Amygdala responsivity related to memory of emotionally neutral stimuli constitutes a trait factor for depression

NeuroImage 54 (2011) 1677–1684

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Amygdala responsivity related to memory of emotionally neutral stimuli constitutes a trait factor for depression Philip van Eijndhoven a,b,⁎, Guido van Wingen b,c, Guillén Fernández b,c, Mark Rijpkema b, Robbert Jan Verkes a, Jan Buitelaar a, Indira Tendolkar a,b a b c

Radboud University Nijmegen Medical Centre, Department of Psychiatry, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Radboud University Nijmegen Medical Centre, Department of Neurology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

a r t i c l e

i n f o

Article history: Received 10 May 2010 Revised 13 August 2010 Accepted 17 August 2010 Available online 26 August 2010 Keywords: MDD fMRI Hippocampus Amygdala Memory

a b s t r a c t Episodic memory impairment is considered to be a core cognitive deficit of Major Depressive Disorder (MDD) and has motivated a line of research investigating the role of the amygdala and the hippocampus in depression. While functional neuroimaging studies have focused on memory for emotional but not for neutral stimuli, in order to probe amygdala function, structural imaging studies have tied episodic memory to hippocampal function. We therefore investigated the neural correlates of episodic memory formation for neutral stimuli in 20 patients with a first depressive episode, 20 patients recovered from a first episode and 20 healthy controls. Because there is evidence that the amygdala exhibits hyperactive responses even to neutral stimuli in depressed subjects, we specifically explored the potential role of the amygdala in forming episodic memories with neutral content. Both patient groups showed stronger subsequent memory effects in the amygdala when compared to controls, in the absence of any differences in hippocampal activity between groups. Patients with a first episode of MDD showed increased activity related to episodic memory formation in a fronto-limbic network. These state-related activations may be related to a compensatory mechanism, which is supported by the absence of any differences in memory performance between groups. These findings represent initial evidence for a neurocognitive trait or vulnerability marker of depression— amygdala involvement in episodic memory formation of neutral stimuli. © 2010 Elsevier Inc. All rights reserved.

Introduction Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and is the leading cause of disability worldwide (WHO, 2001). In addition to a sad mood, depressed patients display cognitive deficits in several domains, in particular impairment in episodic memory (Burt et al., 1995). Episodic memory depends on the integrity of the medial temporal lobe (MTL) (Eichenbaum et al., 2007) which has motivated a line of research investigating the role of amygdala and the hippocampus in the pathophysiology of depression (Bremner et al., 2004; Campbell et al., 2004; Drevets, 2003; MacQueen et al., 2003; Ramel et al., 2007). Functional neuroimaging studies of episodic memory formation in MDD have thus far focused on memory for emotional stimuli, in order to probe amygdala function (Hamilton and Gotlib, 2008; Ramel et al., 2007). Amygdala hyperactivity has been interpreted as a valencespecific effect, which causes a negative memory bias (Hamilton and ⁎ Corresponding author. Radboud University Medical Center Nijmegen, Department of Psychiatry, P.O. Box 9101, 6500-HB Nijmegen, The Netherlands. Fax: +31 24 3540561. E-mail address: [email protected] (P. van Eijndhoven). 1053-8119/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2010.08.040

Gotlib, 2008; Ramel et al., 2007), but hyperactivity is also a common finding during baseline conditions in MDD (Drevets et al., 2002). Further, studies inducing acute stress in healthy subjects hint towards an unspecific, hyperactive amygdala engagement (van Marle et al., 2009) that could lead to involvement of the amygdala during episodic memory independent of the biological salience of the stimulus. Past research has exclusively linked neutral memory to the structural and functional integrity of the hippocampus (MacQueen et al., 2003). Although direct imaging evidence with event-related functional magnetic-resonance imaging (fMRI) is lacking, combined structural MRI and neuropsychological studies have linked memory performance with hippocampal volume over the course of MDD. Results early in the course of MDD provide evidence that episodic memory can even be impaired in the absence of macroscopic changes of the hippocampus (MacQueen et al., 2003; Vythilingam et al., 2004) underlining the need of a direct functional imaging investigation. Therefore, we set out to answer two questions related to the early course of MDD: First, does the amygdala play a role in the formation of neutral memories in MDD? Second, is there evidence for hippocampal dysfunction in the absence of structural changes in MDD? To tackle these questions, we used an event related fMRI design of associative memory formation for neutral stimuli (Tendolkar et al., 2007) that is

