神经病理学医学知识培训ppt课件

文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。神经病理学医学知识培训ppt课件1 1文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。SchizophreniaEmil Kraepelin“Dementia Praecox(1896)Emil Kraepelin“Dementia Praecox(1896)Blueler“Schizophrenia”Blueler“Schizophrenia”Onset:adolescence or young adulthoodOnset:adolescence or young adulthoodDSM-IV review:DSM-IV review:Positive symptoms(delusions,hallucinations,Positive symptoms(delusions,hallucinations,disorganized speech or behavior)disorganized speech or behavior)Negative symptoms(catatonia,affective flattening,Negative symptoms(catatonia,affective flattening,withdrawal,or avolition)withdrawal,or avolition)Social-occupational disturbanceSocial-occupational disturbance 6+months6+monthsSchizophreniaEmil Kraepelin“D2 2文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Associated FeaturesCognitive DisturbancesMemoryMemorySensory filteringSensory filteringAttentionAttentionEmotion recognitionEmotion recognitionEye-trackingEye-trackingInterpersonal DysfunctionAssociated FeaturesCognitive 3 3文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。SubtypesCatatonicParanoidDisorganizedUnlikely to be a related to a single physiopathologySubtypesCatatonic4 4文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。NeuropathologyNeurodevelopmental hypothesisNeurodegenerative hypothesisDopamine hypothessisGlutamatergic hypothesis*These are not exclusiveNeuropathologyNeurodevelopment5 5文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。What causes schizophrenia?l lHeritable Heritable(Shastry,2002)(Shastry,2002)l lEnvironmental factorsEnvironmental factors Epidemiological Epidemiological studiesstudiesl lBirth complicationsBirth complicationsl lMaternal stressMaternal stressl lSeasonality effectSeasonality effectl lViral epidemicsViral epidemicsl lLatitude effectLatitude effectl lRh incompatibilityRh incompatibilityWhat causes schizophrenia?Heri6 6文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。NeuropathologyStructural alterationsBehavioral symptoms indicative of brain damage(unusual rates of blinking,poor control of eye movements,unusual facial expressions)Enlarged ventricles(Weinberger&Wyatt,1982;(Weinberger&Wyatt,1982;Andreason)Andreason)NeuropathologyStructural alte7 7文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Ventricular enlargement in monozygotic twin with schizophreniaBarondes,1993Ventricular enlargement in mon8 8文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Hippocampal volume loss and enlarged ventriclesVan Heron et al.,2005Hippocampal volume loss and en9 9文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。NeuropathologyStructural alterations(cont)Alterations in numerous areas,including frontal Alterations in numerous 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 cerebellumWhite matter deficitsWhite matter deficitsEvidence of disorganized neurons and failures Evidence of disorganized neurons and failures of migrationof migration Altered density and disorganization of neurons found Altered density and disorganization of neurons found in the white matter below layer VI in the cortexin the white matter below layer VI in the cortex Disorganized pyramidal cells in the hippocampusDisorganized pyramidal cells in the hippocampusNeuropathologyStructural alte1010文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Altered development of hippocampal pyramidal neuronsAltered development of hippoca1111文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。神经病理学医学知识培训ppt课件1212文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Neurodevelopmental HypothesisHome movies from families with schizophrenic Home movies from families with schizophrenic child displayed abnormal behavior child displayed abnormal behavior(Walker et al,1994;(Walker et al,1994;1996)1996)Children who later become schizophrenic exhibit Children who later become schizophrenic exhibit poor social adjustment and school performancepoor social adjustment and school performanceDevelopmental delaysDevelopmental delaysPremorbid psychopathology(anxiety,Premorbid psychopathology(anxiety,depression,conduct disorders,ADHD)depression,conduct disorders,ADHD)(Kim-Cohen(Kim-Cohen et al,2003)et al,2003)Physical abnormalities Physical abnormalities(Schiffman,et al.2002)(Schiffman,et al.2002)Rates of concordance are higher in Rates of concordance are higher in monochorionic twins compared dichorionic twins monochorionic twins compared dichorionic twins(60%vs.11%)(60%vs.11%)(Davis,et al,1995)(Davis,et al,1995)Neurodevelopmental HypothesisH1313文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。But why are symptoms not observed until adolescence?Something must trigger the degenerative process at the period of adolescenceLoss and disorganization of neurons become unmasked with pruning and synaptic reorganizationBut why are symptoms not obser1414文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Rapid loss of brain volume during adolescence in schizophrenicsThompson et al,2001Rapid loss of brain volume dur1515文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Thompson et al,2001Thompson et al,20011616文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。