1. Neuromodula1on* 2. The*role*of*neuromodulators*in*mood,*stress,*depression*and* anxiety*
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1 SerotoninergicSystem Contribu1onto DepressionandAnxiety Transla1onalNeuromodelingand Computa1onalNeuroeconomicsSeminar FallSemester2013 CarolineJahn
2 Neuromodula1on Mood&neuromodulators Cogni1vemodel Biologicalmodel 1. Neuromodula1on 2. Theroleofneuromodulatorsinmood,stress,depressionand anxiety 3. Acogni1veneuropsychologicalmodelofADdrugac1on 4. AbiologicalmodelofSSRIsac1on Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
3 Neuromodula1on Introduc1on Theory Mood&neuromodulators Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Neurotransmission/Neuromodula1on Neurotransmission=chemicalcommunica1onbetweenneuronsatsynapses Classic Retrograde VolumeTransmission Neuromodulators: Serotonin Acetylcholine Dopamine Noradrenaline LongTlas1ngeffects Targetsofpsychoac1vedrugs Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
4 Neuromodula1on Introduc1on Theory Mood&neuromodulators Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Neuromodulatorsandbehaviors/cogni1vefunc1ons Dopaminergic,system:reward,learning,goalTorientedbehavior,mo1va1on Noradrenergic,system:alertness,arousal,aXen1on Serotoninergic,system:foodintake,reproduc1veac1vity,emo1on The5THTsystemoriginatesfromasmallamount ofneurons(roughly300000)intheraphenuclei andinnervatesawiderangeofregionsofthe brainandspinalcord. ESDenerisandSCWyler,Nature'Neurosciences'(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
5 Neuromodula1on Introduc1on Theory Mood&neuromodulators Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Howistheac1onofserotoninmodulated? Synthesis,and,recycling:availabilityofserotonin saminoacidprecursor tryptophanfromplasma,enzymes(tryptophanhydroxylase,aroma1camino aciddecarboxylase)andcofactors Reuptake:SertoninTransporterSERT(targetofSSRIs) Metabolism:Monoamineoxydase(targetofMAOIs) Autoreceptors:5THT1aand5THT1b Receptors:5THT1T7 Tryptophan (TRP) 5-HT1a Tph2 TRP 5-HTP Regeneration BH 4 pathway BH 4 C Spr Qdpr Pcbd qbh 2 Gfrp PTP Ptps Gch1 H 2 NTP GTP De novo synthesis of BH 4 Aadc Vmat2 5-HT Mao, Aldh 5-HIAL 5-HT1b Sert 5-HT 1a 1b 1d 1e 1f 5-HT 2a 2b 2c 5-HT3 5-HT HIAA ESDenerisandSCWyler,Nature'Neurosciences'(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
6 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Serotoninanddepression(1/4) 1997:deficient'func0on'of'brain'serotonin'pathways'is'implicated'in' depression'because'drugs'that'selec0vely'increase'brain'serotonin'ac0vity'are' effec0ve'ads.'however,'there'is'no'direct'evidence'that'lowered'serotonin' func0on'causes'major'depression.'' ' Study:15womenwhohadsufferedrecurrentepisodesofmajordepression buthadrecoveredandwerenolongerondrugtreatmentreceivedtwo aminoacidmixtures: onewasnutri1onallybalancedandcontainedtryptophan theotherwasiden1calexceptitcontainednotryptophan. Bloodsampleswerealsotakenatbaselineand7hformeasurementofplasma tryptophan.thetryptophantfreemixtureproduceda75%reduc1oninplasma tryptophanconcentra1on. KASmith,CGFairburnandPJCowen,The'Lancet(1997) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
7 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Serotoninanddepression(2/4) Modified HAM-D score Trytophan-free mixture Nutritionally balanced mixture Time (h) Figure 1: Individual scores on modified HAM-D scale before and 7 h after tryptophan-free or nutritionally balanced aminoacid mixture Patients who also had had bulimia nervosa. Line represents two Par1cipantswerescoredonthe Hamiltonra1ngscalefordepression (HAMTD)beforeand7haierdrinking eachmixture. ThemeandifferenceintotalHAMTD scores(7hminusbaseline)were significantlyhigheraierthetryptophant freemixturethanaierthenutri1onally balancedmixture. Nochangesinmoodwereseenaier takingthenutri1onallybalanced mixture. KASmith,CGFairburnandPJCowen,The'Lancet(1997) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
