Journal of Affective Disorders 190 (2016) 880–888
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Abnormal brain activation during directed forgetting of negative memory in depressed patients Wenjing Yang a,b,1, Qunlin Chen a,b,1, Peiduo Liu a,b, Hongsheng Cheng a,b, Qian Cui c, Dongtao Wei a,b, Qinglin Zhang a,b,n, Jiang Qiu a,b,n a
Key Laboratory of Cognition and Personality (SWU), Ministry of Education, Chongqing 400715, China Faculty of Psychology, Southwest University, Chongqing 400715, China c School of Political Science and Public Administration, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, China b
art ic l e i nf o
a b s t r a c t
Article history: Received 1 November 2014 Received in revised form 14 May 2015 Accepted 14 May 2015
The frequent occurrence of uncontrollable negative thoughts and memories is a troubling aspect of depression. Thus, knowledge on the mechanism underlying intentional forgetting of these thoughts and memories is crucial to develop an effective emotion regulation strategy for depressed individuals. Behavioral studies have demonstrated that depressed participants cannot intentionally forget negative memories. However, the neural mechanism underlying this process remains unclear. In this study, participants completed the directed forgetting task in which they were instructed to remember or forget neutral or negative words. Standard univariate analysis based on the General Linear Model showed that the depressed participants have higher activation in the inferior frontal gyrus (IFG), superior frontal gyrus (SFG), superior parietal gyrus (SPG), and inferior temporal gyrus (ITG) than the healthy individuals. The results indicated that depressed participants recruited more frontal and parietal inhibitory control resources to inhibit the TBF items, but the attempt still failed because of negative bias. We also used the Support Vector Machine to perform multivariate pattern classification based on the brain activation during directed forgetting. The pattern of brain activity in directed forgetting of negative words allowed correct group classification with an overall accuracy of 75% (P¼ 0.012). The brain regions which are critical for this discrimination showed abnormal activation when depressed participants were attempting to forget negative words. These results indicated that the abnormal neural circuitry when depressed individuals tried to forget the negative words might provide neurobiological markers for depression. & 2015 Elsevier B.V. All rights reserved.
Keywords: Depression Directed forgetting Inhibitory control Functional magnetic resonance imaging Multi-voxel pattern analysis
1. Introduction Major depressive disorder is a prevalent and debilitating psychiatric illness that is often comorbid with other mental disorders and physical difficulties (Gotlib et al., 2014). Thus, exploring the cognitive characteristics of depressed individuals is important. Negative cognitions are a symptom of depression and are associated with the maintenance and the recurrence of depression. Many studies have demonstrated that depression is associated with the frequent occurrence of uncontrollable negative thoughts and memories (Beck, 2008; Disner et al., 2011; Gotlib et al., 2014; Nolen-Hoeksema, 2000; Roberts et al., 1998). Knowledge on the mechanism underlying intentional memory control in depressed
n Correspondence to: Department of Psychology, Southwest University, Chongqing 400715, China. E-mail addresses:
[email protected] (Q. Zhang),
[email protected] (J. Qiu). 1 Equal contribution.
http://dx.doi.org/10.1016/j.jad.2015.05.034 0165-0327/& 2015 Elsevier B.V. All rights reserved.
