The World Journal of Biological Psychiatry, 2011; 12: 349–363
ORIGINAL INVESTIGATION
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
Enhanced brain responsiveness during active emotional face processing in obsessive compulsive disorder
NARCÍS CARDONER1,2,3,5, BEN J. HARRISON3,6, JESÚS PUJOL3,7, CARLES SORIANO-MAS1,3,4, ROSA HERNÁNDEZ-RIBAS1,2,3, MARINA LÓPEZ-SOLÀ3,5, EVA REAL1, JOAN DEUS3,8, HECTOR ORTIZ3,9, PINO ALONSO1,2 & JOSÉ M. MENCHÓN1,2,5 1Department
of Psychiatry, Bellvitge University Hospital-IDIBELL, Barcelona, Spain, 2Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain, 3Institut d’Alta Tecnologia–Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain, 4Carlos III Health Institute, Madrid, Spain, 5Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Spain, 6Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Australia, 7Centro de Investigación Biomédica en Red en Bioenginiería, Biomaterials y Nanomedicina, Barcelona, Spain, 8Department of Clinical and Health Psychology, Autonomous University of Barcelona, Barcelona, Spain, and 9Department of Electronic Engineering, Technical University of Catalonia, Barcelona, Spain Abstract Objectives. The abnormal processing of emotional stimuli is common to a variety of psychiatric disorders. Specifically, patients with prominent anxiety symptoms generally overreact to emotional cues, which has been linked to increased amygdala activation. However, in OCD, enhanced responses are predominantly obtained using disease-specific stimuli and preferentially involve frontostriatal systems. Methods. We assessed 21 OCD patients and 21 healthy controls with fMRI during an emotional face-processing paradigm involving active response generation to test for alterations in both brain activation and task-induced functional connectivity of the frontal cortex, the amygdala and the fusiform face area. Results. OCD patients showed significantly greater activation of “face-processing” regions including the amygdala, fusiform gyrus and dorsolateral prefrontal cortex. The reciprocal connectivity between face-processing regions was enhanced in OCD. Importantly, we detected significant correlations between patients’ clinical symptom severity and both task-related region activation and network functional connectivity. Conclusions. The results suggest that OCD patients may show enhanced brain responsiveness during emotional face-processing when tasks involve active response generation. Our findings diverge from previously described alterations in anxiety disorders, as patients showed enhanced amygdala-prefrontal connectivity as opposed to negative reciprocal interaction. This pattern would appear to be disorder-specific and was significantly related to obsessive-compulsive symptom severity.
Key words: Functional imaging, obsessive-compulsive disorder, emotion, amygdala, prefrontal cortex
Objectives Accurate recognition of facial expressions of emotion is critical to adaptive behaviour and is supported by distributed brain areas including the visual cortex and fusiform gyrus, amygdala and hippocampus, and subregions of prefrontal cortex (Haxby et al. 2000; Ishai et al. 2005). The functionally defined “fusiform face area” appears to be a common feedforward modulator of amygdala activity particularly when faces express emotion (Fairhall and Ishai 2007). Visual sensory processing can also be modified via feedback modulation from emotion-related regions and via interaction
with attentional mechanisms assigned to dorsal prefrontal cortical regions (Phillips et al. 2003b; Bishop 2007; Vuilleumier and Driver 2007). Alterations in the normal response and interaction of components of this brain network, as studied with functional neuroimaging, have been linked to disturbances of emotion perception and behaviour in a variety of psychiatric disorders, including mood disorders, schizophrenia and autism spectrum disorders, among others (Williams et al. 2004; Dalton et al. 2005; Surguladze et al. 2005, Chen et al. 2006; Holsen et al. 2008). Arguably, however, the most solid evidence of
Correspondence: Dr Narcís Cardoner, Department of Psychiatry, Bellvitge University Hospital-IDIBELL, Feixa Llarga s/n, Barcelona, 08907, Spain. Tel: 34 932 602839. Fax: 34 932 605878. E-mail:
[email protected] (Received 29 June 2010 ; accepted 20 January 2011) ISSN 1562-2975 print/ISSN 1814-1412 online © 2011 Informa Healthcare DOI: 10.3109/15622975.2011.559268
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
350 N. Cardoner et al. abnormal emotional face-processing in a psychiatric context has been with respect to anxiety-related symptoms or to individual differences in anxiety traits. In particular, patients with anxiety disorders and of individuals with high trait anxiety have consistently shown a heightened response of the amygdala and other key elements of the network when compared to healthy and low trait anxious subjects (Fredrikson and Furmark 2003; Rauch et al. 2003, Etkin and Wager 2007; Stein et al. 2007; Monk et al. 2008; Pujol et al. 2009) Patients with obsessive-compulsive disorder (OCD) typically show both higher scores on clinical scales assessing general anxiety symptoms and a temperamental vulnerability to anxiety (Hoehn-Saric et al. 1995; Alonso et al. 2008). While several functional neuroimaging studies have reported that OCD patients primarily show enhanced brain responses to specific disorder-related stimulation (Mataix-Cols et al. 2004; Schienle et al. 2005; van den Heuvel et al. 2005), it is less clear to what extent these patients also respond to basic (disease-unrelated) emotional cues. In two existing studies, the passive viewing of emotional faces did not lead to hyperactivation of the amygdala or other face-processing regions in OCD patients (Cannistraro et al. 2004; Lawrence et al. 2007). Despite these existing findings no study to date has examined brain responses in OCD patients during active emotional face-processing. Tasks in which subjects are required to form a decision and provide a response based on stimulus features can more effectively engage dorsal prefrontal and parietal regions that have become of increasing interest in the study of emotional dysregulation in psychiatric disorders (Davidson 2002; Phillips et al. 2003a; Bishop 2007). Altered striatal interaction with ventral and orbital frontal regions is considered to be prominent in OCD (Pujol et al. 2004; Soriano-Mas et al. 2007; Menzies et al. 2008; Harrison et al. 2009), but abnormal task activation (Pujol et al. 1999;Yucel et al. 2007; Henseler et al. 2008; Rotge et al. 2008; Jung et al. 2009) and altered functional connectivity at rest (Harrison et al. 2009) are also present in the dorsal prefrontal cortex involving regions that participate in the processing of emotional faces. It is also noteworthy that no study has investigated the integrity of functional interactions or “connectivity” of major regions of the putative face-processing network in OCD patients. The analysis of functional connectivity of this network may permit a more detailed evaluation of its response to basic visual emotional stimuli, as demonstrated in other anxiety disorders (Evans et al. 2008; Monk et al. 2008; Pujol et al. 2009). Specifically, we were interested to investigate interactions between posterior brain regions related to the early stages of emotional stimuli perception and higher-order prefrontal “attentional” regions which
are also of pathophysiological relevance to OCD (Pujol et al. 1999; van den Heuvel et al. 2005). In this study, we used fMRI to assess OCD patients performing an active emotional face-processing task (Pujol et al. 2009), originally developed by Hariri et al. (2000) where the subject is required to correctly match probe emotional faces to a target face by forced-choice response. This task has been shown to reliably activate visual cortical areas, the amygdala and the dorsolateral prefrontal cortex in healthy subjects (Sergent et al. 1992; Haxby et al. 2000; Ishai et al. 2005). We sought to evaluate (i) whether a generally heightened responsiveness of these regions to disease non-specific emotional face stimuli occurs in OCD patients, and (ii) whether or not such disturbances reflect an alteration of their functional connectivity during task performance. We also set out to investigate how such findings may relate to the clinical severity of obsessive-compulsive symptoms.