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known to reveal robust correlates of episodic memory formation in the hippocampus, but not the amygdala (Nitschke et al., 2004). By studying both patients with a first episode of MDD and patients who recovered from a first episode and healthy control subjects, we were able to dissociate state and trait markers of depression. Importantly, we included a region of interest analysis with manually traced anatomical masks to avoid confounds due to volumetric differences between patients and controls. This method yields the most accurate measurement of activation of these structures independent of volume (Dolcos et al., 2004; Sandstrom et al., 2006) and avoids mislocalization of activations in the medial temporal lobe as a consequence of anatomical variability and effects of normalization (Ramsoy et al., 2009). Materials and methods Participants We investigated 20 medication-naïve MDD patients with a current first episode (mean age ± SD 34.1 ± 11.6 years; range 18–56 years), 20 medication-free MDD patients recovered from a first episode (mean age ± SD 35.8 ± 11.6 years; range 18–53 years) and 20 healthy controls (mean age ± SD 37.3 ± 12.7 years; range 18–53 years). MDD was diagnosed using mood sections of the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1996) by a trained psychiatrist (PvE). Inclusion criterion for the depressed group was a moderate to severe depression defined as a Hamilton Rating Scale for Depression (HDRS) 17-item score ≥ 18. Inclusion criteria for the recovered group were the absence of clinically relevant symptoms over the preceding 6 to 24 months defined as an HDRS 17-item score ≤7 (Frank et al., 1991) and discontinuation of antidepressant therapy for at least 2 months. Patients with other current or lifetime DSM-IV Axis-I disorders (assessed with the Mini International Neuropsychiatric Interview (MINI)) (Sheehan et al., 1998) were excluded. Exclusion criteria for healthy controls were lifetime DSM-IV Axis-I disorder and a history of psychiatric disorders in first degree relatives. All participants were physically healthy, and did not use any medication other than hormonal contraceptives. Other exclusion criteria were a history of substance abuse or traumatic brain injury, claustrophobia, metal implants, and for women, postpartum depression, pregnancy, lactation or menopause. The study was approved by the local ethics committee (CMO region Arnhem-Nijmegen, The Netherlands). Participants were recruited via the outpatients' clinic of the Department of Psychiatry and by local newspaper advertisements. All participants gave written informed consent after full explanation of the experiment. All participants underwent neuropsychological assessment. Experimental design After a training session, participants viewed in total 270 photographs of either buildings or natural landscapes (135 for each category), selected to be similar in complexity, brightness, and contrast (Tendolkar et al., 2007). The experiment was divided into six study–test cycles with breaks in between. During each of the study phases, subjects were required to make a color-decision on 30 pictures dyed in red-, blue- or green-shades. During each of the subsequent test phases, 45 (30 old and 15 new) plain gray-scale photographs were presented. Source memory for the color was tested following a standard old/new decision. Stimuli were counterbalanced across participants so that six subjects saw the same setup of pictures. For each of these six subjects, different subsets of pictures each were dyed in red-, blue- and green shades, so that no two subjects within one group saw the pictures in the same color (see Fig. 1). At study, stimuli were presented sequentially for 1400 ms with a randomized interstimulus interval (ISI) of 2500–4100 ms (mean

