Présentation au sujet: "Bases anatomo-fonctionnelles de la dépression"— Transcription de la présentation:
1 Bases anatomo-fonctionnelles de la dépression Fossati, P; Allilaire, J.FCNRS UMR 7593, Service de Psychiatrie d’Adultes, GH Pitié-SalpétrièreParis
2 Hippocampus, Parahippocampal C ABNORMALITIES OF METABOLISM, STRUCTURE IN MDDDorsal Anterior CingulateDorsal CaudateDorsal Medial /Anterolateral PFCPosterior CingulateVentral Anterior CingulateMedial ThalamusOrbital C, Ventrolateral PFC, Anterior InsulaMedial CerebellumOFC: promotes extincition of fear conditioningPFC:promotes extincition of fear conditioningInhibits acquisition of fear conditioning.Hippocampus, Parahippocampal CVentral StriatumAmygdalaAreas where neuropathological / morphometric changes reportedIndicates direction of metabolic abnormality relative to controlor
3 Other Neuromorphometric Abnormalities in Mood Disorders Corpus callossal areas reduced in MDD and BD mothers and their high risk, female offspringThird ventricle enlarged in BDMay implicate medial dorsal, paraventricular thalamic nucleiRaphe size (area stained by 8-OH-DPAT) decreased in depressed suicidesLateral ventricle enlargement in bipolar type I, psychotic, and late-onset depression* Reviewed in Drevets, Dialogues Clin Neurosci, 6(2): , 2004
4 Limitations to the Sensitivity of Neuroimaging Small effect size of abnormalities (generally < 1)Low spatial resolutionSmall signal sizeMeasurement variabilityAnatomical variabilityVariability imposed by clinical/ biological heterogeneity within samples identified using current nomenclatureDiagnostic specificity not establishedSensitivity to medication effectsLimited number of radioligands available
5 METABOLIC CHANGES ASSOCIATED WITH EFFECTIVE ANTIDEPRESSANT-DRUG TREATMENTDrevets et al, Eur Neuropsychoparmacology, 2002 & Neurobiological Found-ation of Mental Illness, Oxford, 2004; Kennedy et al Am J Psychiatry, 2001
6 METABOLIC CHANGES ASSOCIATED WITH EFFECTIVE ANTIDEPRESSANT-DRUG TREATMENTDrevets et al, Eur Neuropsychoparmacology, 2002 & Neurobiological Found-ation of Mental Illness, Oxford, 2004; Kennedy et al Am J Psychiatry, 2001
7 Treatment Effects on Ventral Prefrontal Cortex (PFC), Anterior Cingulate Cortex (ACC) Activity in MDDTreatmentChange: post- vs pre-TxBrody et al 2001ParoxetineBuchsbaum et al 1997Setraline Ventral ACCCohen et al 1992Phototherapy Medial Orbital CDrevets & Raichle 1992Desipramine Left VLPFCDrevets et al VLPFC and Orbital C, Ventral ACCDrevets et al 2002CitalopramDuan et al. 2004PramipexoleEbert et al 1991Sleep deprivation Orbital C- respondersMalizia et al. 1994Subcaudate Tractotomy Ventral PFC, Ventral ACCMayberg et al 1999Various AD drugs Orbital/Ant insula, Ventral ACCNobler et al 1994ECT Left VLPFC, respondersKennedy et al 2002Fluoxetine Left Lateral Orbital/ Ant insulaRubin et al 1994Nortriptyline or sertralineTrivedi et al 1994 Orbital CWu et al 1992 ACC, responders VLPFC, Orbital C
8 Models of Mood Disorders (II) Need to explainrecurrent and episodic nature of mood disordersprogressive nature of the disorder over timepersistent impairment in cognition and emotion regulationNew Framework: impairment in structural plasticity and cellular resilienceChronicbrain changes may be associated with depression or bipolar disorderModels of mood disorders need to explain these chronic brain changes in patients as well as the persistent impairment in cognition and emotion regulation and the progressive nature of the disorder over timeRecent framework suggest that impairment in structural plasticity and.... May be relevant in mood disordersPllasticity defines how brain adapts his structure to internal and external stimuli and how it repairs itselfIn this talk I would like to review evidence from imaging and cognitive studies supporting this framework and the neural network
10 Structural findings in Bipolar Disorder (I) Increase of Amygdala volumeDecrease of subgenual volumeChange in left dorsal cingulate volumeNo change in temporal and hippocampus volumeWhitematter hyperintensities in young patientsStructural brain imaging studies using MRI in bipolar disorder have shown..have been described in patients with early depression and familial bipolar depression- Unlike depressed patients, bipolar did not show- in untreated patients compared to patients with lithiumFinallyThese White matter intensities disrupt neural connectivity necessary for normal affective and cognitive functioning