Materials and methods Subjects Twenty-four outpatients with OCD were recruited for the study on the basis of their ongoing contact with the OCD service at the Department of Psychiatry, University Hospital of Bellvitge, Barcelona. All patients were required to satisfy DSM-IV diagnostic criteria for OCD in the absence of relevant medical, neurological and other major psychiatric disorders (First et al. 1998). A primary diagnosis of OCD was made when (i) OCD symptoms were the primary reason for patients seeking medical intervention, and (ii) OCD symptoms were persistent and constituted the primary cause of distress and interference with the patient’s life. The Yale-Brown Obsessive-Compulsive Scale (YBOCS) (Goodman et al. 1989) and a clinician-rated Yale-Brown Obsessive-Compulsive Scale symptom checklist (Goodman et al. 1989) were used to assess illness severity and to characterize OCD symptoms (Mataix-Cols et al. 1999) (see Table I). None of the patients met criteria for Tourette’s syndrome or had a history of psychoactive drug use/abuse. Comorbid anxious and depressive symptoms were not considered as an exclusion criterion, provided that OCD was the primary clinical diagnosis. The severity of comorbid symptoms of depression and anxiety was measured by the Hamilton Depression (HAM-D) (Hamilton 1960) and Anxiety (HAM-A) (Hamilton 1959) inventories. All patients were on stable doses of medication for at least three months before scanning, except for one patient who had not received medication for 1 month (Table I).
Emotional face-processing in OCD 351 Table I. Sample characteristics and task behavioral performance.
Characteristic
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
Age, years Sex, M/F, no. Handedness, right/left, no. WAIS Vocab, scaled score Age at onset of OCD, years Duration of illness, years Y-BOCS-Total Y-BOCS-Obsessions Y-BOCS-Compulsions HAM-D HAM-A
Healthy controls (n 21) Mean (SD), range
OCD patients (n 21)† Mean (SD), range
26.2 (3.4), 21–33 10/11 19/2 11.71 (1.9), 10–14
28.52 (5.9), 19–39 10/11 19/2 12.43 (1.8), 9–16 20.4 (6.7), 9–34 8.7 (5.7), 2–28 20.7 (6.3), 11–36 10.5 (3.2), 5–18 10.2 (3.6), 2-18 7.6 (4.7), 0–19∗∗ 11.2 (5.7), 2–21∗∗
2.8 (3.7), 0–13 4.8 (5.2), 0–17 Present no. (% cases)
Comorbidity Depressive and anxiety Disorders Major depression Generalized anxiety disorder Social anxiety disorder Panic disorder
7 2 2 2 1
OCD symptom dimensions‡
(33.3) (9.5) (9.5) (9.5) (4.8)
0 (absent)
Symmetry, ordering Hoarding Contamination, cleaning Aggressive, checking Sexual, religious obsessions
14 15 11 5 16
Treatment status Never treated with an SSRI 1 previous SSRIs trial 2 previous SSRIs trials 3 or more previous SSRIs trials Previous low-dose antipsychotic use
Absent no. (% cases)
(66.7) (71.4) (52.4) (23.8) (76.2)
14 19 19 19 20 no. (% cases) 1 (mild) 3 6 6 3 1
(14.3) (28.6) (28.6) (14.3) (4.8)
(66.7) (90.5) (90.5) (90.5) (95.2)
2 (prom) 4 0 4 13 4
(19) (0) (19) (61.9) (19)
no. (% cases) 7 (33.3) 5 (23.8) 6 (28.6) 3 (14.3) 5 (23.8)
Cumulative SSRI treatments
Mean (SD) 1.33 (1.2)
Medication at study time Medication-free (4 weeks) Fluoxetine Fluvoxamine Citalopram Clomipramine Clomipramine with SSRI
no. (% cases) 1 (4.8) 4 (19) 2 (9.5) 1 (4.8) 2 (9.5) 11 (52.4)
Response accuracy Fearful face matching Happy face matching Shape matching
% correct, mean (SD) 93.6 (14) 94.9 (15) 94.8 (12)
% correct, mean (SD) 78.9 (24) 80.3 (29) 83.1 (25)
Reaction time Fearful face matching Happy face matching Shape matching
milliseconds, mean (SD) 1464.1 (309) 1084.9 (210) 782.5 (95)
milliseconds, mean (SD) 1925 (607) 1433.7 (348) 1081.2 (269)
OCD, obsessive-compulsive disorder; WAIS, Wechsler Adult Intelligence Scale;Y-BOCS,Yale-Brown Obsessive-Compulsive Scale; HAM-D, Hamilton Rating Scale for Depression; HAM-A, Hamilton Rating Scale for Anxiety; SSRI, selective serotonin reuptake inhibitor. ∗∗P 0.001. †The single unmedicated OCD patient recorded a total YBOCS score of 15 and was unremarkable across the other clinical domains. ‡The Yale-Brown Obsessive-Compulsive Scale symptom checklist was used to derive scores on five previously identified OC-symptom dimensions: symmetry/ordering, hoarding, contamination/cleaning, aggression/checking, and sexual/religious obsessions, classified as absent, present (mild), or prominent (Mataix-Cols et al. 1999).