3300 ms). Ninety trials of baseline stimulation (i.e. black screen), each lasting 2000 ms, were randomly intermixed as so-called null events. ISI variation and inclusion of null events increase the statistical efficiency of event-related designs (Friston et al., 1999). Encoding trials were sorted into (1) trials that were subsequently recognized as being old and for which the correct color was recollected (“Source Hits”), (2) items that were subsequently recognized as being old without correct color judgment (“Item Hits”) and (3) trials that were subsequently not recognized (“Misses”). Differences in memory performance between groups were analyzed with mixed model ANOVAs in SPSS 15.0. Accuracy of item recognition was assessed by the difference in probabilities of a correct old judgment and an old judgment for a new item (Pr = probability hit − probability false alarm). Response bias (Br) was calculated with the formula derived from Snodgrass and Corwin (1988): probability false alarm divided by one minus Pr. Accuracy of source memory was assessed by the percentage of “Source Hits” of old trials. MR data acquisition MR data were acquired with a 1.5 T Siemens (Erlangen, Germany) Sonata MR scanner, equipped with a standard head coil. T2*-weighted blood oxygenation level-dependent (BOLD) images were acquired using echo-planar imaging (EPI), with each image volume consisting of 33 axial slices (3 mm, 0.5 mm slice-gap, TR = 2.290 s, TE = 30 ms, 64 × 64 matrix, FOV = 224 mm, FA = 90°). High-resolution anatomical images (voxel size = 1 mm3) were acquired using a 3D T1-weighted magnetization prepared rapid acquisition gradient echo sequence (MPRAGE). Anatomical masks We combined whole brain analyses with a region of interest (ROI) analyses of individually outlined masks of hippocampus and amygdala (Dolcos et al., 2004; Sandstrom et al., 2006) within native space. A rater (IT), blinded to the subject characteristics, segmented the amygdala and hippocampus manually as described previously (van Eijndhoven et al., 2009). fMRI data analysis Image analysis was performed with SPM5 (Wellcome Department of Imaging Neuroscience, London, UK). The first five EPI-volumes were discarded to allow for T1 equilibration. The remaining images were realigned to the first volume, corrected for differences in slice acquisition time, spatially normalized to the Montreal Neurological Institute (MNI) T1 template, resampled into 2 × 2 × 2 mm3 voxels, and smoothed with a Gaussian kernel of 8 mm FWHM. Statistical analysis was performed within the framework of the general linear model (Friston et al., 1995). Trials during encoding were sorted according to the subsequent memory test into “Source Hits”, “Item Hits”, and “Misses” (1.4 s). Together with null events (2 s), they were temporally convolved with the canonical hemodynamic response function of SPM5. Realignment parameters were included to model potential movement artifacts, as well as a high-pass filter (cutoff at 1/128 Hz). The relevant parameter images contrasting each condition to null events were entered in a mixed-model ANOVA (full factorial design) with non-sphericity correction for dependent measures. Sex and age were entered as covariates in the GLM to control for confounding effects. Episodic memory formation was assessed by the subsequent source memory effect (the contrast between source hits and item hits) and item memory formation was assessed by the positive and negative subsequent item memory effect (the contrast between item hits and misses and vice versa). State effects on episodic and item memory formation were assessed by comparing the group of acutely depressed patients with

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Fig. 1. Study design.

the group of recovered patients and healthy controls [2 * depressed − (recovered + control)], while trait effects were assessed by comparing the group of acutely depressed patients and recovered patients with healthy controls [(depressed + recovered) − 2 * control)]. Statistical tests were family-wise error rate corrected for multiple comparisons across the entire brain (p b 0.05), using random field theory-based cluster correction with an initial height-threshold of p b 0.001. Based on our a priori hypothesis about involvement in memory and depression, a small volume correction was used to correct for multiple comparisons across the search volume for regions of interest within the medial temporal lobe (Worsley et al., 1996). The search volume for the amygdala was defined as a sphere with 15 mm radius around the probabilistic cytoarchitectonic center of the basolateral amygdala [(−26,−8,−18) and (28,−8,−18)]. Correspondingly, the hippocampal search volume was defined as a sphere with 15 mm radius around the center of the cornu ammonis [(−28, −28−8) and (28,−26,−8)] (Amunts et al., 2005; Eickhoff et al., 2005). For the ROI analyses, functional images were coregistered to the structural images and the individually defined anatomical masks to allow further analysis in native space. Relevant contrast parameter images were generated for each subject and the mean percentage signal change of all voxels within in the anatomical masks was extracted with the MARSBAR toolbox (Brett et al., 2002) and used for further analysis with SPSS. For group analyses, repeated measures ANOVAs were performed with the within subject factor condition and the between subject factor group and age and sex as covariates.