8 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Serotoninanddepression(3/4) Visual analogue scale rating of sad mood (mm) Tryptophan-free mixture Nutritionally balanced mixture Time (h) Figure 2: Mean (SE) scores on a 100 mm visual analogue scale of sad mood represented as change from baseline of participants who had tryptophan-free or nutritionally balanced aminoacid mixture Par1cipantsratethemselveseachhouron three100mmvisualanaloguescalesofmood (happy,sad,andanxious)toprovidea subjec1vemeasureofmoodchangeover 1me. Themeanareaunderthecurvera1ngof happy(resp.anxious)moodwassignificantly lower(resp.higher)aierthetryptophantfree thanaierthenutri1onallybalancedmixture. KASmith,CGFairburnandPJCowen,The'Lancet(1997) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
9 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Serotoninanddepression(4/4) Interpreta1on:rapidloweringofbrainserotoninfunc1oncanprecipitate clinicaldepressivesymptomsinwell,untreatedindividualswhoare vulnerable,to,mdd.thefindingssupportakeyrolefordeficientserotonin func1onindepression. KASmith,CGFairburnandPJCowen,The'Lancet(1997) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
10 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Rela1onbetweenmoodandmonoamineslevels(1/3) 2007:MDD'is'characterized'by'a'lowered'mood'and'oEen'treated'with'ADs,' mostly'monoamines'reuptake'inhibitors.' MDD'might'par0ally'be'explained'by'a'deficiency'in'monoamine.' ' BUTdeple1onstudiesfoundconflic1ngresultsinheterogeneouspopula1ons: healthycontrols,pa1entswithpreviousmddinremissionandpa1entssuffering frommdd. HGRuhe,NSMasonandAHSchene,Molecular'Psychiatry'(2007) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
11 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Rela1onbetweenmoodandmonoamineslevels(2/3) Study:metaTanalysisofmonoaminesdeple1onstudies,thatcanbeachieveby: loweringofessen1alaminoacidslevel blockingmonoaminesynthesiswithenzymetblocking. Findings: Nodecreaseofmoodinhealthycontrols MoodisslightlydecreasedinhealthycontrolswithafamilyhistoryofMDD DecreaseofmoodandrelapseintoadepressedstateinremiXedMDD pa1entswhousead InremiXedpa1entswithoutADrelapsesarelessprominent. Thesiteofac1onoftheseADs(5THTorNA/DA)predictstheoccurrenceofa loweringofmoodorashortrelapseinmddaierdeple1onofthe correspondingmonoamine. HGRuhe,NSMasonandAHSchene,Molecular'Psychiatry'(2007) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
12 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Rela1onbetweenmoodandmonoamineslevels(3/3) Conclusion:thereisnosimpledirectcorrela1onof5THTorNElevelsinthebrain andmood.thedeple1onof5thtandne/damostclearlydecreasesmoodin vulnerablepa1entswhoareinremissionfromtheirmdd,whiles1llusingad(if thetargetofthedeple1on(5tht,ne)coincideswiththeworkingmechanismof theadused). HGRuhe,NSMasonandAHSchene,Molecular'Psychiatry'(2007) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
13 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion DNA,SERTandvulnerability(1/3) 2011:The'serotoninergic'system'is'implicated'in'the'pathology'of'MDD.'But' how?'a'polymorphism'in'the'promoter'region'of'the'sert'gene'(5phttlpr)'has' been'found'to'affect'the'transcrip0on'rate'of'the'gene,'with'the'short'(s)'allele' transcrip0onally'less'efficient'than'the'alternate'long'(l)'allele.'' Exon I 12 Chromosome 17 SLC6A4 II III VII XII XIV Promoter Variants of regulation S AAA L 5-HTTLPR mrna AAA AAA AAA MAOA Storage vesicle Serotonin transporter Serotonin KKarget'al.,Arch'Gen'Psychiatry'(2011) Serotonin receptor ESDenerisandSCWyler,Nature'Neurosciences'(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
14 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion DNA,SERTandvulnerability(2/3) Study:MetaTanalysisofstudiesontherela1onbetween5THTTLPRandstress anddepression. Findings: strongevidencethat5thttlprmoderatestherela1onshipbetweenstress anddepression,withthes'alleleassociatedwithanincreasedriskof developingdepressionunderstress strongevidenceforanassocia1onbetweenthes'alleleandincreased stresssensi1vityinthechildhoodmaltreatmentgroup. KKarget'al.,Arch'Gen'Psychiatry'(2011) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
15 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion DNA,SERTandvulnerability(3/3) Linkbetween5THTTLPR(s)andserotonin: Inrhesusmacaques,whoselengthvaria1onofthe5THTTLPRisanalogousto thatofhumans,theallele(s)isassociatedwithdecreasedserotonergic func1on[lowercerebrotspinalfluid(csf)5thydroxyindoleace1cacid concentra1ons]amongmonkeysrearedinstressfulcondi1onsbutnotamong normallyrearedmonkeys. The5THTTgenemaynotbedirectlyassociatedwithdepression,itcould moderatetheserotonergicresponsetostress. JournalClub KKarget'al.,Arch'Gen'Psychiatry'(2011) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