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
352 N. Cardoner et al. Of the original sample, three patients were excluded from the final analysis; one male patient due to an incidental finding on MRI (medial wall hyperintensity); and two female subjects due to excessive movement during scanning (2 mm in z-axis translation). The remaining 21 patients were matched for age, gender, handedness and estimated IQ to a sample of twenty-one healthy control subjects (case-matched prior to any analyses from a larger cohort obtained through an ongoing research program), so that there were no significant group differences in any of these measures (Table I). General intelligence was estimated using the vocabulary subtest of the WAIS (Wechsler 1999). Each control subject underwent the Structured Clinical Interview for DSM-IV (SCID) non-patient version (First et al. 2007) to exclude any Axis I or II psychiatric disorders. None of this cohort had a personal history of neurological or psychiatric illness. All participants had normal or corrected-to-normal vision and gave written informed consent to participate, following a complete description of the protocol, which was approved by the Institutional Review Board of the University Hospital of Bellvitge, Barcelona. Emotional Face Matching Task Subjects were assessed using a modified version of the emotional face-matching task originally reported by Hariri et al. (2000). During each 5-s trial, subjects were presented with a target face (centre top) and two probe faces (bottom left and right) and were instructed to match the probe expressing the same emotion to the target by pressing a button in either their left or right hand. A block consisted of six consecutive trials in which the target face was either happy or fearful, and the probe faces included two out of three possible emotional faces (happy, fearful and angry). As a sensorimotor control condition, subjects were presented with 5-s trials of ovals or circles in an analogous configuration and were instructed to match the shape of the probe to the target. Shape stimuli were preferred to neutral faces for the task as the latter may be experienced as emotionally ambiguous or affectively laden, which has been shown to evoke significant activation of amygdala and prefrontal regions (Forman 1995; Schwartz et al. 2003). A total of six 30-s blocks of faces (three happy and three fearful) and six 30-s blocks of the control condition were presented interleaved in a pseudo-randomized order. A fixation cross was interspersed between each block. For each trial, response accuracy and response latency (reaction time) were obtained. The paradigm was presented visually on a laptop computer running Presentation software (http://www.neurobehavioral systems.com). MRI-compatible high-resolution goggles (VisuaStim Digital System, Resonance Technology
Inc., Northridge, CA) were used to display the stimuli. Subjects’ task responses were registered using a right and a left hand response device based on optical fibre transmission (Nordic Neuro Lab, Bergen, Norway). Task responses were unavailable for two OCD patients due to a technical error in saving Presentation log files after scanning had been completed. Image acquisition and preprocessing A 1.5-T Signa Excite system (General Electric, Milwaukee, WI, USA) equipped with an eight-channel phased-array head coil and single-shot echoplanar imaging (EPI) software was used. Functional sequences consisted of gradient recalled acquisition in the steady state (time of repetition [TR], 2000 ms; time of echo [TE], 50 ms; pulse angle, 90°) within a field of view of 24 cm, with a 64 64-pixel matrix and a slice thickness of 4 mm (inter-slice gap, 1 mm). Twenty-two interleaved slices, parallel to the anterior-posterior commissure line, were acquired to cover the whole brain. The functional time series consisted of 270 consecutive image sets obtained over 9 min. Imaging data were transferred and processed on a Microsoft Windows platform running MATLAB version 7 (The MathWorks Inc, Natick, Mass). Image preprocessing was performed in SPM5 (http:// www.fil.ion.ucl.ac.uk/spm/), and involved motion correction, spatial normalization and smoothing using a Gaussian filter (full-width, half-maximum, 8 mm). Motion correction was performed by aligning (within-subject) each time-series to the first image volume using a least-squares minimization and a sixparameter (rigid body) spatial transformation. Data were normalized to the standard SPM-EPI template and resliced to 2 mm isotropic resolution in Montreal Neurological Institute (MNI) space.
Statistical analyses Behavioural. Individual demographic measures of sex, handedness, age, and premorbid IQ were compared across groups using univariate analyses of variance (ANOVAs) in Statistical Package for the Social Sciences (SPSS) version 11.0. Analyses of behavioural data were conducted using a mixed ANOVA with “task condition” (fearful faces, happy faces or control condition) as the within-subject variable and “study group” (healthy subjects, OCD patients) as the between-subject variable. Response errors and reaction times (correct) were estimated and compared separately for each condition. Errors were calculated by summing all commission errors (incorrect matching) and omissions (missed responses) within each condition.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
Emotional face-processing in OCD 353 Functional MRI: main task effects. First-level (singlesubject) SPM contrast images were estimated for the following three task effects of interest; (1) all faces control task; (2) fearful faces control task; (3) happy faces control task. For these analyses, the BOLD response at each voxel was convolved with a canonical hemodynamic response function and its temporal derivative (using a 128-s high-pass filter).The resulting first-level contrast images for each subject were then carried forward to second-level random-effects (group) analyses. For the main task effects, within-group activation maps were thresholded at PFDR 0.05 (corrected for wholebrain volume) with a minimum cluster size extent (KE) of five contiguous voxels. To assess for differences in the activation pattern across the task effects of interest, the groups were compared using two-sample t-tests and adopting a more lenient statistical threshold of P 0.005 (uncorrected; KE 5 voxels), which provides a good balance against both Type I and Type II errors (see Lieberman and Cunningham 2009). This particular whole-brain threshold was adopted in order to approximate the region-of-interest (ROI) based thresholds used in previous studies of amygdala function in OCD (Cannistraro et al. 2004) and amygdala activation with our specific task (Paulus et al. 2005). We reasoned that this lower threshold would allow us to detect potential differences in amygdala activation with the same sensitivity as relevant prior studies, while facilitating a comparison of the groups at the whole-brain level. Nevertheless, this whole-brain uncorrected threshold may be considered liberal and therefore the strength of corresponding results should be interpreted accordingly. Psychophysiological interactions analysis. To assess the influence of task (the “psychological” factor) on the strength of functional coupling (“functional connectivity”) between each brain region of interest (ROI) (amygdala, prefrontal cortex and fusiform gyrus) and the other brain voxels, we performed a series of psychophysiological interactions (PPI) analyses in SPM5 (Friston et al. 1997). Specifically, we evaluated an effect of the task (emotional face matching in contrast with shape matching) on the strength of time-course correlations between the selected ROIs and all other brain regions. First level analyses was performed for each subject to map areas where activity was predicted by the cross-product (PPI interaction term) of the “physiological” (deconvolved time-course of the given ROI) and the “psychological” factor (regressor representing the experimental paradigm). Both the physiological and the psychological factors were also included in the final SPM model as confound variables (Pujol et al. 2009). First-level individual contrast images representing the PPI effect for each subject were then included in second level random-effects analyses to test within-group results
(one-sample t-test thresholded at PFDR 0.05, wholebrain corrected) and between-group differences (two sample t-test adopting the threshold of P 0.005, uncorrected; KE 5 voxels) of each PPI analysis. The placement of source ROIs was determined by a conjunction analysis (global null approach) of the task effect “all faces control task”. This analysis identified regions that were consistently activated in both OCD patients and control subjects (PFDR 0.05, whole-brain corrected): peak activation for right amygdala ROI (x, y, z 20, –2, –24); right prefrontal ROI (x, y, z 44, 12, 28); right fusiform gyrus ROI (x, y, z 40, –50, –30). The “physiological” factor of each PPI analysis was the first eigenvariate time series extracted, for each subject, from a 5-mm radial sphere centred on the above-mentioned coordinates. Brain-behavioural associations.We investigated the extent to which patients’ symptom severity demonstrated significant linear correlation with the patterns of brain activation and functional connectivity reported in association with the primary study contrast “ all faces control task”. Patients’ total YBOCS score was entered as a regressor of interest in corresponding second-level analyses (one sample t-tests) thresholded at P 0.005 (uncorrected).
