Paul Keedwell

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Subgenual cingulate and visual cortex responses to sad faces predict clinical outcome during antidepressant treatment for depression.

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Journal of Affective Disorders
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j a d

Research report

Subgenual cingulate and visual cortex responses to sad faces predict clinical outcome during antidepressant treatment for depression☆
Paul A. Keedwell a,⁎, Dominique Drapier b, Simon Surguladze b, Vincent Giampietro c, Mick Brammer c, Mary Phillips a
a b c

Neurobiology of Mood Disorders, Department of Psychological Medicine, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom Section of Neuroscience and Emotion (PO 69), Institute of Psychiatry, Decrespigny Park, London SE5 8AF, United Kingdom Brain Image Analysis Unit, Centre for Neuroimaging Sciences (PO 89), Institute of Psychiatry, Decrespigny Park, London SE5 8AF, United Kingdom

a r t i c l e

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a b s t r a c t
Background: Previous follow-up studies indicate that increased visual cortical, ventral cingulate and subcortical responses of depressed individuals to sad facial stimuli, but not happy stimuli could represent reversible markers of disease severity. We hypothesized that greater responses in these areas to sad stimuli, but not happy stimuli, would predict better subsequent clinical outcome. We also explored areas that would predict a poor outcome. Methods: Twelve melancholically depressed individuals in the early stages of antidepressant treatment in a secondary care setting participated in two experiments comparing responses to varying intensities of sad and happy facial stimuli, respectively, using event related functional MRI. They repeated the experiments after a mean delay of 12 weeks of treatment. Results: There was a variation in response to treatment. Greater right visual cortex and right subgenual cingulate (R-BA25) responses to sad stimuli, but not happy stimuli, in the early stages of treatment were associated with a good clinical outcome. Greater ventrolateral prefrontal cortex responses to either stimulus type were associated with a relatively poor outcome. Limitations: The sample size was modest and patients were taking a variety of antidepressants. Conclusions: Right subgenual cingulate and right visual cortical responses to sad stimuli predict good clinical outcome in the context of antidepressant treatment for severe depression in a naturalistic setting. Ventrolateral prefrontal cortex activity may indicate poor prognosis due to its relationship with negative rumination. © 2009 Elsevier B.V. All rights reserved.

Article history: Received 27 November 2008 Received in revised form 18 March 2009 Accepted 16 April 2009 Available online xxxx Keywords: Treatment Depression fMRI Emotion recognition Antidepressant Prognosis

1. Introduction Neuroimaging techniques offer great promise in helping researchers to predict responses to treatment in depression. Previous follow-up studies have indicated that increased visual cortical, ventral cingulate and subcortical responses of depressed individuals to sad facial stimuli, but not happy stimuli, decrease after a period of antidepressant treatment

☆ This research was funded by the Goldsmith Charitable Foundation. ⁎ Corresponding author. Tel.: +44 2920687065; fax: +44 2920687068. E-mail address: keedwellpa@cf.ac.uk (P.A. Keedwell). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.04.031

(Keedwell et al., 2008; Davidson et al., 2003; Fu et al., 2004; Sheline et al., 2001). Most have demonstrated a direct correlation between change in neural response and change in symptoms (Keedwell et al., 2008; Fu et al 2004, Davidson et al., 2003). However, markers of clinical response are not the same as predictors of response at baseline. We conducted further analysis of data arising from a recent follow-up study (Keedwell et al., 2008) to compare the predictive power of responses to sad versus happy stimuli by examining correlations between brain responses in the early stages of treatment and the size of the subsequent drop in depression scores. More speciﬁcally, we hypothesized that, on the basis of data on markers of response, greater responses to

Please cite this article as: Keedwell, P.A., et al., Subgenual cingulate and visual cortex responses to sad faces predict clinical outcome during antidepressant treatment for depression, J. Affect. Disord. (2009), doi:10.1016/j.jad.2009.04.031