神经病理学医学知识培训ppt课件1717文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Twin studyloss of dlPFC and temporal cortical tissueCannon et al 2002Twin studyloss of dlPFC and t1818文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。HypofrontalityReduced activation of the dorsolateral prefrontal cortex contributes to negative symptoms and cognitive deficitsFunctional imaging studies report reduced Functional imaging studies report reduced activationactivationEvidence of executive functioning deficitsEvidence of executive functioning deficitsHypofrontalityReduced activati1919文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Reduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first episode/drug nave schizophrenicsMacDonald et al.,2005Reduced activation of the dors2020文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。poorly innervatedtoxic or genetic insultdysfunctiondeathpoor neuronal migrationinadequate synapse selectionpoorly innervatedtoxic or gene2121文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Could altered development be related to glutamatergic dysfunction?-Underactivation of systems alters migration,synaptic organization and cell survival-Overactivation of systems can lead to altered synaptic connectivity and cell deathCould altered development be 2222文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。SPECTRUM OF EXCITATION BY GLUTAMATEExcess excitation-Mania-PanicExcitotoxicity-Damage to neuronsExcitotoxicity-Slow neuro-degenerationExcitotoxicity-Catastrophic neurodegenerationNormal excitationNeurodegenerative HypothesisSPECTRUM OF EXCITATION BY GLUT2323文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Could the psychotic symptoms themselves be producing additional excitotoxicity?Could the psychotic symptoms t2424Neurochemical AlterationsNeurochemical Alterations2525文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Dopamine HypothesisOriginal FormulationOveractivity of subcortical D2 receptors Overactivity of subcortical D2 receptors contributes to positive symptomscontributes to positive symptomsClassical antipsychotics were DA D2 antagonistsClassical antipsychotics were DA D2 antagonistsDA agonists induce psychotogenic effectsDA agonists induce psychotogenic effectsDopamine HypothesisOriginal Fo2626文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。hypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYShypothalamusdcNucleus accumben2727文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。mesolimbic pathwaymesolimbic pathway2828文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。mesolimbic overactivity=positive symptoms of psychosismesolimbic overactivity=posi2929文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。pure D2 blocker11-2Stahl S M,Essential Psychopharmacology(2000)pure D2 blocker11-2Stahl S M,3030文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Re-formulation of dopamine hypothesisImaging studies indicate loss of tissue in the frontal lobes as well as reduced activationDeficit in activation of D1 receptors in the prefrontal cortex contributes to negative symptoms and cognitive deficitsRe-formulation of dopamine hyp3131文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。meso-cortical pathwaymeso-cortical pathway3232文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Amphetamine-induced dopamine release is enhanced in schizophrenicsLaruelle et al 2003Amphetamine-induced dopamine r3333文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Amphetamine-induced dopamine release produces positive symptomsLaruelle et al,1996Amphetamine-induced dopamine r3434文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Increased dopamine release in medication-nave schizophrenic patientsHietala,et al.1995Increased dopamine release in 3535文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。D2 receptors?Mixed dataSome find no differencesOthers find moderate increases(Kestler et al.,2001)What about D3 and D4 receptors?D2 receptors?Mixed data3636文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。