individuals might contribute ultimately to the development of an effective method of remediation. The capacity for memory control is commonly explored in the laboratory through two kinds of paradigms: directed forgetting task and think/no-think (TNT) task (Aron et al., 2004; Basden, 1996; Paz-Caballero et al., 2004; Wylie et al., 2008). The directed forgetting paradigm is often used to investigate how inhibitory control at the level of encoding influences intentional forgetting, whereas the TNT paradigm is focused on retrieval suppression (Anderson and Hanslmayr, 2014). The directed forgetting paradigm has two common variants: the item method and the list method. In the item-method directed forgetting, participants are asked to either “remember” (R) or “forget” (F) stimulus in accordance with specific instructions (Wylie et al., 2008). The directed forgetting effect is obtained when items instructed to be forgotten (TBF) are remembered worse than items instructed to be remembered (TBR) during the test phase (Basden, 1996; PazCaballero et al., 2004; Wylie et al., 2008). The present study used the item-method directed forgetting paradigm to explore whether
W. Yang et al. / Journal of Affective Disorders 190 (2016) 880–888
or not inhibition can be engaged during encoding to limit the retention of unwanted memories. Many studies used the directed forgetting paradigm and the TNT paradigm to explore intentional forgetting, but only a few studies investigated this phenomenon in depressed participants (Joormann et al., 2009; Power et al., 2000; Cottencin et al., 2008). Using the item-method directed forgetting paradigm, Power et al. (2000) found that depressed participants showed less forgetting of negative materials. Hertel and Gerstle (2003) used the TNT paradigm to explore this phenomenon and found a reduced inhibition of negative stimuli among dysphoric students. Joormann et al. (2009) obtained similar results. In sum, though some studies have found the opposite results (Joormann et al., 2005), many previous studies found that depressed participants had difficulties in directed forgetting of negative memories. The reduced directed forgetting of negative stimuli is associated with serious rumination and deficient attentional control (Hertel and Gerstle, 2003; Joormann, 2010). Recent studies have attempted to explore the neural mechanism underlying intentional forgetting using functional magnetic resonance imaging (fMRI) and found that frontal cognitive control is important in memory control (Anderson et al., 2004; Depue et al., 2007; Nowicka et al., 2011; Rizio and Dennis, 2013; Wylie et al., 2008). In contrast to intentional remembering, intentional forgetting is associated with activities in the medial frontal gyrus, middle frontal gyrus (MFG), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), superior parietal gyrus (SPG), parahippocampal gyrus, and cingulate gyrus. A few studies explored the neural mechanism underlying intentional forgetting of emotion stimuli (Depue et al., 2007; Nowicka et al., 2011; Yang et al., 2013). Nowicka et al. (2011) explored the different neural substrates of directed forgetting of emotionally negative events. fMRI data showed that forgetting negative information, different from neutral information, is associated with widespread activations extending from the anterior to posterior regions. The involvement of the frontal gyrus in this network seemed to be apparent. Depue et al. (2007) used the TNT paradigm and demonstrated that prefrontal regions controlled the memory suppression of emotional stimuli. Previous neuroimaging studies also revealed that depressed individuals had reduced gray matter volumes in the MFG, bilateral IFG, SFG, left IPG, right anterior cingulate cortex, and left parahippocampal gyrus (Denson et al., 2009; Hooker et al., 2010; Kross et al., 2009; Putnam and McSweeney, 2008). The abnormal frontal and parietal regions involved in the inhibitory and attention processes are apparent in depression (Aron et al., 2004; Fan et al., 2005; Jacobson et al., 2011; Raz and Buhle, 2006; Rubia et al., 2001). Previous evidence suggests that the dysfunctional brain patterns of depressed individuals are similar to the neural mechanism underlying directed forgetting. To the best of our knowledge, no study has directly explored the neural mechanism underlying the directed forgetting of negative memories in depressed patients. In this study, we used the itemmethod directed forgetting paradigm to explore this phenomenon. During the directed forgetting task, participants should control their attention to the TBF items and use the inhibitory control mechanism to inhibit the rehearsal of TBF items or suppress their memory activation (Levy and Anderson, 2008; Zacks et al., 1996). However, depressed individuals experience difficulties in inhibiting negative stimuli because of the negative biased processing (Disner et al., 2011) and dysfunctional prefrontal gyrus of these individuals. Thus, we hypothesized that depressed participants would experience difficulties in intentional forgetting of negative stimuli. The neural mechanism underlying this process might be associated with the prefrontal gyrus (e.g., SFG, MFG, and IFG), which supports inhibitory control. Previous studies also observed that the degree of intentional forgetting was negatively correlated with self-report measures of rumination (Hertel and Gerstle, 2003), and that rumination
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was correlated with the cognitive control of inhibition and thought suppression (Kühn et al., 2012). Therefore, we hypothesized that a correlation existed among rumination, directed forgetting effect, and brain regions that underpin inhibitory control. In this study, we also conducted a tentative analysis based on multivoxel pattern analysis (MVPA) to examine the sensitivity and specificity of the diagnosis of depression achieved with the neural mechanism of directed forgetting. MVPA can be used to separate patients from healthy individuals with structural or functional MRI data (Fu et al., 2008; Orrù et al., 2012). Many studies have already demonstrated that depression is associated with negative bias and impairments in the intentional control of negative memory (Disner et al., 2011; Gotlib et al., 2014; Nolen-Hoeksema, 2000; Roberts et al., 1998). Thus, we assumed that there would be significant classification of depressed patients from healthy controls in the mechanism underlying directed forgetting of negative memory. In our study, the Support Vector Machine (SVM) method (MourãoMiranda et al., 2005; Orrù et al., 2012) was used to discriminate depressed individuals from healthy individuals based on the patterns of neural responses to directed forgetting as evaluated using blood oxygenation level-dependent (BOLD) fMRI. We hypothesized that brain regions which had a stronger contribution to discrimination would be the differences between the depressed and control groups during directed forgetting of negative memories.