Results Behavioural Response accuracy and reaction time (RT) scores are reported in Table I. There was no significant interaction between task condition and study group in relation to task accuracy (F(2,76) 0.92, P 0.40) and no significant main effect of task condition (F(2,76) 2.49, P 0.09). There was, however, a group main effect with OCD patients showing less accuracy than their healthy counterparts (F(1,38) 4.3, P 0.04). There was no significant interaction between task condition and study group in relation to RT performance (F(1,76) 1.28, P 0.29). There was a main effect of task condition on RT performance in both groups (F(2,76) 10.4, P 0.001) in that RTs to fearful faces were RTs to happy faces which were RTs to shapes (all P values 0.05). There was also a group main effect with OCD patients’ RTs being slower overall in comparison to healthy subjects (F(1,38) 17.5, P 0.001).
Functional MRI Main task effects. Both groups demonstrated significant and overlapping activation of distributed brain
–
44 –40 –28 28 –30 32
–20 24 40 –40 42 –42 20 –22
26 –24 –38 38 42 –52 8 –32 30 18 –22
–20 26 40 –38 44 –44 32 20 –22 8
x
–
10 2 –74 –68 26 28
–96 –98 –50 –56 12 –2 –2 –2
–94 –92 –48 –52 12 34 14 22 28 –4 –2
–96 –98 –50 –48 12 20 32 –2 –2 14
y
–
30 28 22 30 –4 0
–8 0 –28 –20 28 54 –24 –26
–6 –10 –28 –30 28 16 50 –4 –6 –20 –26
–8 –2 –30 –28 26 22 –18 –24 –26 50
z
–
1904 1226 2457 1208 294 145
1422 769 39 58
8000
6187 6066 901 376 413 66 23
8000
4751 4722 388 74 59 591
8000
CS
Z
–
5.28 4.51 4.61 4.23 4.36 3.50
8 7.31 7.18 6.27 4.68 3.95 3.64 3.65
8 7.81 6.91 7.75 6.59 5.89 4.35 4.48 3.97 4.01 3.14
8 8 7.76 6.81 6.55 5.67 4.12 4.45 4.44 3.93
Statsb
Happy Fear –
Premotor Ant. insula cortex
Extrastriate/parietal
Fear Happy Middle frontal gyr.
Ant. insula cortex
Amygdala
Middle frontal gyr.
Fusiform gyr.
Happy Shapes Visual cortex
Amygdala
Supp. Motor area Ant. insula cortex
Middle frontal gyr.
Fusiform gyr.
Fear Shapes Visual cortex
Supp. motor area Ant. insula cortex Amygdala
Middle frontal gyr.
Fusiform gyr.
Visual cortex
Faces Shapes
OCD patients
–
40 –42 38 –28 8 –34
–22 14 –38 40 42 –58 24 –18 30
24 –22 –36 40 44 –42 6 30 –32 18 –18
–22 16 40 –38 –46 44 –4 –30 24 –22 32
x
FDR
–
2586 2543 4182 4805 384 364
2733 2990 120 118 61
8000
8000 5602 1786 458 510 154 148
8000
8000 3828 1330 316 154 148 334
8000
CS
Z
–
4.77 4.26 4.68 4.56 3.61 4.24
8 7.72 6.71 6.71 5.60 4.45 5.21 3.96 2.96
8 8 7.46 7.22 6.42 6.51 4.84 5.12 4.81 5.00 4.13
8 7.58 7.16 7.26 6.66 6.55 4.75 3.89 5.40 4.76 4.61
Statsb
Happy Fear –
–
Fear Happy Middle frontal gyr. Ant. insula
Intra parietal sul. Visual cortex Fusiform gyr. Amygdala
Happy Shapes Middle frontal gyrus
Globus pallidus Hippocampus Fusiform gyr Amygdala Thalamus
Brainstem Middle frontal gyr.
Fear Shapes Visual cortex Precuneus Parahippocampal gyr.
Premotor Fusiform gyr. Intra parietal sul. Thalamus Hippocampus Amygdala
Faces Shapes Precuneus Parahippocampal gyr. Visual cortex Middle frontal gyr.