11 Structural findings in Bipolar Disorder (II) Contradictory findingsDefinition of anatomical regionsSmall samplesSample heterogeneitybipolar I and IIwith or without psychotic symptomsTrait vs stateComorbidity: alcohol or substance abuseTreatmentImaging studies produced contradictory resultsSeveral factors may explain these contradictory findingsThe treatment is also a major factor as some recent studies showed than chronic administration of lithium may increase the gray matter volume
12 Structural findings in Bipolar Disorder (III) Meta-Analysis (Mac Donald et al, Biol Psy, 2004)Age between years26 studies404 patientsDSMIII-R or DSM-IV bipolar disorderRecurrent illnessMetaanalyses tried to control the effects of these factorsA recent metanalysis included 26 studies using quantitative MRI techniques404 Patients aged …were includedPatients had…All subject had a recurrent illness with at least two affective episodes
13 Structural findings in Bipolar Disorder (IV) Right lateral Ventricular enlargementHippocampus normal (250 patients)Great heterogeneity and publication biasOnly the right later ventricular enlargement distinguished controls from bipolar patientsThe hippocampus was normal and this analysis included 250 patientsThe authors emphasized the great….
14 Structural findings in Depression Whitematter hyperintensities in elderlyAbnormalities in prefrontal cortex: orbital, medial, ventral and dorsolateralReduction of subgenual volumeReduction of caudate nucleusAmygdala?Smaller hippocampal volumeStudies in depression have shownOr in patient with late onset depressionAbnormalities… was found inThe reduction..; has been described in pure familial depressive diseaseFindings on amydala are more inconsistent with some studies reporting increase, normal or decrease volumeFinally the most robust finding is the reduction of hippcampal volume rangign from 9 to 19 %
15 Structural findings in Depression (II) Hippocampus atrophyLength of illness and duration of depression (Sheline et al, 1999)The hippocampus atrophy has been related to the duration of depression as shown on that picture
16 Structural findings in Depression (III) Hippocampus and contradictory findingsDuration of depressionNumber of depressive episode (Mc Queen, 2003)TreatmentGender (women > men)Sexual abuseSlice thicknessClinical characterstics have been implicatedin hippocampal volume differences in depressionAtrophy of hippocampus has been related to the..Some recent data suggest that the duration of exposure to antidepressant treatment is negatively correlated to the hippocampal volumeFinally parameters of MRI such as the slice thickness may also explain divergent findings…
17 Structural findings in Depression (IV) Meta-Analysis (Campbell et al, 2004)434 patients and 379 controlsAge from 23 to 86 yearsSmaller hippocampus if analysis does not include amygdalaA recent meta analysis of structural changes of hippocampus in depression included…The hippocampus of depressed patients were smaller than controls if the analysis does not …No other variables were significant moderators of the results
18 Summary of Structural Imaging studies Implication of a cortico-limbic network in depression and bipolar disorderMorphometric distinction within the affective spectrum:Amygdala and Bipolar disorderHippocampus and depressionConsistent with post-mortem studies: reduction in number, density and size of glia cells + /- neurons in the same neural networkThere is a morphometric distinctionThese brain imaging findings are consistent with
19 Depression and hippocampus Cause of atrophy?Specificity of atrophy?Functional and clinical signification of atrophy?In the last part of this talk I would like to focus on the hippocampus and depressionWe have previously said that there is hippocampal volumetric changes in depression
20 We don’t know yet if the hippocampus changes in depression reflect developmental abnormalities, compensatory changes or consequences of the recurrence of depressive episodes per seOne main hypothesis relates hippocampus atrophy in depression to Stress and corticosteroidsThe so-called neurotoxic hypothesis relies on animal studies and studies on Cortisol dysregulation in depressionINdeed There are Several corticosteroids receptors in the hippocampus
21 Cause of Hippocampus atrophy Tissue lossNeuronal loss due to stress and steroidsStress induced reduction of neurotrophic factor (CREB, BDNF) and neurogenesisGlial loss due to glutamate toxicityAccording to this hypothesis Hippocampal damage in depression…
22 Specificity of the hippocampus atrophy Borderline PersonalityDisorderPTSDDepressionCushing’ s syndromeThe hippocampus is involved in …..