16 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Mood,depressionandADs(1/3) 2009:'primary'psychological'ac0on'of'ADs'is'to'elevate'mood'and'that' improvement'in'the'various'symptom'domains'i'sa'secondary'consequence'of' this'effect,'but'ads'do'not'reliably'elevate'mood'in'nonpdepressed'people'and' the'psychos0mulant'drugs'that'can'produce'mood'eleva0on'do'not'appear'to' be'clinically'useful'an0pdepressants.'' Hypothesis:ataneuropsychologicallevel,ADsworkbyremedia1ngnega1ve affec1vebiasesindepressionandanxiety CJHarmer,GMGoodwinandPJCowen,The'Bri0sh'Journal'of'Psychiatry'(2009) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
17 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Mood,depressionandADs(2/3) (a) (b) Increased Delay Downstream Improved Change in 5-HT neuroadaptive mood emotional effects bias Increased Delay Downstream 5-HT 7 neuroadaptive effects 6 7 Change in emotional Delay 7 bias Improved mood (a)acceptedview,(b)proposedview ADadministra1ondonotdirectly enhancemood,butmayprovidea plaqormforsubsequentcogni1veand psychologicalreconsolida1on.thisview isconsistentwithcogni1vetheoriesof depressionwhichemphasisetheroleof nega1vebiasesininforma1on processingintheae1ologyand maintenanceofdepressionandthe importanceofcorrec1ngsuchbiasesin successfultreatmentofthisdisorder. CJHarmer,GMGoodwinandPJCowen,The'Bri0sh'Journal'of'Psychiatry'(2009) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
18 Neuromodula1on Introduc1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Mood,depressionandADs(3/3) Aweek streatmentwithssriandsnriinhealthyvolunteers: decreasedtherecogni1onoffearfulfacialexpressions,andaxenuatedthe amygdalaresponsetomaskedfearfulfaces,whichmayreduceaberrant hypervigilancetonega1veaffec1ves1muliindepressionandanxiety increasedthenumberofposi1vewordsrecalledinaselftdescriptor memorytask. TreatmentwithSSRI: increasedtherecogni1onofhappyfacialexpressionsandtheac1vityofthe fusiformgyrustopresenta1onofhappyfaces,whichmayreflectincreased axen1onalprocessingofposi1veandaffilia1vecues. TheseeffectsofADsseeninhealthyvolunteersareoppositetotheneural biasesreportedindepression. CJHarmer,GMGoodwinandPJCowen,The'Bri0sh'Journal'of'Psychiatry'(2009) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
19 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion SERTfunc1onintheRN/SERTavailabilityinprojec1onareas BlockageofrapheSERTsraiseslocalextracellular5THTlevelsandreduces firingratesviaincreased5tht1atmediatedautotinhibi1on.thisinturn reducestheextracellular5thtlevelsatnerveterminalsinprojec1onareas. BlockageofSERTsinprojec1onareasincreasestheextracellular5THTin theseregions. Tryptophan (TRP) 5-HT1a Tph2 TRP 5-HTP Regeneration BH 4 pathway BH 4 C Spr Qdpr Pcbd qbh 2 Gfrp PTP Ptps Gch1 H 2 NTP GTP De novo synthesis of BH 4 Aadc Vmat2 5-HT Mao, Aldh 5-HIAL 5-HT1b Sert 5-HT 1a 1b 1d 1e 1f 5-HT 2a 2b 2c 5-HT3 5-HT HIAA JBest,HFNijhoutandMReed,Pharmacopsychiatry'(2011) ESDenerisandSCWyler,Nature'Neurosciences'(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
20 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion BurstsandtheefficacyofSSRIs,amathema1calmodel(1/4) 2011:'5PHT'neurons'in'the'DRN'and'MRN'have'2'func0ons:' by'rhythmic'tonic'firing'they'maintain'(or'change'if'they'change'their' frequency)'the'5pht'tone'in'target'0ssues'by'volume'transmission.'' by'burst'firing'they'convey'specific'informa0on'to'oneponpone'synapses'that' are'known'to'exist.'these'drn'and'mrn'bursts'are'very'short,'a'longer'signal' would'raise'e5pht'in'the'drn'and'mrn'and'dampen'the'response'via'the' autopreceptors.'' b 50 V (mv) Time (seconds) 8 10 JBest,HFNijhoutandMReed,Pharmacopsychiatry'(2011) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
21 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion BurstsandtheefficacyofSSRIs,amathema1calmodel(2/4) Hypothesis:SSRIsreducetherateoffiringofDRNorMRNcellswithoutreducing theamplitudeofindividualspikesorbursts. Study:mathema1calmodelforserotoninsynthesis,release,andreuptakein terminalstoillustratetheresponsesinterminalregionstoburstsinanormal individualandinanindividualwithlowvesicularserotonin. a 50 V (mv) 0 50 b 50 V (mv) Time (seconds) 8 10 JBest,HFNijhoutandMReed,Pharmacopsychiatry'(2011) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