What about the mesocortical DA system?One postmortem study indicated a decrease in DA innervation of the dorsolateral prefrontal cortex(Akil,et al 1999)(Akil,et al 1999)Two 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)More recently,there is evidence of an upregulation of D1 receptors in the DLPFCWhat about the mesocortical DA3737文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Increased D1 receptor availability in schizophrenics suggests underactivationAbi-Dargham et al,J Neurosci,2002Increased D1 receptor availabi3838文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Increases in D1 receptor availability in the DLPFC are correlated with working memory deficitsAbi-Dargham et al,J Neurosci,2002Increases in D1 receptor avail3939文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Reduction in dendritic spines in dopaminergic neurons in the dorsolateral prefrontal cortexLewis et al,2003Reduction in dendritic spines 4040文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Glutamate HypothesisDeficiencies in glutamatergic neurotransmissionDysregulation of DA systems may be secondary to a deficit in the function of the glutamatergic NMDA receptorGlutamate HypothesisDeficienci4141文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Glutamate HypothesisNoncompetitve NMDA receptor antagonists(like PCP and ketamine)induce both positive and negative symptomsUnmedicated schizophrenic patients are more sensitive to the effects of NMDA receptor antagonistsAdjunctive treatment with NMDA agonists might provide a modest improvement in symptomsGlutamate HypothesisNoncompeti4242文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Evidence from human studiesAlterations in CSF glutamate levels,altered glutamate metabolism and altered NMDA receptor subunit gene expression(Keshavan,1999)(Keshavan,1999)Direct evidence is still lacking and a coherent picture has not yet emergedLack of adequate radioligands to visualize the GLU system in the living brain is a major impedimentEvidence from human studiesAlt4343文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Glutamate-Dopamine InteractionsLaruelle et al,2003Glutamate-Dopamine Interaction4444文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Chronic PCP treatment reduces dorsolateral prefrontal cortex dopamine and leads to negative symptomsHuman studiesAnimal studiesChronic PCP treatment reduces 4545文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Jentsch and Roth,1999Jentsch and Roth,19994646文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Chronic PCP leads to behavioral deficits consistent with dorsolateral prefrontal cortex dysfunctionJentsch et al,Science,1997Chronic PCP leads to behaviora4747文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Chronic PCP reduces cortical dopamineJentsch et al,Science,1997Chronic PCP reduces cortical d4848文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Effects are reversed with clozapine Jentsch et al,Science,1997Effects are reversed with cloz4949文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。NMDA receptor antagonism enhances amphetamine-induced subcortical DA releaseKegelles et al 2000NMDA receptor antagonism enhan5050文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Reduced prefrontal cortex activation in schizophrenicsMeyer et al.,2002Reduced prefrontal cortex acti5151文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Reduced dlPFC activation was negatively correlated with striatal dopamine releaseMeyer et al.,2002Reduced dlPFC activation was n5252文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Subcortical Dopamine-Glutamate InteractionsSubcortical Dopamine-Glutamate5353文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。GABA alterationsGlutamate or GABA?Glutamate or GABA?GABA alterationsGlutamate or G5454文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Put it all togetherNeurodevelopmental brain damage,leads to dysfunction in areas like the prefrontal cortex,which leads to increased DA in the mesolimbic areasPut it all togetherNeurodevelo5555文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。What about the temporal lobe damage?Hippocampus and amygdala control a gate that influences the effects of the prefrontal cortex on n.accumbens neuronal firingThis gate modulates reactions of the n.accumbens given the contextWhat about the temporal lobe d5656文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Hippocampus may modulate prefrontal activation of n.accumbensGrace,2000Hippocampus may modulate prefr5757文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Grace,2000Grace,20005858文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。How does exaggerations of mesolimbic DA activity lead to positive symptoms?Could altered dopamine in the nucleus accumbens alter the salience attributed to internal and external stimuli?Kapur readingHow does exaggerations of meso5959文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。神经病理学医学知识培训ppt课件6060文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。TreatmentsConventional neurolepticsChlorpromazineChlorpromazineHaloperidolHaloperidolLoxapineLoxapinePimozidePimozideThieoridazineThieoridazinethirothixenethirothixeneTreatmentsConventional neurole6161文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。pure D2 blockerpure D2 blocker6262文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Typical antipsychotics are D2 receptor antagonistsTypical antipsychotics are D2 6363文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。