2. Methods 2.1. Participants Eighteen depressed outpatients were included in our experiment. These patients would also participate in a prospective depression treatment. Two of these participants were removed from the final data analysis because of excessive head motions. Therefore, 16 depressed participants were included in the data analysis. All the depressed patients were right handed and met the Diagnostic and Statistical Manual of Mental Disorder-IV criteria (American Psychiatric Association, 1996) for major depression. All the depressed participants were in an acute episode of major depressive disorder of the unipolar subtype, with a minimum score of 18 on the 17-item Hamilton Rating Scale for Depression (Hamilton, 1960). At the beginning of the experiment, the participants were asked to complete the Beck Depression Inventory (BDI) (Beck et al., 1961) and the 10-item Chinese Short Ruminative Responses Scale, which was revised from Ruminative Responses Scale (Zhang and Xu, 2010). We also recruited 16 healthy participants as the control group through standard advertisements. The control participants had no history of psychiatric or neurological disorder and matched in age and education with the depressed participants (Table 1). All the participants provided an informed consent. This study was approved by the Academic Committees of Southwest University and Chongqing Medical University in China. Table 1 Demographic features of participants.
Gender (male/female) Age (M 7SD) Education year HRSD scores (M 7SD) BDI scores (M 7 SD)
Depressed group
Control group
P value
7/9 327 8.24 137 2.6 21.3 75.4 16.8 7 8.7
6/10 307 8.98 13 7 3.7 2.6 7 1.4 5.5 7 4.1
0.72 0.87 o 0.001 o 0.01
Note: HRSD: Hamilton Rating Scale for Depression; BDI: Beck Depression Inventory; M: mean; SD: standard deviation.
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2.2. Design and materials A 2 (instruction:R vs. F) 2[valence:neutral (NE) vs. negative (NG)] 2(group:depression vs. control) design was used in this study. The stimuli of this experiment were 120 negative and 120 neutral adjective words. All these neutral and negative adjectives consisting of two Chinese characters were selected from established Chinese Affective Words pools (Wang et al., 2008). To test the validity of the selected words, another 30 students were recruited to rate the valence and the arousal of these words using the Self-Assessment Manikin procedure (SAM; Lang et al., 1997; Riegel et al., 2015). These participants would not participate in the following directed forgetting studies. Using a self-report nine-point rating scale, we asked the participants to rate the emotion valence from very calm to very unpleasant (from 1¼“very unpleasant” to 9¼“very pleasant”) and arousal from very calm to very excited (from 1¼“very calm” to 9¼“very excited”). The sequence of the two ratings was counterbalanced across subjects. These two types of words differed in valence (mean: negative¼2.9070.41; neutral¼ 5.2470.56; T(238)¼19.97, Po0.001) and arousal (mean:negative¼6.4770.76; neutral¼4.6870.48; T (238)¼ 14.31, Po0.001). The familiarity of these neural and negative words was not significant T(238)¼0.14, P40.05. All of the words were randomly divided into two sets, with each set consisting of 120 words. One set served as the learning items, whereas the other was used as distractions in the recognition task. The study and distraction items matched in valence, arousal, and familiarity. The study items were randomly separated into the forget and remember conditions. 2.3. Directed forgetting task The experiment consisted of study and test phases. The participants were scanned only during the study phase. All the participants practiced the experimental procedure until they were familiar with the procedure. The study phase was divided into four runs, with each run consisting of 30 trials. Each trial was initiated by the prompt “ready” which lasted for 2 s. Then, one word of the study sets was displayed on the screen for 2 s. After a 2 s fixation, the memory cue (i.e., remember or forget) was presented on the screen for 2 s. The participants were asked to remember or forget the former presented words based on these memory cues. A random blank lasted for 2, 4, or 6 s at the end of each trial. All the experimental trials were pseudo-random to avoid the same type of instruction or the same type of stimuli continuously presented. The participants finished the test phase outside the scanner. The study words were mixed with the new foil words (60 neutral and 60 negative words). The participants were asked to categorize each word. Each word was displayed on the screen for 2 s after a 2 s prompt “ready”. The participants should press one button if the word had been presented during the study phase, irrespective of the “F” or “R” instruction, and press another button if the word had not been presented before (New) (Fig. 1). A random blank lasted for 2 s or 4 s at the end of each trial. 2.4. fMRI data acquisition Images were acquired with a Siemens 3T scanner (Siemens Magnetom Trio TIM, Erlangen, Germany) equipped with an eightchannel phased array coil. T2*-weighted gradient echo planar imaging (EPI) was used to obtain the functional images [32 slices, voxel size¼3.4 mm 3.4 mm 3 mm voxels; repetition time¼2000 ms; echo time¼30 ms; field of view (FOV)¼220 220 mm2; flip angle¼90°; matrix size¼64 64]. T1-weighted high-resolution anatomical images were also acquired to serve as the anatomical reference (176 sagittal slices, TR¼1900 ms; TE¼ 2.52 ms; FOV¼ 256 256; voxel size¼1 mm 1 mm 1 mm).