Differencec
–
–
28 –34
–46 –52 30 –2 40 22
–6 –2 –26 28 –10 24 –52 40 20 –28 40 18 –14
–4 –16 –2 –48 24 40 40 32 –16 36 18
x
–
–
26 18
20 12 –68 –86 –36 –10
–80 –66 –32 –36 –14 58 12 8 –2 –12 –30 0 –32
–66 –32 –84 18 58 8 –32 –62 –32 –28 –6
y
Anatomya
–
–
24 14
48 28 44 –8 –18 –18
–4 38 –14 2 –14 14 38 52 8 –16 –20 –14 2
–40 0 –8 48 14 50 –20 42 0 –4 –14
z
–
–
12 14
48 71 74 26 10 6
462 129 94 109 43 19 42 77 76 36 29 7 22
99 52 326 276 17 61 39 112 52 21 8
CS
Z
–
–
3.01 2.7
3.30 2.91 2.99 2.89 2.74 2.70
3.58 3.48 3.38 3.31 3.22 3.12 3.04 2.98 3.03 3.02 3.25 2.99 2.83
3.42 3.42 3.39 3.29 2.88 2.98 3.18 3.09 3.42 2.99 2.86
Statsc
and extent statistics correspond to a minimum threshold of PFDR 0.05 (whole–brain 0.005 (whole–brain uncorrected). CS, cluster size.
–
26 38 –4 24 52 –8
–10 –10 –30 –26 28 26 –20 –16 –16
–8 –10 –28 –28 28 20 52 –8 –6 –18 –16
–10 –10 –30 –28 22 28 50 –6 –22 –26 –8
z
bMagnitude
–
8 0 –78 –76 18 24
–96 –96 –48 –48 12 15 –8 –8 34
–92 –96 –48 –50 10 18 16 28 22 –2 –8
–96 –96 –50 –48 18 12 16 22 –8 –2 28
y
Anatomya
co–ordinates (x, y, z) are given in Montreal Neurological Institute (MNI) Atlas space. corrected). cResults correspond to statistical differences (OCD patients healthy controls) of P
aActivity
Happy Fear –
Ant. insula cortex
Extrastriate/parietal
Fear Happy Middle frontal gyr.
Amygdala
Middle frontal gyr.
Fusiform gyr.
Happy Shapes Visual cortex
Amygdala
Supp. Motor area Ant. insula cortex
Middle frontal gyr.
Fusiform gyr.
Fear Shapes Visual cortex
Premotor
Inf. frontal cortex Amygdala
Middle frontal gyr.
Fusiform gyr.
Faces Shapes Visual cortex
Healthy controls
Anatomya
Table II. Activation of extended brain regions during performance of the emotional face recognition in patients with OCD and healthy control subjects.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
354 N. Cardoner et al.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
Emotional face-processing in OCD 355 regions for the contrasts that compared matching emotional faces to matching shapes (Table II). Regions included a large cluster encompassing visual striate and extrastriate cortex and also the posterior thalamus, the fusiform gyrus, hippocampus and amygdala, dorsolateral frontal and pre-motor cortex (Figure 1). When comparing groups, OCD patients showed significantly greater activation of visual striate areas, right fusiform gyrus, left posterior thalamus, right amygdala and parahippocampal cortex as well as dorsolateral prefrontal and right premotor cortex. The extension of the significant differences between OCD and control subjects was larger in the contrast “fearful faces control task” compared to “happy faces control task” (Table II). Conversely, there was no significantly greater activation in control subjects when compared to OCD patients. Figure 1 highlights the corresponding distribution of activations in both groups resulting from the primary contrast “all faces control task”. Figure 2 highlights the corresponding activation of the amygdala region in both groups across the three study contrasts “all faces control task”, “fearful faces control task” and “happy faces control task”. Amygdala activation was significantly larger in OCD patients compared with healthy subjects across the three contrasts (Table II). For the contrast “fearful faces happy faces” both groups demonstrated significant extensive activation of the visual extrastriate cortex extending to the intraparietal sulcus, the dorsolateral frontal and the premotor cortex, as well as the anterior insula (Table II). When comparing groups, OCD patients showed significantly greater activation of the right dorsolateral frontal cortex and the left anterior insula region. There was no significantly greater activation in control subjects compared to OCD patients. There were no significant between-group differences for the contrast “happy faces fearful faces” (Table II). To assess the influence of comorbid anxiety and depression symptoms on these results, all analyses were repeated covarying for subjects scores on the HAM-A and HAM-D. As highlighted in Supplementary Figure 1, minimal appreciable differences were detected between the results of this approach and all results described above.
between-group comparison, OCD patients had significantly increased functional connectivity of the amygdala ROI to right dorsolateral prefrontal, right intraparietal and visual extrastriate cortex (Table III). Prefrontal cortex ROI. Significant task-induced functional connectivity of the right prefrontal ROI to
Functional connectivity (PPI) analysis Right amygdala ROI. Significant task-induced functional connectivity of the right amygdala ROI to visual striate and extrastriate cortex, fusiform gyrus, intraparietal sulcus, dorsolateral frontal and premotor cortex was observed in OCD patients (Table III). There was no significant amygdala functional connectivity observed in control subjects. In a direct
Figure 1. Brain activation during active emotional face processing (A) healthy subjects; (B) OCD patients; and (C) OCD patients healthy subjects. Results correspond to the main task contrast “all faces control task” and are displayed on a high-resolution single-subject MRI in standard neuroanatomical space (Montreal Neurological Institute). Results are displayed in neurological convention (left left).
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
356 N. Cardoner et al.
Figure 2. Amygdala activation during emotional face matching in healthy subjects (top row) and OCD patients (bottom row, marked with asterix) across the task contrasts (A) “all faces control task”; (B) “fearful faces control task”; and (C) “happy faces control task”. Results are displayed in neurological convention (left left) on a high-resolution single-subject MRI in standard neuroanatomical space (Montreal Neurological Institute).
visual striate and extrastriate cortex, fusiform gyrus and intraparietal sulcus was observed in both groups. OCD patients showed additional prefrontal functional connectivity with dorsal premotor and prefrontal cortex, bilateral amygdala and parahippocampal gyrus (Figure 3). In a direct comparison, OCD patients had significantly greater functional connectivity of the right prefrontal ROI to visual extrastriate and parietal cortex, fusiform gyrus, bilateral amygdala and additional dorsal prefrontal regions (Table III).
Fusiform gyrus ROI. Significant task-induced functional connectivity of the right fusiform ROI to bilateral visual striate and extrastriate cortex, left fusiform gyrus and bilateral intraparietal sulcus was observed in both groups. OCD patients showed greater and additional fusiform functional connectivity with dorsal premotor and prefrontal cortex, superior parietal cortex and parahippocampal gyrus. In a direct comparison, OCD patients had significantly greater functional connectivity of the right fusiform ROI to dorsal prefrontal, parietal and visual extrastriate cortex (Table III).
