Hoe het brein bij patiënten met depressie ervoor zorgt dat emotionele geheugen vertekeningen ontstaan

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1 Indira Tendolkar Hoe het brein bij patiënten met depressie ervoor zorgt dat emotionele geheugen vertekeningen ontstaan Department of Psychiatry

2 Overview of the talk Basic principle of emotional memory enhancement The interaction between mood and emotional memory Depressive trait effects in emotional memory

3 Overview of the talk Basic principle of emotional memory enhancement The interaction between mood and emotional memory Depressive trait effects in emotional memory

4 Enhanced memory for emotional events Is a well-recognized phenomenon Has an obvious adaptive value in evolutionary terms It is vital to remember both dangerous and favorable situations

5 Basic principle of emotional memory enhancement Emotional memory enhancement occurs in different memory systems MEMORY Declarative Non-declarative episodic semantic skills priming conditioning others

6 Neural basis of emotional memory enhancement An impression may be so exciting emotionally as almost to leave a scar upon the cerebral tissues. William James (1890)

7 Functional neuroimaging Methods

8 Memory Formation and Retrieval: General Experimental Design Camera Milk Chain Power Milk Study 87 Distraction? Test Trials: (later) remembered (later) forgotten Contrasts: remembered > forgotten

9 Modulation Hypothesis: First functional imaging evidence Stronger correlation between amygdala and entorhinal activity for succesful encoding of emotional pictures Dolcos F et al., Neuron (5):

10 Neural basis of emotional memory enhancement Amygdala modulates regions critical for memory

11 Overview of the talk Basic principle of emotional memory enhancement The interaction between mood and emotional memory Depressive trait effects in emotional memory

12 Mood can bias emotional memory enhancement Facilitation predictions from Bower's Associative Network Model(1981)

13 Deficits in semantic labeling of emotions in depression Currently depressed individuals show a higher neural activation than recovered and healthy individuals during semantic labeling of emotion in contrast to perceptual matching of emotion. This effect was evident in the right amygdala (A), left inferior frontal gyrus (B), and anterior cingulate cortex (C) Psychol Med :1-9

14 Emotional memory enhancement in depression is mood congruent Negative Self referent Thinking Hopelessness Depressed Mood Memory Bias Dysfunctional Attitude Fatigue (model adapted from Williams and colleagues)

15 Study Design: How mood interacts with memory + angst + straat ~ 5 s liefde ~ 5 s 0.5 s 4 Negative, 4 Neutral, 4 Positive words per run (20 runs in total) 0.5 s vriendschap vijand angst straat Free Recall Study (~60 s) Distraction (~40 s) Test (~30 s) Video 1 (15m) Video 2 (6m) Video 3 (4m) Video 4 (7 min) NeuroImage :

16 Study Design Participants: 21 Dutch speaking healthy volunteers (7 males, mean age 22.8 ± 3.7 years) MRI Protocol: Avanto (1.5T) 2340, ms TR, 35 ms TE, 32 slices 3.3 x 3.3 x 3.5 mm voxels Paradigm: - Video clips used to induce mood NeuroImage : Sophie s Choice Happy Feet

17 Behavioral results * * * * * NeuroImage :

18 Imaging results results Successful memory formation was related to an activity increase in left frontal and MTL regions Greater activity for sad compared to happy mood was found in the amygdala Processing of affective words was marked by increased activity compared to neutral words NeuroImage :

19 Imaging results results: Three way interaction Mood-incongruent effect: Subsequent memory effects were larger for negative words during happy compared to sad mood in left MPFC Mood-congruent effect: During sad mood, subsequent memory effects for negative words were significantly greater in left OFC compared to activity for negative words following happy mood induction NeuroImage :

20 Summary of the results Behavioral results confirmed the presence of a mood-congruent memory bias Amygdala and hippocampus were engaged in overall mood and memory formation respectively Increased activity to negative words in the inferior-frontal gyrus for the mood-incongruent condition and in the orbito-frontal cortex for the congruent condition. NeuroImage :

21 Discussion These results suggest that different pre-frontal regions mediate dichotomous interactions between mood and memory: left inferior frontal gyrus may serve semantic control processes in overcoming incongruency between mood state and item valence for successful encoded words orbito-frontal cortex is involved in enhancing congruency between mood and stimulus valence during successful memory formation NeuroImage :

22 How do our findings relate to neural circuit theories of depression Phillips et al., Biological Psychiatry 2003

23 Overview of the talk Basic principle of emotional memory enhancement The interaction between mood and emotional memory Depressive trait effects in emotional memory