Post hoc tests with Bonferroni correction revealed that state anxiety within the depressed group differed significantly from the recovered group (p = 0.015) and the control group (p = 0.002), while there was no difference between the recovered group and the control group (p = 1).Trait anxiety differed significantly between the depressed group and both the recovered (p = 0.011) and the control group (p b 0.001) and also between the recovered and the control group (p = 0.002). Behavioral results An overview of the mean memory performance is listed as supplementary material Table 1. Recognition accuracy did not differ between groups (mean (± s.d.): Prcurrent = 0.50 (± 0.20), Prrecovered = 0.44 (±0.14) and Prcontrol = 0.50 (±0.17), F(2,57) = 0.93, p = 0.40, and it was well above chance level (t(59) = 21.7; p b 0.001). In addition, response bias did not differ between groups: Brcurrent = 0.58 (±0.22), Brrecovered = 0.56 (±0.22) and Brcontrol = 0.56 (±0.20); F(2,57) = 0.05, p = 0.96. The accuracy of source memory did not differ between groups (mean correct± s.d %): current depression = 43.6 ± 17%, recovered = 41.7 ± 15%, control = 43.9 ± 15%; F (2,57) = 0.12, p = 0.88) and was well above chance level (t(59) = 11.4, p b 0.001). fMRI results

Results

1. Whole brain analysis In an initial analysis we explored activations related to episodic and item memory formation across groups.

Subject characteristics

Subsequent source memory effect

Table 1 shows the clinical variables and results of neuropsychological assessment. There were no significant differences between the three groups on any of the variables, except for psychopathological differences between the currently depressed and the recovered patients and the control subjects on HDRS score and STAI, as expected. There were no traumatic life events detected in our sample.

The whole brain analysis showed a set of frontal and posterior brain regions being engaged in associative memory formation. The maxima of all activation clusters (corrected for multiple comparisons at the cluster level) are presented as supplementary material Table 2. The most robust effect was found in the right anterior medial temporal lobe including the hippocampus.

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Table 1 Demographical, clinical and neuropsychological characteristics of the MDD patients and the healthy controls. Depressed

Recovered

Healthy

Group effecta

N = 20

N = 20

N = 20

p

Age (years) Sex (male/female) Handedness (left/right) Educational level (1–5)c HDRS 17-item score STAI State Trait Age at onset (years) Duration episode (months) Duration since onset (months) Medication use (number/all)f Duration medication use (months) Hormonal contraceptives (number/all) DART-IQ

34.1 (11.6) 7/13 0/20 3.75 (0.85) 21.08 (4.03) 43.6 (9.0) 53.3 (12.4) 33.7 (11.4) 7.1 (5.5) 7.1 (5.5) – – 5/20 93.45 (13.70)

35.8 (11.7) 6/14 1/19 3.60 (0.60) 3.40 (2.04) 36.0 (7.2) 43.7 (9.1) 33.4 (11.5) 21.6 (14.3) 33.7 (17.3) 18/20 16.7 (11.7) 5/20 100.05 (8.08)

37.3 (12.7) 7/13 1/19 3.95 (0.69) 0.9 (1.7) 33.8 (8.2) 31.7 (7.3) – – – – – 4/20 100.40 (17.38)

0.71 0.92b 0.64b 0.40b b0.001d 0.001 b0.001d 0.85e b0.001e b0.001e

Episodic memory AVLT Immediate Recall (no) Delayed Recall (no) Complex Figure Task

50.95 (10.15) 10.9 (3.1) 22.73 (5.5)

52.75 (8.77) 11.1 (2.25) 21.78 (6.12)

49.45 (7.78) 10.9 (2.2) 23.05 (4.77)

0.51 0.96 0.75

Attention and psychomotor speed TMT Test A (in seconds) DSST Completed (no)