Fig. 1. Time sequence of a trial of directing forgetting.
2.5. fMRI data preprocessing and GLM analysis SPM8 (Welcome Department of Cognitive Neurology, London, UK, http://www.fil.ion.ucl.ac.uk/spm/spm8) was used to preprocess the functional images. In the first processing stage, slice timing was used to correct the differences in image acquisition time between slices, and realignment was performed to correct for head motion. These images were then normalized to the MNI EPI template and simultaneously resampled onto a 3 mm 3 mm 3 mm grid. The normalized data were spatially smoothed with a Gaussian kernel with a full width at half maximum of 8 mm 8 mm 8 mm. Low-frequency noise was removed by applying a high-pass filter set at 128 s. After preprocessing, significant hemodynamic changes for each condition were examined with the General Linear Model (Friston et al., 1994). Considering our goal to examine neural activity associated with the cognitive control of memory, we focused our analysis on neural activity associated with the onset of memory cues (F/R). Given the material type (negative/neutral) and the memory cues, the model consisted of four trial types of interest: Remember-Negative (R-NG), Remember-Neutral (R-NE), ForgetNegative (F-NG), and Forget-Neutral (F-NE). The four runs were modeled in one GLM for each participant. The onset of each condition and trial was modeled as a separate event. To correct for movement-related artifacts, six head motion parameters from subject-specific realignment were also included in the model. Contrast coefficients were calculated at the individual level with T-test and were subsequently entered into group-level random-effect analysis to estimate error variance across individuals. The contrasts of interest were F-NG4R-NG and F-NE 4R-NE, which reflected the brain activation when participants attempted to forget the negative and neutral stimuli respectively. To explore the difference between the depressed and control groups when they were attempting to forget the negative and neutral stimuli, we compared contrast images induced by F-NG4R-NG and F-NE4R-NE between these two groups. The whole-brain analysis for a between-group difference was thresholded at a topological FDR cluster-corrected level of P o0.01 (Chumbley et al., 2010). To explore the neural mechanism of successful intentional forgetting, all neutral and negative trials were encoded using a subsequent memory scoring (F/R) system based on previous studies (Bastin et al., 2012; Nowicka et al., 2011; Wylie et al., 2008). BOLD responses were separately modeled for TBR items recognized as “old” at the retrieval session (TBR-R), TBR items not recognized during retrieval (TBR-F), TBF items subsequently retrieved (TBF-R), and TBF items not retrieved (TBF-F). The brain activation of forgetting success was defined by comparing activities associated with successful intentional forgetting (TBF-F) trials and incidental forgetting (TBR-F) trials. Thus, the forgetting success activities were
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independently obtained for the two types of stimuli at the first level for the two groups. Two-sample T-test was conducted at the second level to explore the different brain activations between the control and depressed groups on the two types of materials. These results were thresholded at Po0.001 uncorrected for multiple comparisons with a threshold for minimum spatial extent of 20 contiguous voxels. 2.6. SVM analysis We examined whether or not the function activation profiles during directed forgetting can be used to separate depressed individuals from healthy individuals. The Binary Support Vector Machine was implemented on the Pattern Recognition for Neuroimaging Toolbox to perform multivariate pattern classification based on brain activation during directed forgetting (Schrouff, 2013). Considering our hypothesis that healthy and depressed participants had different responses to negative stimuli during directed forgetting, we firstly created a mask for the directed forgetting network. This mask was then used to constrain the search of significant group differences during directed forgetting of negative memories. Masks for SVM analysis were gained by setting uncorrected threshold of P ¼0.005 on the contrast images of F based on R for each