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sad faces, but not happy faces, in the subgenual cingulate gyrus at baseline would predict greater clinical improvement in the context of antidepressant treatment. In addition, we explored indicators of poor outcome. 2. Methods 2.1. Subjects The study was conducted with the approval of the NHS Research Ethics Committee and the local NHS Trust and Institute Research Governance committee. Participants gave their full informed consent. We recruited 12 subjects, 6 males and 6 females, with a mean age of 49 from the inpatient and outpatient departments of the Maudsley Hospital, Decrespigny Park, London. They all met ICD-10 criteria for a major depressive episode. Participants had a variable number of depressive episodes in the past. They were not systematically recruited on the basis of depression severity, number of previous episodes, or prior response to antidepressants because of the naturalistic nature of the investigation and because a range of treatment responsiveness was required in order to make conclusions about prediction of response. Patients with psychotic symptoms, a history of mania or hypomania, comorbid current or past alcohol or drug misuse, cognitive deﬁcits, and organic brain disease, including history of trauma, were excluded by a trained psychiatrist. In this naturalistic study we endeavoured to recruit patients who were severely depressed and who had just commenced antidepressant treatment in real clinical settings (Time 1). They had all been started on new treatments within the previous 2 weeks. They were being treated with a variety of different antidepressant treatments. The mean follow-up time (Time 2) was 12 weeks (range 8–16 weeks). Depression severity was measured at Time 1 and Time 2 using the 21 item Hamilton Rating Scale for Depression (HRSD, Hedlung and Vieweg, 1979) and the Beck Depression Inventory (BDI, Beck et al., 1961). 2.2. Functional neuroimaging task This was identical to the task carried out in previously published studies (Keedwell et al., 2008; Surguladze et al., 2005). All individuals participated in two six minute experiments employing event related functional magnetic resonance imaging (fMRI). They were presented with a baseline ﬁxation cross, 20 neutral expressions, or emotional expressions of either 50% or 100% (prototypical) intensity (n = 20 for each intensity). In one experiment the emotional expression was of sadness and in the other it was of happiness. Expressions were posed by 10 different volunteers (4 male volunteers) from a standardized computer-morphed series (Ekman and Friesen, 1976). Participants were asked to focus on the gender rather than emotional content of faces to investigate involuntary responses. Their task was to choose the gender of the face using a button box. The order of experiment was counter-balanced and within each experiment both the order of expressions and the inter-stimulus interval (3–8 s) were randomized. During the ISI patients viewed the ﬁxation cross. Facial expressions were always presented for 2 s.

2.3. Neuroimaging data analysis Imaging acquisition employed a GE Signa 1.5 T Neurooptimised MR system (General Electric, Milwaukee, Wisconsin) at the Maudsley Hospital, London, using the same EPI parameters as described in our previous study. The data were analyzed using the Institute of Psychiatry software (Brammer et al., 1997; Bullmore et al., 1999a). Neural responses to prototypic (100%) emotion were compared with baseline by time series analysis using gamma variate functions (peak responses between 4 and 8 s) to give the best-ﬁt (leastsquares) model of the time series of the BOLD response at each intracerebral voxel. This parametric data-driven, permutation-based approach for determining %BOLD change and signiﬁcance at each voxel and cluster of voxels is set out in detail in Bullmore et al. (1999b). The Generic Brain Activation Map (GBAM) levels of signiﬁcance were set at p = 0.05 at the voxel level and p = 0.01 at the cluster level. The statistical thresholds for detection of clusters showing signiﬁcant correlations between behavioural measures (change in HRSD score) and whole brain responses (BOLD effect sizes) to prototypically sad or happy faces (100% intensity) were set at: voxelwise p = 0.05, clusterwise p = 0.005 This level of signiﬁcance ensured b1 false positive cluster in each correlation. Voxel dimensions were 3 mm× 3 mm× 7 mm. The minimum number of voxels to form a cluster was 2 voxels. 3. Results 3.1. Behavioural results Consistent with a secondary care setting HAMD scores at Time 1 were in the severe range (mean = 25, range = 15–35; SD = 0.7), dropping by a mean of 14 points to the mild range by Time 2 (mean = 11; range = 2–24; SD = 10.4). There was a broad range of clinical improvement (change in score varied from − 2 to 27; SD = 11.3), evidenced by the lack of correlation between scores at Time 1 and Time 2 (r = 0.19, p = 0.556, 2 tailed). Variance in the size of change (SD = 11.3) was correlated with variance in scores at Time 2 (SD = 10.3), not Time 1 (SD = 0.7). There was no main effect of emotion (happy, sad; F = 1.226, p = 0.269) on the accuracy of gender recognition. Response predictors at Time 1: Correlations between neural responses to prototypical stimuli measured at Time 1 (GBAMs for 100% sad and happy faces) and subsequent change in HRSD score measured at Time 2 (at threshold signiﬁcance level p = 0.005). A positive correlation indicated an increasing neural response with greater subsequent changes in HRSD score and hence was indicative of a favourable response to antidepressant therapy. A negative correlation indicated an increasing neural response with smaller subsequent changes in HRSD score and hence was indicative of a poor response to antidepressant therapy. For sad stimuli (in order of cluster size), positive correlations were seen in the right subgenual cingulate gyrus (Brodmann Area 25; cluster size 11; Talairach coordinates 7,15,−7), right primary visual cortex (BA18; 8; 4,−74,−7), right cerebellum (BA71; 9; 0,−41,−13), left primary visual cortex (BA18; 9; −4, −70,−2), right parahippocampal area (BA36; 8; 22,−26,