30.75 (11.07) 62.00 (9.62)

26.20 (6.65) 64.20 (8.49)

28.95 (6.47) 59.00 (8.90)

0.23 0.20

Executive function WCST Categories completed, no Perseverative errors, no TMT Interference (%)

5.0 (1.9) 14.4 (15.5) 52.6 (43.4)

5.1 (1.7) 16.3 (13.2) 54.1 (56.5)

5.8 (0.9) 9.4 (9.6) 50.5 (33.0)

0.23 0.26 0.97

0.91b 0.20

Abbreviations: AVLT, Dutch modified version of the Rey Auditory Verbal Learning Test; CFT, Rey-Osterrieth Complex Figure Test; DART, Dutch version of the National Adult Reading Test; DSST, Digit Symbol Substitution Test; HDRS, Hamilton Rating Scale for Depression; STAI, State Trait Anxiety Inventory; TMT, Trail Making Test; WCST, Wisconsin Card Sorting Test. Data are expressed as mean (SD). a One way ANOVA. b P-value of likelihood ratio (categorical variables). c Educational level is coded level 1 to 5 (5 = academic), according to the Dutch education system (Loozen and Post, 1991). d Depressed N recovered N healthy; independent-sample t-tests. e One way ANOVA with two groups only (= 2-sample t-test). f Seventeen patients used SSRIs or SNRIs (sertraline, paroxetine, citalopram, venlafaxine), one patient used SSRI (paroxetine) followed by TCA (amitryptiline).

Subsequent item memory effect

Trait effect on memory formation

Table 1 of supplementary material also shows brain regions associated with a larger response for subsequent item hits compared to subsequent misses in the fusiform gyrus and parahippocampal regions, inferior temporal gyrus and middle occipital gyrus in both hemispheres. A negative subsequent item effect was found in the left precuneus and right anterior cingulate cortex.

When comparing subsequent memory effects observed in depressed patients and recovered patients with those effects obtained in healthy controls, we found a larger subsequent source memory effect for the patient group in the right amygdala (number of voxels: 83, MNI coordinates 24, −4, −18, Z value: 4.33, psvc b 0.05) (see Fig. 3). No other trait related changes in subsequent source or item memory effects were found.

Group comparisons Next we investigated state- and trait-effects on episodic and item memory formation. State effect on memory formation A state related subsequent source memory effects was found in a large cluster extending from the left inferior frontal gyrus to the left insula, a cluster within the left posterior cingulate cortex and the precuneus, the right caudate nucleus and bilateral thalamus (see Table 2 and Fig. 2 for an overview). There were no regions of greater activation in the recovered and healthy control group compared to the currently depressed group related to subsequent source memory. As is also evident from Table 2, the depressed group revealed a larger negative subsequent memory effect (i.e. subsequent misses N subsequent item hits) in the left angular gyrus in comparison with the recovered and healthy control group. However, no other state related differences between groups were found related to item memory formation.

Table 2 State effects of depression on subsequent source memory and negative subsequent item memory (acutely depressed patient vs. recovered patients and healthy controls). The local maxima of the significant clusters (pcluster b 0.05) are reported in MNI coordinates. MNI coordinates x

y

Cluster size

Z score

z

No. of voxels

6 26 28 38 −2 18 6

495 345 398 166 213 166 254

4.84 4.39 4.36 4.51 4.10 4.17 3.84

Negative subsequent item memory (misses N item hits) L angular gyrus −44 −48 24

181

4.46

Subsequent source memory (source hits N item hits) L inferior frontal gyrus/insula −26 22 L posterior cingulate cortex 0 −30 L precuneus −8 −63 L middle frontal gyrus −38 24 R middle orbital gyrus 32 50 R caudate nucleus 26 0 R thalamus 16 −12

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Fig. 2. State-effects of depression for subsequent source memory. Activations (pcluster b 0.05) are shown with corresponding contrast estimates from the local maxima from the three groups (CH: source hits, CF: item hits). (A) Left inferior frontal gyrus, (B) right caudate nucleus, (C) left posterior cingulate cortex and (D) left precuneus.