Brain-behavioural associations Symptom severity correlated significantly with clusters of activation and task-induced functional connectivity strength in visual extrastriate and fusiform gyrus, and the corresponding anatomy of the results showed substantial overlap (Figure 4).
Comment This functional imaging study assessed brain responses during a task that involved active processing of emotional faces in OCD patients. In contrast to previous studies of passive emotional face viewing (Cannistraro et al. 2004; Lawrence et al. 2007), we observed increased activation of distributed “faceprocessing” regions in OCD patients including the amygdala and dorsal prefrontal cortex. While our results partially agree with reports of amygdala hyperactivity as a common alteration across distinct anxiety disorders (Etkin and Wager 2007; Fredrikson and Furmark 2003), they diverge from such studies in terms of the precise nature of amygdala hyperactivation in
x
–80 –74 –62
–52 8 0
34 –36 30
–22 40 48
–98 –82 –54 –56 –50 –58
y
38 30 46
–10 –12 54
14 –10 –22 –20 40 52
z
206 403 14
245
8000
290 156
8000
CS
Z
3.55 3.72 2.95
6.67 6.34 4.03
5.74 5.69 4.62 4.59 3.64 3.36
Statsb
Inferior frontal gyrus. Anterior insula
Middle frontal gyrus. Premotor Parahipp. gyrus
Intraparietal sulcus
Fusiform PPI Visual cortex
Premotor Amygdala
Parahipp. gyrus
Middle frontal gyrus
Fusiform gyrus
Prefrontal PPI Visual/parietal
Intra parietal sulcus
Amygdala PPI Visual cortex Fusiform gyrus Middle frontal gyrus
OCD patients
–26 –36 –26 30 48 –6 –24 24 42 –32 –26
–28 32 40 –36 48 –42 22 –20 4 –30 26
–20 40 –52 42 48 52 –42 28 –24
x
–86 –52 –64 –58 8 6 –30 –28 51 22 –26
–86 –92 –44 –54 4 –14 –30 –30 12 –2 –6
–84 –50 4 6 8 34 10 –68 –52
y
Anatomya
–10 –28 50 46 36 52 –2 –2 –6 –8 38
–4 16 –24 –24 58 26 –2 –6 54 –30 –26
–24 –28 50 60 38 20 24 50 38
z
4514 824 64 86 310 34 16
8000
3011 1882 280 352 694 72 25
8000
136 363 64 47 39 278 193
8000
CS
Statsb
7.78 5.67 6.33 5.87 5.78 4.71 3.55 3.65 3.55 3.01 2.62
7.53 7.33 6.57 6.08 5.57 5.26 3.78 4.19 3.68 3.23 3.10
4.85 4.54 4.06 3.66 3.29 3.26 3.13 3.59 3.40
Z
FDR
Intraparietal sulcus
Middle frontal gyrus
Fusiform PPI Medial frontal gyrus Supramarginal gyrus Visual extrastriate
Fusiform gyrus Amygdala
Prefrontal PPI Supramarginal gyrus Intra parietal sulcus Visual cortex Middle frontal gyrus.
Amygdala PPI Visual cortex Intra parietal sulcus Middle frontal gyrus
Difference
co–ordinates (x, y, z) are given in Montreal Neurological Institute (MNI) Atlas space. bMagnitude and extent statistics correspond to a minimum threshold of P correspond to statistical differences (OCD patients healthy controls) of P 0.005 (whole–brain uncorrected). CS, cluster size.
aActivity
Medial frontal gyr.
Intraparietal sul.
Fusiform PPI Visual cortex
Prefrontal PPI Visual cortex –10 36 Fusiform gyr. 38 –38 Intra parietal sul. –22 30
Amygdala PPI
Healthy controls
Anatomya
Table III. Amygdala and prefrontal ROI functional connectivity during emotional face matching in patients with OCD and healthy control subjects.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
8 –34 –86 –94 44 12 –48 –60
–44 –78 –84 4 40 –52 –2 –8
–74 –42 12
y
52 56 –8 14 24 34 58 42
56 30 4 58 24 –32 –30 –28
–32 44 54
z
397 917 266 111 32 266 236 176
636 1309 272 161 109 192 28 9
312 148 100
CS
Z
4.11 4.01 3.90 3.04 3.56 3.26 3.47 3.20
4.77 4.22 3.72 3.50 3.51 3.36 2.95 3.11
3.38 3.22 2.83
Statsc
0.05 (whole–brain corrected). cResults
46 –54 –26 8 –44 –54 40 30
–36 –24 26 48 –48 –34 –28 32
–6 32 40
x
Anatomya
Emotional face-processing in OCD 357
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
358 N. Cardoner et al.
Figure 3. Dorsal prefrontal functional connectivity during emotional face matching (all faces shapes) in (A) healthy subjects; and (B) OCD patients. Results are displayed in neurological convention (left left) on a high-resolution single-subject MRI in standard neuroanatomical space (Montreal Neurological Institute).
OCD patients as well as the specific involvement of the prefrontal cortex. Although the current study appears to challenge existing reports of amygdala responsiveness in OCD patients (Shapira et al. 2003; Cannistraro et al. 2004; Schienle et al. 2005; Lawrence et al. 2007), we consider that our results complement previous studies in suggesting that amygdala function is altered in OCD patients, but specifically in the context of an active emotional face-processing task. Both study groups showed significant amygdala activation during fearful and happy face matching trials. Although amygdala activation was greater in OCD patients, such activation was unrelated to emotional stimulus valence. This is not a common finding in primary anxiety disorders, where a specific bias of amygdala activation towards negatively valenced emotional faces has been consistently reported (Shin et al. 2005; Phan et al. 2006; Evans et al. 2008; Monk et al. 2008; Beesdo et al. 2009). Interestingly, it has been previously shown that amygdala responses to fearful faces occur with or without conscious awareness (Williams et al. 2005; Vuilleumier and Driver 2007), whereas amygdala activation during happy faces arises, predominantly, when faces are attended selectively (Williams et al. 2005). This may suggest that enhanced amygdala response to emotional faces in OCD patients may be partially related to attentional processes.
