate synapse selection第22页，共89页，编辑于2022年，星期二Could altered development be related to glutamatergic dysfunction?-Underactivation of systems a
18、lters migration,synaptic organization and cell survival-Overactivation of systems can lead to altered synaptic connectivity and cell death第23页，共89页，编辑于2022年，星期二SPECTRUM OF EXCITATION BY GLUTAMATEExcess excitation-Mania-PanicExcitotoxicity-Damage to neuronsExcitotoxicity-Slow neuro-degenerationExcito
19、toxicity-Catastrophic neurodegenerationNormal excitationNeurodegenerative Hypothesis第24页，共89页，编辑于2022年，星期二Could the psychotic symptoms themselves be producing additional excitotoxicity?第25页，共89页，编辑于2022年，星期二Neurochemical Alterations第26页，共89页，编辑于2022年，星期二Dopamine HypothesislOriginal FormulationOverac
20、tivity of subcortical D2 receptors contributes to positive symptomsl lClassical antipsychotics were DA D2 antagonistsClassical antipsychotics were DA D2 antagonistsl lDA agonists induce psychotogenic effectsDA agonists induce psychotogenic effects第27页，共89页，编辑于2022年，星期二hypothalamusdcNucleus accumbens
21、TegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS第28页，共89页，编辑于2022年，星期二mesolimbic pathway第29页，共89页，编辑于2022年，星期二mesolimbic overactivity=positive symptoms of psychosis第30页，共89页，编辑于2022年，星期二pure D2 blocker11-2Stahl S M,Essential Psychopharmacology(2000)第31页，共89页，编辑于2022年，星期二Re-formulation of do
22、pamine hypothesislImaging studies indicate loss of tissue in the frontal lobes as well as reduced activationlDeficit in activation of D1 receptors in the prefrontal cortex contributes to negative symptoms and cognitive deficits第32页，共89页，编辑于2022年，星期二meso-cortical pathway第33页，共89页，编辑于2022年，星期二Amphetam
23、ine-induced dopamine release is enhanced in schizophrenicsLaruelle et al 2003第34页，共89页，编辑于2022年，星期二Amphetamine-induced dopamine release produces positive symptomsLaruelle et al,1996第35页，共89页，编辑于2022年，星期二Increased dopamine release in medication-nave schizophrenic patientsHietala,et al.1995第36页，共89页，编
24、辑于2022年，星期二D2 receptors?lMixed datalSome find no differenceslOthers find moderate increases(Kestler et al.,2001)lWhat about D3 and D4 receptors?第37页，共89页，编辑于2022年，星期二What about the mesocortical DA system?lOne postmortem study indicated a decrease in DA innervation of the dorsolateral prefrontal cort
25、ex(Akil,et al 1999)(Akil,et al 1999)lTwo PET studies had mixed findings,but the ligands used for D1 receptors were not selective(Okubo et al 1997;Karlsson et al 2002)(Okubo et al 1997;Karlsson et al 2002)lMore recently,there is evidence of an upregulation of D1 receptors in the DLPFC第38页，共89页，编辑于202
26、2年，星期二Increased D1 receptor availability in schizophrenics suggests underactivationAbi-Dargham et al,J Neurosci,2002第39页，共89页，编辑于2022年，星期二Increases in D1 receptor availability in the DLPFC are correlated with working memory deficitsAbi-Dargham et al,J Neurosci,2002第40页，共89页，编辑于2022年，星期二Reduction in
27、dendritic spines in dopaminergic neurons in the dorsolateral prefrontal cortexLewis et al,2003第41页，共89页，编辑于2022年，星期二Glutamate HypothesislDeficiencies in glutamatergic neurotransmissionlDysregulation of DA systems may be secondary to a deficit in the function of the glutamatergic NMDA receptor第42页，共8
28、9页，编辑于2022年，星期二Glutamate HypothesislNoncompetitve NMDA receptor antagonists(like PCP and ketamine)induce both positive and negative symptomslUnmedicated schizophrenic patients are more sensitive to the effects of NMDA receptor antagonistslAdjunctive treatment with NMDA agonists might provide a modes
29、t improvement in symptoms第43页，共89页，编辑于2022年，星期二Evidence from human studieslAlterations in CSF glutamate levels,altered glutamate metabolism and altered NMDA receptor subunit gene expression(Keshavan,1999)(Keshavan,1999)lDirect evidence is still lacking and a coherent picture has not yet emergedlLack
30、 of adequate radioligands to visualize the GLU system in the living brain is a major impediment第44页，共89页，编辑于2022年，星期二Glutamate-Dopamine InteractionsLaruelle et al,2003第45页，共89页，编辑于2022年，星期二Chronic PCP treatment reduces dorsolateral prefrontal cortex dopamine and leads to negative symptomslHuman stud
31、ieslAnimal studies第46页，共89页，编辑于2022年，星期二Jentsch and Roth,1999第47页，共89页，编辑于2022年，星期二Chronic PCP leads to behavioral deficits consistent with dorsolateral prefrontal cortex dysfunctionJentsch et al,Science,1997第48页，共89页，编辑于2022年，星期二Chronic PCP reduces cortical dopamineJentsch et al,Science,1997第49页，共8
32、9页，编辑于2022年，星期二Effects are reversed with clozapine Jentsch et al,Science,1997第50页，共89页，编辑于2022年，星期二NMDA receptor antagonism enhances amphetamine-induced subcortical DA releaseKegelles et al 2000第51页，共89页，编辑于2022年，星期二Reduced prefrontal cortex activation in schizophrenicsMeyer et al.,2002第52页，共89页，编辑于