2. ROI analyses To assess state and trait related effects of depression on source and item memory formation, we conducted region of interest analyses of amygdala and hippocampus defined anatomically in native space. Hippocampus A repeated-measures ANOVA on percent signal change within the right and left hippocampus revealed a main effect of subsequent source

memory in the right hippocampus (F(1,57)=5.8; p=0.019), indicating larger signal changes for “Source Hits” compared to “Item Hits” across all three groups. There was, however, no interaction with the factor group (F (2,57)=0.89; p=0.41), indicating that this effect was equally evident in both patient and control groups. The same analysis but now addressing subsequent item memory (“Item Hits” versus “Misses”) did not reveal a subsequent item memory effect within the hippocampus, supporting earlier findings of selective hippocampal engagement during source but not item memory formation (Davachi et al., 2003; Ranganath et al., 2004).

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Fig. 3. Trait-effect of depression for subsequent source memory. A) Activation within right amygdala (psvc b 0.001) along with corresponding percentage signal change from the ROI analysis. CH: source hits, CF: item hits (asterisks indicate significant differences between the two conditions). B) Correlation between difference in right amygdala activity and source memory performance.

Amygdala A repeated-measures ANOVA on percent signal change between groups within the right and left amygdala revealed an interaction of the factors source memory formation and group in the right amygdala (F(2,57) = 3.49; p = 0.037), in line with the trait effects in the whole brain analyses. Post-hoc tests showed that this interaction reflects larger signal changes related to subsequent source memory in currently depressed patients compared to controls (F(1,38) = 5.18; p = 0.028) as well as in recovered patients compared to controls (F (1,38) = 5.86; p = 0.020). There was however no significant differences between both patient groups, suggesting that the memoryrelated amygdala activation in depression is trait rather than state related (see Fig. 2). Post-hoc analyses further revealed a significant correlation between difference in right amygdala activity and source memory performance (ρ = 0.36; p = 0.028) in the group of currently depressed and recovered patients (see Fig. 3). Partial correlation controlling for levels of state and trait anxiety as assessed by STAI revealed a similar result (correlation 0.36; p = 0.030). The correlation was absent in the control group (ρ = 0.09; p = 0.70). There was no subsequent item memory effect in the amygdala, in line with earlier studies using the same set of stimuli (Tendolkar et al., 2007). Discussion In the present study, we investigated state- and trait-effects of episodic memory formation for neutral stimuli in patients with a first episode of MDD, patients recovered from a first episode of MDD and healthy controls. In line with our hypothesis, we found a trait related amygdala hyperactivity related to successful episodic memory formation. The importance of this finding, discussed in detail below, is that amygdala hyperactivity may constitute a vulnerability factor for MDD, which plays a role in mnemonic processing of neutral information and not only emotional information. Further, while we did not find any differences in hippocampal activation between the three groups, we did find a state related increase of neural activity related to episodic memory formation in a frontolimbic network of the acutely depressed patients. Since there were no differences in memory performance, this allows us to speculate about the potentially compensatory nature of this activity (Price and Friston, 2002). For biologically salient information, amygdala activation enhances hippocampal dependent memory functions (Dolcos et al., 2004). van Wingen et al. (2010) investigated memory formation and retrieval of happy and neutral face stimuli in depression. Whereas amygdala activity was generally found to be involved in memory formation,