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Fig. 1. Correlations between neural responses to prototypical sad faces at Time 1 (percentage change in BOLD signal versus baseline) and subsequent change in HRSD scores (Score at Time 2 − Score at Time 1). BOLD = blood oxygenation level dependent. HRSD = Hamilton Rating Scale for Depression. Good response was predicted by positive correlations in the R subgenual cingulate gyrus (BA25; labelled SG at crosshairs; Talairach coordinates: 7,15,− 7), and R parahippocampal area (PH; 22,−26,−24). Poor response was predicted by correlations in the R orbitofrontal/VLPFC area (BA11/47; labelled OB; at crosshairs; 22,59,− 13).

−24), right postcentral gyrus (BA1; 8; 47,−19,42), right inferior posterior temporal lobe (BA37; 3; 25,−48,−7) and right caudate (3; 7,19,−2). Negative correlations were seen in the right ventrolateral prefrontal cortex (BA47; 17; 18,26,−24), left inferior temporal gyrus (BA19; 9; −43,−74,−2), left primary visual cortex (BA18; 9; −22,−89,9), bilateral pregenual cingulate gyrus (BA24; 7; 0,26,26), bilateral dorsomedial prefrontal cortex (BA9/10; 5; −4,41,20 and 4; 7,44,15), right dorsolateral prefrontal cortex (BA9; 7; 36,−4,42), and right orbitofrontal cortex (BA11; 4; 22,59,−13). Positive and negative correlations for sad stimuli are summarised in Fig. 1.

To examine the strength of the correlation at (R) BA25, we extracted mean effect sizes for response to sad faces for each individual at the centre of mass of the main cluster derived from whole brain correlational analysis at Time 1 (Talairach coordinates 7,15,− 7). Fig. 2 illustrates that there was a strong correlation (Pearson r = 0.827) between mean BOLD signal responses to sad faces in (BA25) at Time 1 (percentage change in BOLD signal versus baseline) and subsequent change in HRSD scores (Score at Time 2 − Score at Time 1), at a signiﬁcance level of p = 0.001. For happy stimuli (in order of cluster size), positive correlations were seen in the right precuneus (BA7; 19; 7,−52,48), right hippocampus (10; 25,−48,4), right postcingulate gyrus (BA31; 12; 0,−48,20), right superior temporal gyrus (BA22; 7; 47,−48,20), left primary visual cortex (BA18; 4, −7,−85,20), left supramarginal gyrus (BA40; 4; −54,−18,20) and right putamen (2; 18,−7,4). Negative correlations were seen in the left hippocampus (27; −36,−29,−2), right ventrolateral prefrontal cortex (BA47; 24; 25,37,−7), left superior temporal gyrus (BA22; 9; −40,−37,20), right cerebellum (BA71; 8; 22,−41,−29), right subgenual cingulate gyrus (BA25; 7; 4,11,−7), right dorsolateral prefrontal cortex (BA9/44; 5, 43,22,31) and left putamen (5; −18,11,9). 4. Discussion Our main ﬁnding is that greater BOLD responses to sad stimuli in right BA25 in the ﬁrst 2 weeks of antidepressant treatment are predictive of greater clinical recovery after 12 weeks. We have also demonstrated that increased responses in the right visual cortex are consistent with better clinical outcomes. These ﬁndings are not a simple index of severity. Higher initial severity could have been correlated with the subsequent size of change in score due to a regression to the mean effect (participants scores had further to drop). However, the variance in scores at Time 2 was much greater than the variance at Time 1.