group. Then, masks obtained from the two groups were combined. Contrast images between F-NG and R-NG served as the input images. The depressed group and healthy control group were treated as two classes in the model. Analyses were restricted to the brain areas defined by the masks. Data in each analysis were mean-centered, and a leave one out crossvalidation (LOOCV) procedure (Lemm et al., 2011) was performed. In the LOOCV method, a pair of subjects from the two groups was left to comprise the test set, while the remaining subjects served as the training set. Statistical significance of the classifications was tested with a random permutation test (1000 times). Aside from this region-of-interest analysis, an SVM analysis of the whole brain was also performed. Another SVM analysis was conducted using the individual contrast images of F-NE based on R-NE to examine whether or not the accurate discrimination between the depressed Table 2 Means and standard deviations (Mean7 SD) of the recognition rate of each type material. Neutral items
Depressed group Control group
Negative items
TBR
TBF
TBR
TBF
0.52 7 0.10 0.667 0.19
0.36 7 0.13 0.517 0.18
0.667 0.17 0.747 0.17
0.62 7 0.15 0.58 7 0.22
Note: TBR: to be remembered; TBF: to be forgotten.
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participants can also be driven by directed forgetting of the neutral items.
3. Results 3.1. Behavioral results The mean proportion of the recognition rate in the test period is shown in Table 2. Repeated-measures ANOVA was performed over the recognition rate of the TBR and TBF stimuli, with the stimulus type (neutral and negative) and the memory cues (F and R) as the within-subject factors and the group (patient and the control) as the between-subject factor. Results showed that the main effect of memory cue was significant [F(1, 30)¼ 65.62, Po0.001, partial η2 ¼0.69], with the TBR items (0.6570.03) more recognized than the TBF items (0.5270.03). The effect of the type of materials was also significant [F(1, 30)¼32.93, Po0.001, partial η2 ¼ 0.52], with the recognition rate of negative stimuli (0.6570.03) higher than that of neutral stimuli (0.5170.03). Moreover, significant two-way interactions of stimulus type memory cue [F(1, 30)¼ 6.18, Po0.05, partial η2 ¼ 0.17] and group stimulus type [F(1, 30)¼7.38, Po0.05, partial η2 ¼0.20] were observed. A significant three-way interaction of memory cue stimulus type group [F(1, 30)¼6.73, Po0.05, partial η2 ¼0.18] was also detected. Simple effect analysis showed that the directed forgetting effect was significant for the control participants both on negative stimuli [F(1, 30)¼20.09, Po0.001, partial η2 ¼0.40] and neutral stimuli [F(1, 30)¼72.55, Po0.001, partial η2 ¼0.71]. Meanwhile, the directed forgetting effect was significant for the depressed participants on neutral stimuli [F(1, 30)¼77.15, Po0.001, partial η2 ¼ 0.72]. However, the directed forgetting effect was not significant for the depressed participants on negative stimuli [F(1, 30)¼ 1.19, P40.05]. The index of directed forgetting effect was the rate of the TBF items that were not retrieved by the participants in the test phase (Bastin et al., 2012; Wylie et al., 2008). Fig. 2B shows a negative correlation (R ¼ 0.57, P o0.05) between scores on the self-report rumination and the directed forgetting effect for negative stimuli in the depressed group but not in the control group. A positive correlation was detected between the rumination and BDI scores of the depressed participants (Fig. 2A). 3.2. GLM analysis results For the between-group analysis, directed forgetting of negative stimuli revealed clear differences between the control and depressed groups. When they intended to forget negative stimuli, the depressed group had stronger activation in the bilateral IFG, right SFG, right SPG, and right ITG than the control group; however, the control and depressed groups revealed no significant
Fig. 2. (A) Positive correlation between the rumination and BDI scores for the depressed individuals; (B) negative correlation between the rumination scores and the negative directed forgetting effect in the depressed participants. (C) Negative correlation between the activation of the right inferior frontal gyrus (IFG) and the rumination scores for the depressed participants. *Means Po 0.05; **means Po 0.001.
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differences when they attempted to forget neutral stimuli. We used a lenient threshold of uncorrected and cluster 450 for explanatory analysis. We did not obtain any significant results (Table 3 and Fig. 3A). We then concentrated on the neural mechanism of successful intentional forgetting. In the case of negative words, the comparison between TBF-F and TBR-F showed that the activation in the bilateral IFG and the right cuneus was higher in the depressed group than in the control group; in the case of neutral words, the two groups did not show any significant differences (Table 3 and Fig. 3B). The rumination score of the depressed individuals significantly negatively correlated with the degree of activation in the right IFG (R ¼ 0.54, P o0.05) (Fig. 2C). A significant negative correlation was also detected between the self-report rumination and the directed forgetting effect for negative stimuli in the depressed group. To establish whether or not rumination mediated the negative correlation between the right IFG and the directed forgetting effect, a mediation analysis was conducted using an indirect macro implemented in SPSS (Preacher and Hayes, 2008). Mediation analysis showed that rumination mediated the association between the right IFG and the directed forgetting effect [95% confidence interval; indirect effect ¼ 0.44; SE¼ 0.009; lower limit ¼ 1.07; upper limit ¼ 0.02].
Table 3 Region of significant activations with Standard General Linear Model analysis on the contrasts of F 4R and TBF-F 4TBR-F of the negative words between the depressed and the control groups. Anatomical region
MNI coordinates
Number of voxels
t-Value
X
Y
Z
F 4R (NG) Inferior temporal gyrus Superior parietal gyrus Inferior frontal gyrus Inferior fontal gyrus Superior frontal gyrus
66 6 30 48 12
33 66 21 42 24
21 36 21 9 54
401 528 577 970 727
5.53 5.47 5.35 4.52 4.45
TBF-F 4TBR-F (NG) Inferior frontal gyrus Inferior frontal gyrus Cuneus
60 60 15
24 30 84
6 6 24
277 83 802
3.87 4.16 4
Note: MNI: Montreal Neurological Institute stereotactic space; F4 R (NG): the brain activations when participants attempted to forget the negative stimuli; TBFF 4TBR-F (NG): the brain activation of successful forgetting of negative stimuli.
3.3. MVPA analysis results SVM analysis with the contrast images between F-NG and R-NG resulted in a significant balance accuracy of 75% (P o0.05) for the classification between depressed participants and healthy individuals when restricting the analysis to the mask of the directed forgetting network. However, no statistically significant classification was found when the SVM analysis performed including the whole brain (balanced accuracy¼50%, P ¼0.442). Fig. 4 shows a multivariate discrimination map of the most discriminating regions between the depressed and control groups. Table 4 presents the important activation regions for discriminating the depressed patients from the healthy individuals. SVM analyses with the contrast images of F-NE over R-NE did not reveal statistically significant classification accuracies whenever the SVM analysis was performed including the defined directed forgetting network mask or the whole brain analysis.
4. Discussion To the best of our knowledge, this study is the first to examine the neural functioning of depressed individuals while doing directed forgetting task. The behavioral results were consistent with previous reported that depressed participants could not intentionally forget negative stimuli (Hertel and Gerstle, 2003; Joormann et al., 2009; Power et al., 2000). The fMRI results revealed that the depressed participants had higher activation in the IFG, SFG, SPG, and ITG than the healthy participants when forgetting the negative words. However, no significant neural difference in directed forgetting of neutral words was observed between the two groups. Rumination may mediate the correlation between the activation of the right IFG and the directed forgetting effect. The SVM results also showed that brain patterns, which reflected abnormal activations in the IFG, SPG, and ITG when depressed individuals intended to forget negative words, can be used to discriminate the depressed participants from the control participants. These results might provide a neurobiological biomarker for depression. The fMRI results showed that the stronger bilateral IFG and SFG activation was associated with the depressed participants than the healthy participants when they attempted to forget the negative words and when this attempt was a success. Previous directed forgetting studies also found that the IFG, SFG, and MFG activation was associated with the inhibitory control during intentional forgetting (Nowicka et al., 2011; Rizio and Dennis, 2013; Wylie et al., 2008). The present results suggested that the depressed group recruited more frontal inhibition resources during directed forgetting of negative
Fig. 3. Different brain activations between the depressed and control groups when attempting to forget negative memory (F_Negative4R_Negative) and when the intentional forgetting attempt success. All significant clusters are shown at the peak effect coordinates.
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Fig. 4. (A) Weight vector map indicating the top 30 percentile discriminating voxels. Blue represents the regions that contributed more to classifying depressed individuals, whereas red represents the regions that contributed more to the classification of healthy controls; (B) this graph shows the projection of each participant onto the weight vector, with a negative pattern (red diamond) discriminating for depressed patients and a positive pattern (green square) discriminating for controls; (C) receiver operating characteristic (ROC) curve shows the trade-off between sensitivity and specificity, including area under the curve (AUC¼ 0.75).
Table 4 Important activation regions for discriminating the depressed and control groups. Anatomical region
Side
MNI coordinates
Wi
X
Y
Z
Control4depressed patient Middle temporal gyrus L Inferior frontal gyrus L Inferior frontal gyrus L Middle occipital gyrus L Inferior parietal gyrus L
57 30 54 33 36
48 27 9 78 57
12 0 15 33 45
26.07 35.4 26.33 29.28 29.28
Depressed patient 4 control Inferior frontal gyrus L Inferior temporal gyrus R Parahippocampa gyrus L Medial frontal gyrus L Inferior frontal gyrus L Inferior frontal gyrus R Superior parietal gyrus R
33 63 15 9 51 57 30
24 36 12 30 36 12 72
21 21 15 21 9 3 54
40.14 43.34 35.07 32.59 31.26 30.63 6.18
Note: L: left; R: right; MNI: Montreal Neurological Institute stereotactic space; Wi: weight of each cluster centroid.
memory than the control group. Numerous fMRI and lesion-based studies demonstrated that the IFG and SFG were centrally involved in inhibitory control (Aron et al., 2004; Chambers et al., 2006; Garavan et al., 1999; Jacobson et al., 2011; Konishi et al., 1999; Li et al., 2008; Rubia et al., 2001; Padmala and Pessoa, 2010; Swick et al., 2008). For example, Hampshire et al. (2010) used the classical response inhibition stop signal task and demonstrated the important role of the right IFG in response inhibition. The inhibition hypothesis of directed forgetting holds directed forgetting results from the
attentional inhibition of information during encoding (Levy and Anderson, 2008; Zacks et al., 1996). Specifically, the “F” instruction triggers attentional inhibition that terminates the rehearsal of TBF items or suppresses their memory activation to below baseline levels (Nowicka et al., 2011; Zacks et al., 1996). However, considerable evidence showed that depressed patients suffer from executive and prefrontal inhibitory dysfunction (Alexopoulos, 2002; Goodwin, 1997; Langenecker et al., 2007; Rogers et al., 2004) and rumination for negative stimuli (Beck, 2008; Gotlib et al., 2014; Joormann, 2010). Thus, depressed patients cannot easily inhibit the negative TBF items. Previous studies also demonstrated that because of the dysfunction of the inhibitory ability of the depressed individuals, they had greater activation in the IFG compared to the control group in the behavioral inhibition task (Langenecker et al., 2007). Our findings suggest that the depressed patients have stronger activation within the neural network of inhibitory control during the directed forgetting of negative words than the healthy individuals. A subsidiary result showed a negative correlation between the self-report rumination and the directed forgetting effect for negative memory. Rumination could partially mediate the relationship between the activation of the right IFG and the directed forgetting effect in the depressed group. These results indicated that the participants who reported more rumination had more trouble in directed forgetting of negative stimuli. It is well documented that the depressed adults reported more rumination than the non-depressed individuals (Alloy et al., 1999; Barnett and Gotlib, 1988). Our study also showed a positive correlation between the BDI scores and the self-report rumination scores. Some studies demonstrated that rumination was associated with volume in the right IFG, which was related to the cognitive control of inhibition and thought suppression (Kühn et al., 2012). These results may indicate that rumination may influence the abnormal
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function of the IFG and then reduce the directed forgetting effect on negative words. In addition to bilateral IFG activation, abnormal activation in the SPG and ITG was also related to the directed forgetting of negative memories among depressed participants. Research of cognitive control proved that the parietal gyrus plays an important role in both motor inhibition (Simmonds et al., 2008) and retrieval suppression (Anderson and Huddleston, 2012). Neuroimaging studies demonstrate that the SPG is part of the attentional control network and participates in mediating voluntary orientation and reorientation of attention (Corbetta and Shulman, 2002; Fan et al., 2005; Hopfinger et al., 2000; Raz and Buhle, 2006; Weissman et al., 2006). An alternative explanation for the association of SPG activation engaged in directed forgetting was that this region might prevent attention from TBF items and oriented their attention to the TBR items (Bastin et al., 2012; Saletin et al., 2011). The negative cognitive bias of depression complicated attention shifting from negative TBF stimuli (Beck, 2008; Gotlib et al., 2014; Joormann, 2010). Several studies demonstrated the important role of ITG in working memory (Desmond et al., 2003; Miller et al., 1993; Nakamura and Kubota, 1995; Ranganath et al., 2004). During the directed forgetting task, the TBF items were not shown on the screen when the “F” instructions were presented. Thus, the participants should first store the TBF items in the working memory and then use the frontal inhibitory mechanism to inhibit these TBF items (Nowicka et al., 2011; Wylie et al., 2008). Depressed participants have a biased memory for the negative stimuli, so the stronger activation of ITG was associated with the negative stimuli (Burt et al., 1995; Koster et al., 2010; Watkins et al., 1996). The stronger activation of the SPG and ITG in forgetting negative stimuli for the depressed participants may indicate that though the depressed participants recruited more frontal and parietal inhibitory resources to inhibit negative stimuli, the bias processing for negative memory contributed to this inhibitory attempt failure. The results also showed that the SVM analysis was able to discriminate the depressed individuals from the healthy individuals on the basis of brain regions associated with directed forgetting. In line with our hypothesis, the critical brain regions that showed significant discrimination were the IFG, ITG, and SPG. These brain regions showed abnormal activation during directed forgetting of negative memory. Aside from these brain regions, other regions (e.g., the MFG and the parahippocampal gyrus) also engaged in this discrimination. Similarly, previous studies demonstrated that the MFG played an important role in inhibitory control (Aron et al., 2003; Chikazoe et al., 2007; Liddle et al., 2001) and that the parahippocampal gyrus was crucial in the working memory (Courtney et al., 1996; Herwig et al., 2010; Reetz et al., 2008). The abnormal activation of these two regions coincided with the GLM results and suggested that the inhibitory attempt failed because of biased attention and memory for negative stimuli, even though the depressed individuals used more frontal inhibitory resources than the healthy individuals to inhibit the TBF items. Previous studies used the brain regions of the fMRI during the emotion task or the working memory task to discriminate the depressed individuals from the healthy ones (Fu et al., 2008; Marquand et al., 2008). The present results indicated that the brain activation in the directed forgetting of the negative memory can be used as a biomarker for distinguishing the depressed participants from the healthy participants. Current depression diagnosis is mainly based on clinical signs and symptoms, and only a few neurobiological diagnostic markers are used for clinical depression diagnosis (Fu et al., 2008; Marquand et al., 2008). The results of the present study might aid in the diagnosis of clinical depression. Nevertheless, the present study still has some limitations. First, the sample size of the present study was modest. LOOCV is highly biased for a small number of subjects. Thus, a large sample size is
needed to testify our results. Second, the classification lacks an additional independent sample to test the classification algorithm. Therefore, caution should be exercised in interpreting the SVM results. In addition, we did not collect the affective ratings of participants who underwent fMRI. Future studies should consider this rating to provide additional information about the clinical population.
5. Conclusion The present study demonstrated that it was difficult for the depressed participants to forget the negative words. The fMRI results indicated that depressed participants had stronger activation in the IFG, SFG, SPG, and ITG when they attempt to forget the negative stimuli. The depressed participants recruited more frontal and parietal inhibitory control resources to inhibit the TBF items, but the attempt still failed because of negative bias. The MVPA results suggested that a multivariate approach could be used to distinguish depressed individuals from healthy individuals on the basis of brain activation in relation to the directed forgetting of negative words. Brain regions that showed abnormal activation when depressed individuals attempt to forget negative memory are critical for this discrimination. Thus, the neural mechanism underlying directed forgetting of negative memory can be used to identify diagnostic biomarkers for depression.
Role of funding source The study was supported by the National Natural Science Foundation of China (31470981; 31400901) and the Fundamental Research Funds for the Central Universities (SWU1509343).
Conflict of interest The authors declare no competing interests.
Acknowledgments We thank Arne Dietrich for his assistance with language, the participants and all the other team members for their support and help.
Appendix A. Supplementary material Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.jad.2015.05.034.
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