enhanced left amygdala activity during encoding of neutral faces, however, predicted subsequent forgetting in currently depressed patients. On first sight this result seems to contradict the results of the present study, in which trait-related increase of amygdala activity predicted enhanced contextual memory formation of neutral stimuli. However, neutral facial stimuli are always emotional ambiguous, biological salient stimuli, while the neutral stimuli used in the present study consisted of pictures of buildings and landscapes which are substantially less salient. Thus, faces elicit prolonged processing and increased amygdala responses, particularly if these stimuli are evaluated negatively (Blasi et al., 2009), and thus, they are not comparable to the neutral stimuli used in the present study. Moreover, one can expect a negative subsequent memory effect, when processing of highly salient stimuli coincides with a state of heightened emotional processing. There appears to be an inverted U-shape relation with an optimal level of activity contrasted by suboptimal and supraoptimal activity levels associated with reduced effectiveness (Henckens et al., 2009). In situations of stress or acute depression, reduced cognitive control processes exerted by the prefrontal cortex or differences in processing pathways appear to cause unselective, increased input to medial temporal lobe structures. This input, however, is supraoptimal, because it contains task relevant and irrelevant information. In this state, an effective reduction of task irrelevant information improves subsequent memory performance. Thus, van Wingen et al. (2010) argued that greater amygdala responses to neutral faces that were later forgotten may impose such a supraoptimal input in acutely depressed patients. By using a paradigm that specifically engages hippocampal but not amygdala activation in healthy controls (Tendolkar et al., 2007; Weis et al., 2004), we show that in MDD patients amygdala activation specifically interacts with hippocampal dependent memory formation of neutral stimuli. Our data provide first evidence that amygdala hyperactivity, which in MDD has been repeatedly shown in baseline or rest conditions (Drevets, 2003), interferes with demanding mnemonic tasks that are not affectively laden. The ROI-analysis within native space adds strength to this finding because it accounts for volumetric differences between groups. These findings are in line with previous suggestions that amygdala hyperactivity will put more brain systems on alert (Whalen et al., 2002). Our results imply that episodic memory formation in MDD is at least partly dependent on activity within the amygdala, which is normally involved in the processing of emotional or arousing information. This dependency was also confirmed by the correlation we found in the group of depressed and recovered patients between the difference in amygdala activation and source memory performance.

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Previous research indicates that amygdala activation during encoding of stimuli without inherent negative or positive valence contributes mainly to a negative evaluation (Blasi et al., 2009). This may result in neutral information getting an emotional, possibly negative, tag, with increased memory sensitivity. In this regard our results imply a neural emotional processing bias independent of current mood state in depressed patients, which seems to share neural processes that have previously been associated with a moodcongruent memory bias (Hamilton and Gotlib, 2008). Mood congruent memory bias is regarded as one of the most important cognitive factors causing and maintaining depression (Mathews and MacLeod, 2005). It is thought to reflect increased processing of negative information, perhaps due to selective ruminative elaboration, which in turn leads to selective memory enhancement for emotionally negative information or a memory decrease for positive information. Recent fMRI studies have associated the neural correlates of moodcongruent memory bias with an over-recruitment of a neural network involved more generally in enhancing memory for affective stimuli including the amygdala (Hamilton and Gotlib, 2008; Ramel et al., 2007). While this certainly needs to be tested in future studies, it is easily envisioned, how a neural emotional processing bias we find as a trait factor of depression constitutes a vulnerability to develop a mood-congruent memory bias during acute depression or during mood induction in recovered patients (Ramel et al., 2007). When discussing our findings in the context of cognitive theories of depression, we would also like to relate our results to the concept of overgeneralized memory. In contrast to our encoding related changes in depression, overgeneral memory in depression appears to be largely due to the retrieval strategy used, given that such overgenerality in recall can be reduced by taking a wider thinking perspective or by encouraging a less analytic self-focus (Watkins and Teasdale, 2001). Overgeneral memory retrieval is thought to serve as a passive avoidance reaction against negative affective features that were encoded within the episodic memory system. By merely recollecting general descriptions instead of specific episodic memories, this strategy reduces or avoids short-term affective disturbance, thus enabling current goal pursuit to be maintained in the face of potential deflection (Williams et al., 2007). The need for such a mechanism would be substantially increased when neutral information is encoded with more affective features, as a result of the traitrelated contribution of the right amygdala and the state-related contribution of the dorsal stream to episodic memory formation. Though we found a selective hippocampal engagement during episodic memory formation in all three groups, we did not find a hippocampal dysfunction in our patients in line with the absence of volumetric differences in this group (van Eijndhoven et al., 2009). The absence of group differences was paralleled by absent memory performance differences. While this may have obvious advantages when trying to evaluate compensatory activity, our results are in contrast to other, indirect, studies combining neuropsychological testing with structural MRI showing that acutely first-episode MDD patients may have impaired episodic memory without hippocampal volume differences (MacQueen et al., 2003; Vythilingam et al., 2004). Our data suggest that in the early course of MDD altered functioning of the amygdala is more prominent than alterations in hippocampal functioning. A possibility that needs to be tested in subsequent studies is whether the trait-related hyperactivity of the amygdala, explains the absence of differences in hippocampal activation due to its modulatory effects. Currently depressed patients showed more activation during episodic memory formation in a brain network involved in processes of mood perception and regulation as well as memory (Mitchell and Johnson, 2009). This state effect was found in the inferior frontal gyrus, a region mediating episodic memory formation and known to serve maintenance of memory performance in spite of a decline in function in other brain areas (Buckner, 2004). It is also implicated as a