6464文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Blockade of receptors in the nigrostriatal dopamine pathway causes them to up-regulateThis up-regulation may lead to tardive dyskinesiaBlockade of receptors in the n6565文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Conventional antipsychotics have other sites of actionMuscarinic cholinergic blockadeSide effects of constipation and blurred visionSide effects of constipation and blurred visionReduce the likelihood of extrapyramidal Reduce the likelihood of extrapyramidal symptomssymptomsConventional antipsychotics ha6666文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Problems with conventional antipsychoticsBecause of side effects,many patients discontinue treatments,relapse,go back on treatment repeatedlyNeuroleptic malignant syndromeProblems with conventional ant6767文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Atypical antipsychotic drugsSerotonin-dopamine antagonistsClozapineClozapineRisperidoneRisperidoneOlanzapineOlanzapineQuetiapineQuetiapineZiprasidoneZiprasidoneAtypical antipsychotic drugsSe6868文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。5HT-DA InteractionsSubstantia nigraraphe nucleusbrakebrake5HT-DA InteractionsSubstantia 6969文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。serotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptorserotonin neurondopamine neuro7070文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。serotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptor11-19Stahl S M,Essential Psychopharmacology(2000)serotonin neurondopamine neuro7171文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。serotonin neurondopamine neuronSubstantia nigraRaphe5HT2A receptor11-20Stahl S M,Essential Psychopharmacology(2000)serotonin neurondopamine neuro7272文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。DA neuron5HT neuronpostsynaptic neurondopamineD2 receptor5HT2A receptorNigrostriatal pathwayDA neuron5HT neuronpostsynapti7373文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。serotoninNigrostriatal pathwayno dopamine release11-22Stahl S M,Essential Psychopharmacology(2000)serotoninNigrostriatal pathway7474文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。SDAD2 receptor11-23Stahl S M,Essential Psychopharmacology(2000)Nigrostriatal pathwaySDAD2 receptor11-23Stahl S M,7575文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。5HT2A receptorNigrostriatal pathway11-24Stahl S M,Essential Psychopharmacology(2000)5HT2A receptorNigrostriatal pa7676文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。conventional antipsychoticcaudate nucleusconventional antipsychoticcaud7777文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。serotonin-dopamine antagonistcaudate nucleusserotonin-dopamine antagonistc7878文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。mesocortical pathwayprimary dopamine deficiencysecondary dopamine deficiencydopamine releaseserotoninSDA11-27Stahl S M,Essential Psychopharmacology(2000)mesocortical pathwayprimary do7979文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。conventional antipsychoticCortex11-28Stahl S M,Essential Psychopharmacology(2000)conventional antipsychoticCort8080文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。serotonin-dopamine antagonistCortex11-29Stahl S M,Essential Psychopharmacology(2000)serotonin-dopamine antagonistC8181文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Fortunately,the serotonin 2A antagonists do not block dopamine antagonism in the mesolimbic systemThis suggests that combination drugs may enhance DA activity in the prefrontal cortex while reducing DA activity in the mesolimbic systemFortunately,the serotonin 2A 8282文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。What about glutamate agonists?What about glutamate agonists?8383文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。神经病理学医学知识培训ppt课件8484文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Heresco-Levy,et al.2004Heresco-Levy,et al.20048585文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Heresco-Levy et al.,2002Heresco-Levy et al.,20028686文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。SummarySchizophrenia is characterized by damage to Schizophrenia is characterized by damage to brain areas,including the frontal cortices brain areas,including the frontal cortices(particularly the DLPFC),temporal lobes,(particularly the DLPFC),temporal lobes,parietal cortexparietal cortexGlutamate dysfunction may lead to Glutamate dysfunction may lead to developmental disorganization and cell lossdevelopmental disorganization and cell lossDA dysfunction and/or glutamate dysregulation DA dysfunction and/or glutamate dysregulation in the prefrontal cortex and limbic system may in the prefrontal cortex and limbic system may contribute to symptoms of schizophrenia contribute to symptoms of schizophrenia SummarySchizophrenia is charac8787文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Future directionsNeuroprotectionFuture directionsNeuroprotecti8888