33、2022年，星期二Reduced dlPFC activation was negatively correlated with striatal dopamine releaseMeyer et al.,2002第53页，共89页，编辑于2022年，星期二Subcortical Dopamine-Glutamate Interactions第54页，共89页，编辑于2022年，星期二GABA alterationsGlutamate or GABA?第55页，共89页，编辑于2022年，星期二Put it all togetherlNeurodevelopmental brain damag
34、e,leads to dysfunction in areas like the prefrontal cortex,which leads to increased DA in the mesolimbic areas第56页，共89页，编辑于2022年，星期二What about the temporal lobe damage?lHippocampus and amygdala control a gate that influences the effects of the prefrontal cortex on n.accumbens neuronal firinglThis ga
35、te modulates reactions of the n.accumbens given the context第57页，共89页，编辑于2022年，星期二Hippocampus may modulate prefrontal activation of n.accumbensGrace,2000第58页，共89页，编辑于2022年，星期二Grace,2000第59页，共89页，编辑于2022年，星期二How does exaggerations of mesolimbic DA activity lead to positive symptoms?Could altered dopam
36、ine in the nucleus accumbens alter the salience attributed to internal and external stimuli?Kapur reading第60页，共89页，编辑于2022年，星期二第61页，共89页，编辑于2022年，星期二TreatmentslConventional neurolepticsChlorpromazineHaloperidolLoxapinePimozideThieoridazinethirothixene第62页，共89页，编辑于2022年，星期二pure D2 blocker第63页，共89页，编辑
37、于2022年，星期二Typical antipsychotics are D2 receptor antagonists第64页，共89页，编辑于2022年，星期二 第65页，共89页，编辑于2022年，星期二Blockade of receptors in the nigrostriatal dopamine pathway causes them to up-regulateThis up-regulation may lead to tardive dyskinesia第66页，共89页，编辑于2022年，星期二Conventional antipsychotics have other
38、 sites of actionlMuscarinic cholinergic blockadeSide effects of constipation and blurred visionReduce the likelihood of extrapyramidal symptoms第67页，共89页，编辑于2022年，星期二Problems with conventional antipsychoticslBecause of side effects,many patients discontinue treatments,relapse,go back on treatment rep
39、eatedlylNeuroleptic malignant syndrome第68页，共89页，编辑于2022年，星期二Atypical antipsychotic drugslSerotonin-dopamine antagonistsClozapineRisperidoneOlanzapineQuetiapineZiprasidone第69页，共89页，编辑于2022年，星期二5HT-DA InteractionsSubstantia nigraraphe nucleusbrakebrake第70页，共89页，编辑于2022年，星期二serotonin neurondopamine neu
40、ronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptor第71页，共89页，编辑于2022年，星期二serotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptor11-19Stahl S M,Essential Psychopharmacology(2000)第72页，共89页，编辑于2022年，星期二serotonin neurondopamine neuronSubstantia
41、 nigraRaphe5HT2A receptor11-20Stahl S M,Essential Psychopharmacology(2000)第73页，共89页，编辑于2022年，星期二DA neuron5HT neuronpostsynaptic neurondopamineD2 receptor5HT2A receptorNigrostriatal pathway第74页，共89页，编辑于2022年，星期二serotoninNigrostriatal pathwayno dopamine release11-22Stahl S M,Essential Psychopharmacolo
42、gy(2000)第75页，共89页，编辑于2022年，星期二SDAD2 receptor11-23Stahl S M,Essential Psychopharmacology(2000)Nigrostriatal pathway第76页，共89页，编辑于2022年，星期二5HT2A receptorNigrostriatal pathway11-24Stahl S M,Essential Psychopharmacology(2000)第77页，共89页，编辑于2022年，星期二conventional antipsychoticcaudate nucleus第78页，共89页，编辑于2022
43、年，星期二serotonin-dopamine antagonistcaudate nucleus第79页，共89页，编辑于2022年，星期二mesocortical pathwayprimary dopamine deficiencysecondary dopamine deficiencydopamine releaseserotoninSDA11-27Stahl S M,Essential Psychopharmacology(2000)第80页，共89页，编辑于2022年，星期二conventional antipsychoticCortex11-28Stahl S M,Essenti
44、al Psychopharmacology(2000)第81页，共89页，编辑于2022年，星期二serotonin-dopamine antagonistCortex11-29Stahl S M,Essential Psychopharmacology(2000)第82页，共89页，编辑于2022年，星期二lFortunately,the serotonin 2A antagonists do not block dopamine antagonism in the mesolimbic systemlThis suggests that combination drugs may enha
45、nce DA activity in the prefrontal cortex while reducing DA activity in the mesolimbic system第83页，共89页，编辑于2022年，星期二What about glutamate agonists?第84页，共89页，编辑于2022年，星期二第85页，共89页，编辑于2022年，星期二Heresco-Levy,et al.2004第86页，共89页，编辑于2022年，星期二Heresco-Levy et al.,2002第87页，共89页，编辑于2022年，星期二Summaryl lSchizophren
46、ia is characterized by damage to brain Schizophrenia is characterized by damage to brain areas,including the frontal cortices(particularly areas,including the frontal cortices(particularly the DLPFC),temporal lobes,parietal cortexthe DLPFC),temporal lobes,parietal cortexl lGlutamate dysfunction may
47、lead to developmental Glutamate dysfunction may lead to developmental disorganization and cell lossdisorganization and cell lossl lDA dysfunction and/or glutamate dysregulation in the DA dysfunction and/or glutamate dysregulation in the prefrontal cortex and limbic system may contribute to prefrontal cortex and limbic system may contribute to symptoms of schizophrenia symptoms of schizophrenia 第88页，共89页，编辑于2022年，星期二Future directionslNeuroprotection第89页，共89页，编辑于2022年，星期二