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key region in the interplay between mood and cognition in MDD (Wang et al., 2008). The insula has been implicated before in memory formation (Kirwan et al., 2008), but is more generally known for its role in mood regulation (Reiman et al., 1997). A memory-specific involvement of caudate nucleus (Voermans et al., 2004) as well as thalamus (Aggleton and Brown, 1999) has been found under circumstances of higher cognitive demand where MTL memory function may not be sufficient as could be the case during acute depression. The memory-specific increase of activity in these subcortical structures is further supported by increased activity of the retrosplenial cortex, a key junction between prefrontal regions and hippocampal based mnemonic processing (Nestor et al., 2003). In the absence of direct evidence for impaired hippocampal functionality, our data suggest that depressed patients recruited more brain resources during episodic memory formation when maintaining similar levels of performance. The fact that recruitment of these brain regions was only seen during the more cognitive demanding episodic memory formation supports the compensatory nature of this activation. Part of the brain regions that appear recruited for compensation, such as the insula, retrosplenial cortex and thalamus are part of a limbic circuit that is known for its modulating effects on memory, especially in case of affective material. The overactivation of these structures during acute depression could reflect a ‘limbic shift’ mechanism whereby currently depressed patients show emotional processing for stimuli that have no intrinsic emotional value (Whalen et al., 2002). Interestingly, the state-related changes of neural activity during successful memory formation are largely overlapping with the structures that are part of the dorsal stream. This dorsal stream has an important impact for intrusive memories that are frequently found in depression (Brewin et al., 2010). According to the so-called revised dual representation theory for PTSD, the ventral and visual streams make differential contributions to the formation of episodic memories. The dorsal stream (precuneus, retrosplenial cortex, insula, amygdala) supports sensory-bound representations, such as the perceptual and affective features of an experience (Brewin et al., 2010). The theory predicts that increased frequency of intrusive memories in depression is the result of a larger contribution of the dorsal stream pathway during memory encoding. Our results constitute a confirmation of these theoretical predictions, although we do not have independent data to show that these state-related changes are actually related to the occurrence of memory intrusions. We also found a state-related increase of negative subsequent item memory in the left angular gyrus, which is thought to be part of a default mode network that needs to be deactivated during demanding cognitive tasks (Daselaar et al., 2009). Depressed patients exhibit a higher baseline activity in this network, which may account for disordered self-referential thoughts that are particularly relevant during an acute phase of depression (Sheline et al., 2009). Therefore, our data suggest that depressed patients have to make more efforts to inhibit processes that otherwise would interfere with successful memory formation. A limitation of the present study is its cross-sectional design as state- and trait related changes might be most accurately addressed in a longitudinal design. Further, although we carefully tried to exclude comorbid anxiety disorders, group differences in state and trait levels of anxiety existed and may have confounded our results. It is currently unknown whether symptoms of anxiety are inherently associated with depression or whether anxiety and depression represent two distinct entities with different neural correlates. In sum, we found memory related hyperactivity of the amygdala during memory formation of neutral stimuli representing a neurocognitive trait or vulnerability marker of depression. Moreover, our data show state-related activation of a cortico-limbic network related to episodic memory and mood-regulation that may play compensatory role early in the course of MDD.

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