22 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion BurstsandtheefficacyofSSRIs,amathema1calmodel(3/4) normal a b extracellular [ 5HT ] c time window area action potentials normal normal average [ 5HT ] = nm a b extracellular [ 5HT ] c time window area action potentials low vesicular 5HT acute SSRI low vesicular 5HT acute SSRI average [ 5HT ] = nm acute Hypothesis: depressed pa1entshavelowlevelsof 1ssue5HT. Table 1 Steady states values and parameters for simulations. Status s. s. v5ht s. s. e5ht TPH tonic rate SERTs d extracellular [ 5HT ] low vesicular 5HT d extracellular [ 5HT ] low vesicular 5HT chronic SSRI normal 21.5 M nm 100 % 100 % 100 % depressed 4.57 M nm 5 % 100 % 100 % SSRI acute 4.68 M nm 5 % 33 % 33 % SSRI chronic 3.26 M nm 5 % 33 % 10 % low e time window area low vesicular 5HT 0 2 average [ 5HT ] = nm 4 6 Time (seconds) 8 10 e time window area low vesicular 5HT chronic SSRI average [ 5HT ] = nm Time (seconds) 8 10 chronic Responsetospikesandbursts fornormalandlowvesicular 5THT Responsetospikesandburstsofthe lowvesicular5thtpa1entsaieracute andchronictreatmentswithssris JBest,HFNijhoutandMReed, Pharmacopsychiatry'(2011) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
23 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion BurstsandtheefficacyofSSRIs,amathema1calmodel(4/4) Interpreta1on:ChronicdosesofSSRIscanbringtheresponseinterminalregions todrnormrnburstsbacktonormalandreducetherateoftonicfiringof5tht neuronsforindividualswithlowvesicular5ht. Loweredtonicfiringof5THTneuronsresultinadownTregula1onofSERTsin terminalregionsbecausethetonicfiringrateof5thtneuronsdeterminessert densityinprojec1onareas. JBest,HFNijhoutandMReed,Pharmacopsychiatry'(2011) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
24 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Predic1onofSSRItreatmentresponseinMDpa1ents(1/4) 2012:'the'interplay'between'SERT'availability'in'the'raphe'nuclei'and'SERT' availability'in'serotonergic'projec0on'areas'may'be'an'important'indicator'of' serotonergic'transmission.'' Hypothesis:loweredrapheSERTbindingincomparisontoterminalSERT bindingaierprolongedssriadministra1onwouldleadtotheeffectofssris. predictoroftreatmentresponse RLanzenbergeret'al.,NeuroImage(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
25 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Predic1onofSSRItreatmentresponseinMDpa1ents(2/4) Study:transporteravailabilitywasmeasuredbeforeandaierasingleoral dose,andaier3weeksofcon1nuousoralssritreatmentinsubjects sufferingfrommddbypet. SV:screeningvisit PET1:beforetreatment PET2:6haierfirstdrugintake PET3:3weeksaierfirstdrugintake Responders=50%orgreaterreduc1onrela1vetoini1al scores NonTresponders=below50%reduc1on RemiXers=responderswithafinalHAMTDscore<7 RLanzenbergeret'al.,NeuroImage(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
26 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Predic1onofSSRItreatmentresponseinMDpa1ents(3/4) Significantassocia1onsbetween pretreatmentsertbindingra1osin amygdalaandhabenulaand treatmentresponse Brainareasshowingsignificantdifferencesbetween respondersandnontresponders(upperrow)and betweenandnontresponders(boxomrow)forsert bindingra1os RLanzenbergeret'al.,NeuroImage(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
27 Introduc1on Neuromodula1on Mood&neuromodulators Theory Experiment Cogni1vemodel Applica1on Biologicalmodel Conclusion Predic1onofSSRItreatmentresponseinMDpa1ents(4/4) BothremiXersandrespondersshowedhigheradjustedSERTbindinginthe sgacc,theofc,thehabenula,theamygdala anteriorhippocampuscomplex, theanteriorinsula,striatumandmidbrain. AieraminimumtreatmentperiodofthreeweekswithSSRIsinpreliminary unmedicatedpa1entswithmd.lowersertbindinginthemrncomparedto SERTbindinginterminalprojec1onregionspredictedbeneficialtreatment outcome. RLanzenbergeret'al.,NeuroImage(2012) Transla1onalNeuromodelingandComputa1onalNeuroeconomicsSeminar Fallsemester201329/11/13
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