Fig. 2. Further correlational analysis following extraction of mean effect sizes for each individual at the centre of mass of the main cluster in the right subgenual cingulate gyrus (BA25) derived from whole brain correlational analysis. The ﬁgure demonstrates a strong positive correlation between mean BOLD signal responses to sad faces in BA25; (Talairach coordinates 7,15,−7) at Time 1 (percentage change in BOLD signal versus baseline) and subsequent change in HRSD scores (Score at Time 2 − Score at Time 1). Pearson correlation r = 0.827, p = 0.001.

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Temporal decreases in BOLD responsiveness in these areas to sad stimuli (Time 1 − Time 2) have previously been shown to be positively correlated with decreases in depression severity (Time 1 − Time 2; Keedwell et al., 2008). We also previously demonstrated functional connectivity between these areas (Keedwell et al., 2008). In vivo human studies have shown that the cingulate gyrus and occipital cortex have anatomical connectivity in the form of the fast ﬁbres of the inferior fronto-occipital fasciculus (Catani et al., 2002). Our ﬁndings are in contrast to those of a recent study which showed that increased responses in BA25 to a sustained emotional attention task predicted poor outcome with CBT (Siegle et al., 2006). However, earlier work demonstrated that prefrontal response patterns associated with better response to CBT were different to those associated with improvements during antidepressant treatment (Goldapple et al., 2004).The discrepant ﬁndings may also be due to methodological differences. When using a masked paradigm similar to ours, Chen et al (2007) also demonstrated an association between greater ventral anterior cingulate responses to sad faces at baseline and subsequent clinical improvement. The same research group found that more dorsal cingulate activity was predictive of good response to CBT (Fu et al., 2008) providing further support for divergent predictors that are speciﬁc to treatment modality. Our results also diverge from the earlier ﬁndings of Davidson et al. (2003). Here, left rather than right ventral cingulate responses to negative stimuli predicted good clinical responses. Again, there are methodological differences: Pleasant or aversive scenes rather than facial stimuli were employed. Neural responses were related to less conventional ‘global’ measures of anxiety and depression scores after only 8 weeks of treatment. There were no brain responses predictive of subsequent changes in HAMD score. The results may have been comparable over a longer treatment duration and/or with the employment of facial stimuli. Another potential cause of disparity might relate to differences in the timing of the baseline scan. For practical and ethical reasons we could not conduct a baseline scan prior to the commencement of antidepressant treatment. In contrast Davidson et al. conducted scans at 3 time points: prior to treatment and after 2 and 8 weeks of treatment. Antidepressants can change brain reactivity early on in administration, thus some important changes predating clinical improvement may have been present in our participants at Time 1 that we were unable to control for. However, it seems unlikely that any changes would have been related to clinical response given the high depression scores in our participants at Time 1. The work of Davidson et al (2003) demonstrated some signiﬁcant changes in insula response at 2 weeks when compared to baseline. However, changes in the ventral cingulate were seen only after 8 weeks. Helen Mayberg's initial study of treatment response predictors suggested that pregenual rather than subgenual cingulate activity predicted good response to antidepressant treatment (Mayberg et al., 1997), but subsequent work suggested that subgenual cingulate activity reduced with antidepressant treatment (Mayberg et al., 2000). Our ﬁndings are consistent with this subsequent work. We have demonstrated that orbitofrontal and pregenual responses to sad stimuli are predictive of a poor outcome.

Kennedy et al (2007) demonstrated that reduced bilateral orbitofrontal and medial prefrontal metabolism correlated with reduced symptom severity during CBT. These areas has been shown to be activated in response to sad mood induction (George et al., 2004; Mayberg et al., 1999; Northoff et al., 2000; Pardo et al., 1993) and they are activated in response to monoamine depletion in both remitted depressives and healthy individuals (Bremner et al., 2003; Neumeister et al., 2004). The oribitofrontal cortex and pregenual cingulate are closely related anatomically (Carmichael and Price, 1996). Evidence from human neuroimaging studies suggests that the orbitofrontal cortex has a more evolved function in the anticipation of reward (Elliott et al., 2004; Elliott et al., 2000; Knutson et al., 2001), whereas the subgenual cingulate may be more intimately related to the physiological experience of emotion, given its anatomical connections with the hypothalamus and the autonomic nervous system (Ongur et al., 1998). Hence, while increased autonomic correlates of depression may predict a better outcome during antidepressant therapy, increased cognitive appraisal may predict a poor response. For happy stimuli, increased responses in the left primary visual cortex at Time 1 predicted a good response to treatment, whereas increased responses in the right subgenual cingulate predicted a poor response. This contrasts with the ﬁndings for sad stimuli. Davidson et al. (2003) found no signiﬁcant neural predictors of response for positive versus neutral stimuli trials, and our previous study (Keedwell et al., 2008) examining relationships between reduced neural responses to happy stimuli and reduced depression score similarly found no signiﬁcant correlations. Further research with a larger sample is required to determine if subgenual cingulate responses do indeed dissociate by stimulus type when considering the relationship to subsequent clinical improvement. Responses to happy stimuli in the putamen demonstrated a lateralization effect, with increased activity in the right putamen being indicative of a good response, and increased activity in the left putamen being indicative of a poor outcome. A similar laterality of response was seen in a previous comparison of depressed individuals and healthy controls (Surguladze et al., 2005). Responses in the left putamen to happy facial stimuli were increased and decreased in healthy volunteers and depressed subjects respectively, whereas for sad stimuli, the right putamen was activated, and showed greater response in the depressed subjects. The ventrolateral prefrontal cortex has emerged as a predictor of poor outcome, irrespective of the stimulus probe used. The ventrolateral prefrontal cortex is activated in healthy individuals in response to aversive outcomes (O'Doherty et al., 2001). Previous research has demonstrated ventrolateral prefrontal responses to sad mood induction in acutely depressed (Keedwell et al., 2005a; Liotti et al., 2002) and remitted (Liotti et al., 2002) subjects when compared with healthy individuals, and a positive correlation between negative cognition scores and BA47 activity in depressed individuals (Dunn et al., 2002; Keedwell et al., 2005b). Furthermore, depressed individuals demonstrated increased responses in BA47/11 to sad words in an emotional Stroop task (Elliott et al., 2002). Activity in BA47 is related to ruminatory processes (Liotti et al., 2002), and in the early stages of depression negative rumination appears to predict more severe and more persistent depression later on (Raes

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et al., 2006). Hence, an exaggerated response to sad stimuli in BA47 may be a trait marker for depression as well as a predictor of poor outcome and vulnerability to relapse. There are a number of limitations in this study. Firstly, depressed individuals were taking a variety of antidepressants at variable doses, which reﬂect the naturalistic design. However, there was no signiﬁcant relationship between medication dose and severity of depression at Time 1. The variance in equivalent antidepressant dose across individuals was relatively low. Secondly, although not out of keeping with previous studies, our sample size of n = 12 was modest. The correlational design improved power but replication using a larger sample would be welcome. Finally, it is commonly asserted in follow-up antidepressant treatment designs that changes in clinical scores over the course of antidepressant treatment are attributable to the therapeutic effects of the antidepressant. However, in order to make such conclusions one would need to include a matched placebo-treated group of depressed patients; recovery can occur as a result of placebo response, spontaneous recovery and psychosocial interventions, prescribed or otherwise. Hence, we would like to emphasize that our conclusions relate to the predictors of clinical improvement per se and not the predictors of improvement that are directly attributable to antidepressant treatment. Future studies should build on this work to further examine the role of subgenual cingulate responses to affective facial stimuli in predicting treatment outcome during antidepressant treatment. There are potential implications for guiding antidepressant treatment choices in individual patients.
Role of funding source Funding for this study was provided by a donation from the Goldsmith Charitable Foundation; the Foundation had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conﬂict of interest The authors are not aware of any conﬂict of interest that might have biased their reporting of these results. There was no sponsorship of this study by industry.

Acknowledgments We are grateful for the technical support provided by Chris Andrew and David Gasston of the Centre for Neuroimaging Sciences. We also acknowledge the generous contribution from the Goldsmith Charitable Foundation.

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