24 Depressive traits in emotional memory enhancement In acute depression (Hamilton et al., 2008): Increased memory sensitivity for negative stimuli Over-activation of amygdala-hippocampus amygdala-caudate-putamen system In remission (with mood induction) (Ramel et al., 2007): Bilateral amygdala response predicted increased recall of negative self-referent words

25 Depressive traits in emotional memory Subject characteristics Remitted Patients Controls N=14 Demographic variables Mean SD Mean SD N=14 Group effect Age Sex (male/female) 0/14 0/ Handedness (left/right) 0/14 0/ Educational level (1-5) Clinical variables HDRS 17-item score STAI State Mean Trait Mean Total Mean Life events PANAS Positive Negative Age of onset (years) Mean p Number of episodes J Affect Disord (1-3):214-23

26 Study Design: Depressive traits in emotional memory J Affect Disord (1-3):214-23

27 Behavioral bias in remission? Remitted Patients N=14 Healthy Control N=14 Group effect Recall Rates Mean SD Mean SD p-values 50 Total Recall Negative words Neutral words Positive words Controls Remitted Total Recall Negative words Neutral words Positive words Controls Remitted J Affect Disord (1-3):214-23

28 MRI Acquisition 1.5T Siemens AVANTO MR scanner (Siemens, Erlangen, Germany) Functional T2*-weighted BOLD EPI images (33 axial slices, 3.4mm, slice-gap= 0.34mm, FOV= 212mm, TR= 2190ms, TE= 35ms, FA=90, final voxel dimension= 3.3x3.3x3.4 and a bandwidth of 1628Hz/Px) Anatomical T1-weighted MP-RAGE sequence (176 slices, voxel size: 1.0 x 1.0 x 1.0mm, TR= 2250ms; TE= 2.95ms, FA= 15 ). MRI Analysis Standardized analysis with SPM5 (Wellcome Department of Imaging Neuroscience, London, UK) Whole brain exploratory analysis Region of interest analysis within amygdala and hippocampus J Affect Disord (1-3):214-23

29 MRI results: three-way interaction Patients show increased neural activity when successfully encoding positive words This effect is evident in - right anterior cingulate - left posterior cingulate - right inferior frontal gyrus - right amygdala J Affect Disord (1-3):214-23

30 Neural correlates of memory bias act as vulnerabilitymarker of depression Prefrontal top-down processes play are involved in mood-related emotional learning Amygdala/hippocampal processes are involved in trait related maintenance of emotional memory bias William James (1890)

31 Cognitive memory bias as intermediate phenotype (Franke et al. Hum Genet (1):13-50.)

32 Brain Imaging Genetics study Ongoing cohort study Data collection started 2009 Healthy subjects (currently N >1000) Excl. criteria: a history of somatic disease potentially affecting the brain, current or past psychiatric or neurological disorder medication (except hormonal contraceptives) or illicit drug use during the past 6 months history of substance abuse, current or past alcohol dependence, pregnancy, lactation, menopause MRI contraindications

33 Additional evidence for an intermediate phenotype Structural MRI (1.5 T Siemens scanner, T1-weighted 3D MPRAGE sequence) in 272 healthy participants (62% female, yrs old) Automatic segmentation of amygdala and hippocampus was performed using the FIRST module of FSL. Negative memory bias was assessed by the self-referent encoding/evaluation test Analysis of general linear models adjusted for age, sex, total brain volume and negative mood was conducted. Psychol Med :1-9 Negative memory bias was associated with larger amygdala (p=0.042) and smaller hippocampal volume (p=0.029)

34 Additional evidence for an intermediate phenotype Spearman correlations, within sample with negative memory bias (N=72). Ratio volumes adjusted for age, sex, total brain volume, scanning protocol and PANAS negative scale The ratio of amygdala to hippocampal volume was most strongly related to negativity bias (p=0.021) There was neither an association between regional brain volumes and positive memory bias nor with negative and total recall Psychol Med :1-9

35 Additional finding: 5 HTTLPR, memory bias and brain

36 Possible underlying mechanism Negative memory bias Depression

37 Science is always a collaborative endeavour Center of Cognitive Neuroimaging, Nijmegen Jennifer Arnold Guillén Fernández Lotte Gerritsen Guido van Wingen Department of Psychiatry Nijmegen Iris van Oostroom Philip van Eijndhoven Anne Speckens Barbara Franke Alessandro Ariez Vasquez Behavioral Science Institute, Department of Clinical Psychology, Nijmegen Daniel Fitzgerald Mike Rinck Eni Becker

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