23 Signification of the hippocampus atrophy Hippocampus functionLearning and MemoryRegulation of stress response- Emotion regulationThe hippocampus is involved in …..
24 Signification of the hippocampus atrophy (II) Memory deficits and acute depressionDepression with HPA abnormalitiesPatients with multiple episode compared to first episode (Fossati et al, 2004)Persistent deficits in euthymic phase associated with the number of depressive episode (Kessing et al, 1998)Correlation of memory deficits and hippocampus volume?Cortisol reduces blood flow in hippocampus during retrieval (De quervain, 2000)Memory deficits have been found inRecently we demonstratedCorrelation od memory deficits and hippocampus changes in structural and function remains to be determinedA recent fMRI study shows acute administration of cortisol
25 Régulation émotionnelle Processus:Maintien, diminution ou augmentation des réactions émotionnelles (expérience, expression)Modulation de la réponse comportementale ou neurovégétativeFonction sociale (ex. inhibition des réactions d’agressivité, de colère; contextualisation des réponses émotionnelles)
27 Capacité de régulation émotionnelle - niveau réflectif inférieur : processus automatiques (non conscients, capacités d’adaptation, mécanismes de défense)- niveau réflectif supérieur : conscience des émotions et des émotions et pensées envers les émotions = mode méta-émotif- Processus cognitifs: réévaluation, suppression….Mayer & Gaschke (1988); Charron et al. (2003)
28 DEPRESSION: TROUBLE MULTIDIMENSIONNEL MotorsymptomsSymptômesmoteursDérégulationHumeurSymptômesvégétatifsDepression is a common disorderMany symptoms define a Depressive episodeThose symptoms include…Thinking the depression as a multidimensional disorder impliesAt a first level there is not a ‘unique cognitive or biological model explaining all the symptoms of depressionAt the brain level we can hypothesize that the depression does not involve discrete brain areas but nmplies multiple neural systems in interactionTroublescognitifs
29 Dérégulation de l’humeur et dépression Tristesse intense et durableLabilité de l’humeurDysphorieMood dysregulation in depression is characterized byan intense and persistent sadness not adapted to the contextWe can also observe mood lability, frequent mood swings especially in bipolar patientsfinally many depressed patients complain about loss of pleasure and interest during activityThis anhedonia is more pronounced for sensorial pleasure rather than social pleasureWhat are the neural structures that regulate normal mood changes in normal subjects?Are these structures involved in the pathophysiology of depression?
30 Expérience d’induction d’une tristesse MéthodesScripts autobiographiquesMusiquefilmsDéplétion en tryptophaneTMSMood induction are experimental techniques used to study mood regulation in normal controls and patientsMood induction technique has a long history in experimental psychologySeveral methods combined with brain imaging technique (especially PET scan) have been used o provoke sadnessMayberg et al, asked subjecct to retrieve personal sad events during scanningThe images of PET scan were acquired only after the sad state was reached in order to avoid confounding effect of due to the memory stategies
31 Induced Sadness Healthy Volunteers F9F9F9F9RtCg25cdCg25insinsinsinsCg25+ 4z-score- 431pCgpCgIn that study published in the American Journal of Psychiatry Helen Mayberg using a memory technique asked normal subject to get sad and maintain that sadness during scanningSo we observe here not the acute change from euthymia to sadness but how the brain maintain an acute sadness during a short timeWhat did she observe?she foundAn increase of cerebral blood flow in ventral areas especially the insula, the subgenual cingulate associated with a decrease in dorsal cortical areas namely-dorso-lateral prefrontal areas (usually involved in working memory task and executive task)posterior cingulate regionThe acute change in normal controls was similar to changes observed when depressed patients recover from their depressionThis result suggest that these regional interactions mediate the behavioral relationships between cognition and emotionAnt25hthhthCg25Cg25Cg25x= 0Healthy Volunteers
33 Induced Sadness Depression Recovery Healthy Volunteers F9F9F9F9RtCg25cdCg25insinsinsinsCg25+ 4z-score- 431pCgpCgIn that study published in the American Journal of Psychiatry Helen Mayberg using a memory technique asked normal subject to get sad and maintain that sadness during scanningSo we observe here not the acute change from euthymia to sadness but how the brain maintain an acute sadness during a short timeWhat did she observe?she foundAn increase of cerebral blood flow in ventral areas especially the insula, the subgenual cingulate associated with a decrease in dorsal cortical areas namely-dorso-lateral prefrontal areas (usually involved in working memory task and executive task)posterior cingulate regionThe acute change in normal controls was similar to changes observed when depressed patients recover from their depressionThis result suggest that these regional interactions mediate the behavioral relationships between cognition and emotionAnt25hthhthCg25Cg25Cg25x= 0Healthy VolunteersDepressed Patients
34 Régulation de l’humeur et dépression (2) Tristesse aigue active les mêmes structures neurales impliquées dans la tristesse chronique de la dépressionRégions Corticales (préfrontale) et Limbiques (subgénuale, hippocampe)This ‘emotional task’ involves cognitive and emotional brain regions and is associated withCortical and limbic interactions
35 Vulnérabilité à la dépression Trait ou dimension de personnalitéGénétiqueEnvironnementMesures de ces traits de personnalité: TCI or NEO‘Neuroticism’: sensibilité accrue aux affects négatifs et un facteur de risque de nombreux états psychopathologiquesAn other way to investigate the neural structures involved in normal and pathologic mood regulation is to investigate subjects at risk for depressionMany risk factors for depression have been described including genetic and environmental factorsPersonality trait or dimension have been associated with an increase susceptibility to depressionNeuroticism, defined as an increased sensitivity to negative affect, a risk factor for depressionIndividual variability in emotional reactivity is an area of growing research interest, as suggested by recent studies examining genetic links to the personality trait Neuroticism (Lesch and Mossner, 1998; Neumeister et al., 2002), the temperamental hypersensitivity to negative stimuli or the tendency to experience exaggerated negative mood states in situations of emotional instability or dissonance (Santor et al., 1997). High trait levels of neuroticism are of potential clinical interest, as this temperament marker has been suggested to increase vulnerability to psychopathology such as depression, anxiety, biopolar disorder and aggression (Beck et al., 1979; Henriques et al., 1994; Teasdale, 1999; Segal et al., 1999)In both groups there was a common pattern of increased activity in subgenual cingulate (Cg25) and hippocampus, along with decreased activity in dorsolateral prefrontal cortex (BA9) associated with acute sadness. This pattern is consistent with previously reported findings in unselected healthy controls (George et al., 1995; Mayberg et al., 1999; Damasio et al., 2000; Liotti et al., 2002) suggesting that these regions are critical to the normal regulation of acute changes in mood state. A second, group-specific pattern was seen only in the hiNloE group under emotional stress (i.e. with sad mood provocation). This pattern again involved increased activity in Cg25 but in association with decreased medial prefrontal activity, a pattern not seen in the loNhiE group..
36 Figure 1. Seed PLS LV1 – + Keightley et al, Neuroimage, 2003 PAS NAS NeutralSaddlpf9oF1147mF10Inspm6pcg31rcg2411Z= -12Z= 0Z= 24Keightley et al,Neuroimage, 2003
37 Mood Induction in Depression Rem UPDF9F9F9F10CgCgF10F10Memory induced sadness/tearfulPET- signal +Liotti et al, 2002
38 Résumé des études d’induction de l’humeur Tristesse aigüe normale et tristesse pathologique engagent les mêmes structures cérébralesRégions corticales, limbiques et paralimbiques (hippocampe, cingulum subgénual)Test d’induction de l’humeur révèle une vulnérabilité à la dépressionNeuroticism, defined as an increased sensitivity to negative affect, a risk factor for depressionVulnerability mediated by cognition and mood dysregulationCognitive model of depression (Beck)Ruminative coping style (Noelen-Hoeksema, 1987)
39 Cortex Médian Préfrontal (CMPF) Cortex préfrontal ventro-médian: intégration des émotions dans les processus de prise de décision (Damasio)Représentation des états d’activation périphérique du SNA (‘cardiovascular arousal’; Critchley et al, 2000)Evaluation émotionnelle (Phan, 2002)Théories de l’esprit (Gallagher et al, 2003)Among these different studies we discussed about a specific regionThe medial prefrontal cortexWhat is the function of this region?Many functional imaging studies activated that regions and several functions have been proposed
42 Sommaire sur le CMPF dans la dépression CMPF: traitement selon une perspective personnelle des stimuli émotionnelsDéprimés ont du mal à moduler l’activité du CMPFActivité anormale du CMPF: corrélat neuronal des biais de traitement dans la dépression
43 Contrôle cognitifFonctions exécutives: planification, monitoring des erreurs, inhibition, allocation des ressources attentionnellesRégulation émotionnelle: distraction, rumination, changement de perspective….
44 Pochon, J.B., Levy, R., Fossati et al, PNAS, 2002 - Subjects performed a letter variant of the « n-back » procedure, during fMRI scanning- the n-back tasks were performed in association with different monetary rewarding values (up to 240 €)vXtpPgn-back100%instructionperformancetempsWe conducted a series of behavioral and fMRI studies in normal subjects and depressed patients using a task known to require executive and attentional resourcesThe task we selected is the n-back taskaccording to which subjects were to indicate whether a letter presented on the screen (the "target" stimulus) is similar of different from a letter previously presented (the "cue stimulus"; see Figure 1). This procedure requires the participant to maintain and permanently update the relevant pieces of information in WM. Load and mental manipulation within WM were incremented by using three different levels of the n-back task : 1-back (maintenance of one piece of information in WM within the interval between the cue and the target stimuli) and 2- and 3-back (interposition of one or two distractors between the cue and the target stimuli, each distractor becoming a cue for the next trial).In a first experiment, in order to assess the influence of the context, we introduced trials rewarded with moneyTherefore there was three levels of complexityAnd two type of trials: rewarded or non rewarded
45 DEPRESSION: TROUBLE MULTIDIMENSIONNEL MotorsymptomsSymptômesmoteursHumeur+ÉmotionsanormalesSymptômesvégétatifsDepression is a common disorderMany symptoms define a Depressive episodeThose symptoms include…Thinking the depression as a multidimensional disorder impliesAt a first level there is not a ‘unique cognitive or biological model explaining all the symptoms of depressionAt the brain level we can hypothesize that the depression does not involve discrete brain areas but nmplies multiple neural systems in interactionTroublescognitifs
46 Population Témoins Déprimés Age 29 ans 33,8 ans 5 H / 5 F 3 H / 7 F Sex ratioEducation14,6 ans14,7 ansBeck / MADRS0 / 017,8 / 26Nb d’épisodes2,4 (1 - 4)
52 Modulation du CPFVL avec l’augmentation de la complexité CPFVL gauche – ROI 10 mm ( )Augmentation de l’activité p/r au 0-Back0,280,360,290,260,160,13Sujets témoinsPatients déprimés
53 Courbe HDR dans le CPFDL (BA 46) CPFDL gauche (BA46) – ROI 5 mm ( )Augmentation de l’activité p/r au 0-Back0,410,270,340,260.240,240,16Sujets témoinsPatients déprimés
54 Modulation du CPFM avec l’augmentation de la complexité CPFM – ROI 10 mm (0 54 3)Diminution de l’activité p/r au 0-Back-0,32-0,23-0,38-0,59-0,45-0,62Sujets témoinsPatients déprimés
55 Résumé des études avec le n-back Sujet normal: effort cognitif associé avec des interactions cortico-limbiquesDéprimé: interactions cortico-limbiques anormales lors d’un effort cognitifTo summarize these fMRI studies using cognitive challenge
56 Interactions cortico-limbiques et dépression dérégulation de l’humeurAugmentation de la sensibilité à l’effort cognitifBiais Emotionnel: anomalie du CMPFTo summarize the studies presentedAbnormal cortical limbic interactionsMay subserve
57 Models of Mood disorders (1) geneticgendertemperamentHPA, SERTBiologicalVulnerabilityExogenousStressorsenvironmentearly insultslife eventsacute v. chronichomeostasisfamily hxHPA reactivitygene polymorphNEO inventorybrain lesionsBraintreatmentdecompensationSeveral factors are implicated in the pathophysiology in depression including genetic, environnemental and the capacity of brain to adapt to cognitive and emotional demandsAffectiveepisodephenotypeAdapted from Mayberg & Fossati, in press, 2004
59 Rostral Cingulate Activity Prognostic Marker:Rostral Cingulate ActivityABCCg24a24a24aAmong these subregionOne area has been described as a predictor of clinical remission of depressive symptoms after six week of antidepressant (fluoxetine)Non-RespondersRespondersFull RemissionPatients vs Controls