In keeping with the above idea is the fact that, in addition to the heightened activation of limbic components of the face-processing network, OCD patients also showed significant hyperactivation of dorsal prefrontal and parietal regions – the socalled “dorsal attention network”. This network comprises dorsal frontal cortex and frontal eye field areas, as well as the intraparietal sulcus, and exhibits a right-hemisphere predominance. Numerous functional imaging studies have highlighted the role of this network in sustained and selective attention processes, in keeping with “top-down” control mechanism (reviewed recently in Vuilleumier and Driver 2007; Corbetta et al. 2008). The involvement of the “dorsal attention network” in OCD pathophysiology is supported by both imaging and neuropsychological studies. Functional neuroimaging studies across a range of experimental task contexts (Pujol et al. 1999; Yucel et al. 2007; Henseler et al. 2008; Rotge et al. 2008; Jung et al. 2009) and a recent structural neuroimaging meta-analysis (Radua and Mataix-Cols 2009) have reported evidence of significant alterations of dorsal attention regions in OCD patients. In addition, neuropsychological studies have reported deficits of sustained and selective attention (Clayton et al. 1999; Cohen et al. 2003; Muller and Roberts 2005; Irak and Flament 2009). Considering other recent evidence of a “baseline” reduction in the functional connectivity of the dorsal striatum and prefrontal cortex in OCD patients (Harrison et al.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
Emotional face-processing in OCD 359
Figure 4. Correlation of total YBOCS scores with brain activation and functional connectivity during emotional face matching in OCD patients. All results correspond to the main task contrast “all faces control task” in (A) regional functional activation alone (B) functional connectivity with right amygdala and (C) functional connectivity with right prefrontal cortex. The strongest associations were observed between symptom severity and strength of right prefrontal-extrastriate (x, y, z 24, –78, –10; z 3.96, clustersize 259, P 0.0001) and right prefrontal-fusiform (x, y, z 34, –58, –16; z 3.78, clustersize 284, P 0.0001) functional connectivity. In D is depicted the strength of brain–behaviour correlation between right prefrontal-fusiform functional connectivity strength and total YBOCS scores by re-plotting Pearson’s linear correlations (two-tailed) between these variables. This relationship accounted for 45.8% (adjusted R2 statistic) of the modeled variance with a zero-order correlation coefficient of r 0.69. Connectivity strength is represented as a summary score (first eigenvariate) of contrast beta weights estimated from a 5-mm ROI centered on the right fusiform gyrus (x, y, z 34, –58, –16). Results are displayed in neurological convention (left left) on a high-resolution single-subject MRI in standard neuroanatomical space (Montreal Neurological Institute).
2009), it is plausible that increased activation of the latter region in the current study represents a compensatory response to a primary level neuronal deficit. We performed specific analyses to assess overall differences in task-induced functional connectivity of major regions of the putative face-processing network in OCD patients; an approach that has provided further insight into the dysfunction of this network in other anxiety disorders (McClure et al. 2007; Monk et al. 2008; Simmons et al. 2008). In summary, compared to control subjects our OCD patients exhibed: (i) a significant increase in task-induced reciprocal connectivity of the right dorsolateral prefrontal cortex and fusiform gyrus; (ii) significant functional connectivity of the right amygdala to fusiform gyrus; and (iii) significant functional connectivity between the right dorsolateral prefrontal cortex and the amygdala. Although this analysis was not intended to address causal links between the activities of distinct regions, the nature of our results are consistent with the suggested alteration of “top-down” regulatory processes in OCD patients.
The idea that our findings may represent a disorderspecific functional correlate of OCD is supported, albeit indirectly, by comparisons with other anxiety disorders, which emphasize a more specific processing bias to negative, threatening or fear provoking stimuli and corresponding limbic hyperactivity. This alteration is typically coupled with a deficient recruitment of prefrontal regions which, in turn, may play a role in sustaining negative processing biases in anxious individuals (Bishop 2007). OCD patients, by comparison, showed distributed hyperactivity of relevant limbic and cortical face-processing regions, and significantly enhanced functional connectivity between the dorsolateral prefrontal cortex and amygdala. We also observed direct correlations between patients’ clinical symptom severity and both task-related regional activation and functional connectivity, which overlapped focally on the right fusiform gyrus. This correlation effect was more pronounced in terms of increased functional connectivity between the fusiform gyrus and right dorsolateral prefrontal cortex.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
360 N. Cardoner et al. Despite the current face matching paradigm being widely used to investigate implicit emotional processing (Hariri et al. 2000; Stein et al. 2007), this task also diverges from other face processing paradigms used in previous studies (Cannistraro et al. 2004; Shin et al. 2005; Lawrence et al. 2007; Monk et al. 2008). For instance, the current paradigm involves an important element of attentional-executive control (forced choice face matching) that may account for the significant cortical activation observed here. Additionally, the current paradigm is not intended to discriminate brain responses associated with the processing of specific emotional face expressions as addressed in prior studies, as different emotional faces (target and probe faces) appear in each individual trial. This feature is likely to generate a large degree of overlap between the patterns of brain response observed in the fearful and happy face matching conditions. Although in both groups we observed greater activation of distributed cortical regions in association with the fearful compared to happy face matching condition, this is likely due to the common finding that matching fearful faces is generally more difficult than matching happy faces. The observation of dorsal prefrontal hyperactivity and enhanced connectivity in OCD patients deserves further comment. In symptom provocation studies, it has been suggested that the activation of dorsal attention regions reflects patients’ efforts to resist obsessive processes (Rotge et al. 2008). In the study by Mataix-Cols et al. (2004), checking-related symptom provocation and patients’ induced checking-related anxiety was associated with hyperactivation of dorsal attention regions. The authors suggested that the provocation of checking-related anxiety (or the suppression of checking rituals) was related to dysfunction of attentional and inhibitory control processes assigned to these regions, as opposed to emotional processing per se. It is plausible that such behaviour may be evoked in other task scenarios in such a way that stimuli unrelated to patients’ primary symptomatic concerns may also act as emotionally salient triggers on prefrontal control processes. Interestingly, a pattern of positive correlation between amygdala and dorsal prefrontal cortex has been previously reported during a version of the emotional matching task (Hariri et al. 2000, 2003), where healthy subjects performed a cognitive (semantic) evaluation of emotional information. In OCD patients, exaggerated responses in frontal regions related to cognitive reappraisal may occur during basic emotional stimuli perception even in low demanding tasks with no explicit cognitive evaluation. Alternatively, it may be argued that our results reflect a simple epiphenomenon of task performance and patients’ motivational state (i.e., desire to perform well, no mistakes, emotional motivation).
However, this is difficult to reconcile with the fact that hyperactivation of dorsal regions is not universally observed in fMRI studies of OCD (Remijnse et al. 2006; Gu et al. 2008). The study was neither designed nor powered to delineate the effects of antidepressant medication on brain activation, and we considered it ethically inappropriate to withdraw patients from their treatment for the purposes of our research. All patients, except one who was free of medication for at least 1 month, were undergoing stable pharmacological treatment. Our data do not allow us to exclude the effect of antidepressant drugs. Treatment with antidepressants could exert a modulatory effect on brain activity (i.e. different SSRIs have been related to downregulation in regions involved in face-processing) (Sheline et al. 2001; Fu et al. 2004). However, a recent study revealed a similar pattern of brain functional alterations in treated OCD patients and untreated OCD relatives (Chamberlain et al. 2008), suggesting that OCD-related brain dysfunction may exist irrespective of medication confounds. In our study we used fearful and happy faces to assess patients’ response to basic (disease non-specific) emotional stimuli. We explicitly eluded emotional expressions that might drive abnormal emotional responses in specific subtypes, such as disgust in OCD patients with washing symptoms and contamination (Stein et al. 2001; Lawrence et al. 2007). Previous neuroimaging studies of OCD using a face-processing paradigm predominantly included patients with washing and contamination symptoms (Cannistraro et al. 2004; Lawrence et al. 2007). In our study, by contrast, patients were characterized by more prominent aggressive and checking symptoms. Findings from different larger-scale neuroimaging studies now support the idea that different OCD symptom dimensions may be mediated by partly overlapping and distinct brain systems (Pujol et al. 2004; van den Heuvel et al. 2009). However, due to our smaller sample size and the absence of certain symptoms in our patient group (i.e. no prominent hoarders), we were unable to appropriately test whether our results could be related to one or another major symptom dimension or generalized to all patients with the disorder. Studies involving larger samples of OCD patients will be needed to test the specificity of the current findings. In conclusion, OCD patients showed enhanced brain responsiveness during active emotional face-processing. Our findings diverge from previously described alterations in anxiety disorders, particularly in relation to amygdala and prefrontal cortex relationships. OCD patients showed enhanced amygdala–prefrontal connectivity as opposed to negative reciprocal interaction. This pattern appears to be disorder-specific and
Emotional face-processing in OCD 361 was significantly related to symptom severity. With respect to the amygdala, our findings suggest that heightened activity of the region was not due to primary alteration in emotional processing, however it is most likely modulated through a heightened engagement of dorsal attention regions.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
Acknowledgments This study was supported in part by the Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental, CIBERSAM (FIS, I.D. PI050884 & PI071029). Dr Harrison is supported by a National Health and Medical Research Council of Australia (NHMRC) Clinical Career Development Award (I.D. 628509). Dr Pujol acknowledges contribution from the Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), Barcelona, Spain. Dr. Soriano-Mas is funded by a Miguel Servet contract from the Carlos III Health Institute (CP10/00604). Ms López-Solà is supported by FPU grants from the Spanish Ministry of Education (I.D. AP2005-0408). Ms Real was funded by the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL). We thank Gerald Fannon for revising the manuscript. The authors thank all the study participants and staff from the Department of Psychiatry of Hospital Universitari de Bellvitge who helped enroll the study sample. Dr Cardoner had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Statement of Interest The authors have no biomedical financial interests or potential conflicts of interest. References Alonso P, Menchon JM, Jimenez S, Segalas J, Mataix-Cols D, Jaurrieta N, et al. 2008. Personality dimensions in obsessivecompulsive disorder: relation to clinical variables. Psychiatry Res 157:159–168. Beesdo K, Lau JY, Guyer AE, McClure-Tone EB, Monk CS, Nelson EE, et al. 2009. Common and distinct amygdala-function perturbations in depressed vs anxious adolescents. Arch Gen Psychiatry 66:275–285. Bishop SJ. 2007. Neurocognitive mechanisms of anxiety: an integrative account. Trends Cogn Sci 11:307–316. Cannistraro PA, Wright CI, Wedig MM, Martis B, Shin LM, Wilhelm S, Rauch SL. 2004. Amygdala responses to human faces in obsessive-compulsive disorder. Biol Psychiatry 56:916–920. Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, del Campo N, et al. 2008. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 321:421–422.
Chen CH, Lennox B, Jacob R, Calder A, Lupson V, BisbrownChippendale R, et al. 2006. Explicit and implicit facial affect recognition in manic and depressed states of bipolar disorder: a functional magnetic resonance imaging study. Biol Psychiatry 59:31–39. Clayton IC, Richards JC, Edwards CJ. 1999. Selective attention in obsessive-compulsive disorder. J Abnorm Psychol 108: 171–175. Cohen Y, Lachenmeyer JR, Springer C. 2003. Anxiety and selective attention in obsessive-compulsive disorder. Behav Res Ther 41:1311–1323. Corbetta M, Patel G, Shulman GL. 2008. The reorienting system of the human brain: from environment to theory of mind. Neuron 58:306–324. Dalton KM, Nacewicz BM, Johnstone T, Schaefer HS, Gernsbacher MA, Goldsmith HH, et al. 2005. Gaze fixation and the neural circuitry of face processing in autism. Nat Neurosci 8:519–526. Davidson RJ. 2002. Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry 51:68–80. Etkin A, Wager TD. 2007. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164: 1476–1488. Evans KC, Wright CI, Wedig MM, Gold AL, Pollack MH, Rauch SL. 2008. A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder. Depress Anxiety 25:496–505. Fairhall SL, Ishai A. 2007. Effective connectivity within the distributed cortical network for face perception. Cerebral Cortex 17: 2400–2406. First MB, Spitzer RL, Gibbon M, Williams JB. 1998. Structured clinical interview for DSM-IV axis 1 disorders. Washington, DC: American Psychiatric Press. First MB, Spitzer RL, Gibbon M, Williams JB. 2007. Structured Clinical Interview for DSM-IV-RS Axis 1 Disorders – Non-patient edition (SCID-I/NP) New York: Biometrics Research, New York State Psychiatric Institute. Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, Noll DC. 1995. Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med 33:636–647. Fredrikson M, Furmark T. 2003. