Psychological Medicine (2010), 40, 425–432. f Cambridge University Press 2009 doi:10.1017/S0033291709990596
O R I G I N A L AR T I C LE
Increased neural response to fear in patients recovered from depression: a 3T functional magnetic resonance imaging study R. Norbury1*, S. Selvaraj1, M. J. Taylor1, C. Harmer2 and P. J. Cowen1 1 2
Psychopharmacology Research Unit (PPRU), University of Oxford, Department of Psychiatry, Oxford, UK Psychopharmacology and Emotion Research Laboratory (PERL), University of Oxford, Department of Psychiatry, Oxford, UK
Background. Previous imaging studies have revealed that acute major depression is characterized by altered neural responses to negative emotional stimuli. Typically, responses in limbic regions such as the amygdala are increased while activity in cortical regulatory regions such as the dorsolateral prefrontal cortex (DLPFC) is diminished. Whether these changes persist in unmedicated recovered patients is unclear. Method. We used functional magnetic resonance imaging to examine neural responses to emotional faces in a facial expression-matching task in 16 unmedicated recovered depressed patients and 21 healthy controls. Results. Compared with controls, recovered depressed patients had increased responses bilaterally to fearful faces in the DLPFC and right caudate. Responses in the amygdala did not distinguish the groups. Conclusions. Our findings indicate that clinical recovery from depression is associated with increased activity in the DLPFC to negative emotional stimuli. We suggest that this increase may reflect a compensatory cortical control mechanism with the effect of limiting emotional dysregulation in limbic regions such as the amygdala. Received 24 November 2008 ; Revised 22 May 2009 ; Accepted 2 June 2009 ; First published online 23 July 2009 Key words : Amygdala, depression, fMRI.
Introduction Acute major depression is associated with pervasive negative biases in the processing of emotional information. Developments in functional brain imaging have allowed the neural circuitry supporting emotional processing to be increasingly well characterized. For example, a ventral system that includes the amygdala, ventral striatum and orbitofrontal cortex has been identified (Phillips et al. 2008), which is involved in detecting the emotional significance of environmental stimuli and representing ensuing affective states. A complementary dorsal system, including the hippocampus, dorsal anterior cingulate and dorsolateral prefrontal cortex (DLPFC), appears to have a regulatory role in emotional processing and integrates emotional input with cognitive processes. In particular, the DLPFC is activated by explicit tasks involving emotional content as compared with more implicit tasks (Hariri et al. 2005). * Address for correspondence : Dr R. Norbury, Psychopharmacology Research Unit (PPRU), University of Oxford, Department of Psychiatry, Neurosciences Building, Warneford Hospital, Headington, Oxford OX3 7JX, UK. (Email :
[email protected])
Neuroimaging studies of acutely depressed patients have consistently reported amygdala hyperactivity (Sheline et al. 2001 ; Fu et al. 2004 ; Siegle et al. 2007) and DLPFC hypoactivity (Johnstone et al. 2007 ; Siegle et al. 2007 ; Fales et al. 2008, 2009) in response to negative emotional stimuli. Taken together, these findings provide evidence for a disrupted cortico-limbic circuitry in major depressive disorder implicating both bottomup and top-down dysfunction in emotional processing. Recovered unmedicated depressed patients continue to show some evidence of negative emotional biases in behavioural studies (Bhagwagar et al. 2004 ; Bhagwagar & Cowen, 2008) ; however, the neural correlates of these enduring changes in emotional processing are unclear ; it is not known, for example, whether the pattern of amygdala hyperactivity and DLPFC hypoactivity persists. Treatment of depressed patients with antidepressant medication does apparently normalize amygdala and DLPFC activity but whether such changes persist once medication is withdrawn is not known (Fu et al. 2004 ; Fales et al. 2009). In the current study we used functional magnetic resonance imaging (fMRI) to assay neural responses in recovered depressed (RD) patients and healthy
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controls (HC) during an emotional face-matching (fearful and happy faces) paradigm designed to activate both the amygdala and regulatory areas involving the DLPFC (Hariri et al. 2005 ; Drabant et al. 2009). We hypothesized that relative to controls, the recovered patients would show increased amygdala activation to fearful versus happy faces but normal DLPFC activity, reflecting regulatory control of limbic activity during clinical recovery. Method Participants We recruited 16 patients who had suffered at least two previous episodes of depression (nine females and seven males, age range 18–57 years) (RD) and 21 never-depressed healthy volunteers (10 females and 11 males, age range 19–63 years) (HC). RD participants had been euthymic and medication free for at least 8 months ; three patients were drug naive. Nine patients had a family history of mood disorder. Three RD patients had co-morbid illness ; one had social phobia and two subjects had a history of alcohol misuse but not dependence. HC subjects and those with previous depression were similar in terms of their age [mean 32.3 (S.D.=12.9) and 36.2 (S.D.=13.9) years, respectively], gender (x2=0.007, df=1, p=0.993), Beck Depression Inventory score [2.3 (S.D.=2.4) and 3.5 (S.D.=3.7)] and State-Trait Anxiety Inventory scores [state 31.9 (S.D.=6.6) and 30.75 (S.D.=7.9), trait 31.9 (S.D.=7.3) and 36.7 (S.D.=9.5)] as assessed immediately prior to scanning. All subjects provided written informed consent prior to entry into the study, which was approved by the Oxford Research Ethics Committee, and received an honorarium for their participation. Subjects were briefed on scanner safety and had no contraindications for fMRI examination. fMRI task design During fMRI scanning, subjects completed a simple perceptual task involving the matching of fearful and happy facial expressions known to robustly engage the amygdala (Hariri et al. 2005 ; Paulus et al. 2005 ; Stein et al. 2007). In this task, nine 30 s blocks of a sensorimotor control task (condition A) were interleaved with eight 30 s blocks of the emotional task [four blocks of fear (condition B) and four blocks of happy (condition C)]. To reduce potential carry-over effects, cycles of alternation between conditions were counterbalanced across subjects. Thus, during the course of the 8.5 min experiment half of the subjects completed the following order : ABACABACABACABACA, the remaining subjects ACABACABACABACABA. During the emotional matching task subjects
viewed a trio of faces, all derived from a standard set of pictures of facial affect (Matsumoto & Eckman, 1988). Faces were presented in a triangular configuration and subjects were asked to select the one of two bottom faces (probes) that expressed the same emotion as the top (target) face. Each emotional block consisted of six trials, presented sequentially for 5 s. During the sensorimotor control task, subjects viewed a trio of geometric shapes (rectangles) in a triangular configuration and selected the one of two bottom shapes that matched the orientation (either vertical or horizontal) of the target (top shape). Each sensorimotor control block consisted of six trials, presented sequentially for 5 s. Stimuli were presented on a personal computer using E-PRIME (version 1.0 ; Psychology Software Tools Inc., USA) and projected onto an opaque screen at the foot of the scanner bore, which subjects viewed using angled mirrors. Subject responses were made via an MRI-compatible keypad. Both emotion matching accuracy and reaction times were recorded by E-PRIME.
fMRI data acquisition All imaging data were collected using a Varian 3T scanner located at the Oxford Centre for Functional MRI of the Brain (FMRIB ; University of Oxford, UK). Functional imaging consisted of 28 T2*-weighted echoplanar image (EPI) coronal oblique slices [3 mm slice thickness ; 64r64 in plane resolution ; field of view 192 ; 258 volumes ; repetition time (TR)/echo time (TE)/flip angle=2000 ms/30 ms/60x]. Slices were prescribed perpendicular to the anterior commissure– posterior commissure (AC–PC) line then tilted about 30x in the rostral direction to provide coverage of the amygdala and prefrontal cortex including the anterior cingulate. These parameters were selected to optimize the amygdala signal and have been used extensively in earlier studies assessing amygdala function (Johnstone et al. 2005 ; Whalen et al. 2008). The first three EPI volumes in each session were discarded to avoid T1 equilibration effects.
fMRI data analyses fMRI data were pre-processed and analysed using freely available software tools within FMRIB’s Software Library (FSL, version 4.1 ; Smith et al. 2004). Preprocessing included within-subject image realignment (Jenkinson et al. 2002), non-brain removal (Smith, 2002), spatial normalization to a study-specific custom template using an affine procedure (Jenkinson & Smith, 2001) and spatial smoothing using a Gaussian kernel (5 mm full-width-half-maximum). The time
Imaging recovery from depression series was high pass-filtered (to a maximum of 0.008 Hz). Analyses of data from individual subjects were computed using the general linear model with local autocorrelation correction (Woolrich et al. 2001). Two explanatory variables were modelled : ‘ fearful faces ’ and ‘ happy faces ’. These explanatory variables were modelled by convolving each emotion block with a haemodynamic response function, using a variant of a c function (i.e. a normalization of the probability density function of the c function) with a standard deviation of 3 s and a mean lag of 6 s). In addition, temporal derivatives were included in the model as covariates of no interest to increase statistical sensitivity. Individual subjects’ data were combined at the group level using a full mixed-effects analysis (Woolrich et al. 2004). This mixed-effects approach enables generalization of the results beyond the sample of subjects tested. Characterising between-group differences on task-specific brain activity may be confounded by the possibility that changes in activation are actually produced by a shifting baseline, rather than by a change in the brain response to the task itself. With this in mind, all comparisons we report directly contrast fearful with happy facial expressions (i.e. groupremotion interactions) rather than to an under-specified, low level baseline or resting condition. Significant activations were identified using cluster-based thresholding of statistical images with a height threshold of Z=2.3 and a (corrected) spatial extent threshold of p80 % correct matching identifications) which was not affected by previous depression [F(1, 34)=2.078, p=0.16]. Similarly, latency was not affected by previous depression [F(1, 34)=3.6, p=0.07]. There was a main effect of face type [F(2, 68)=97.48, p
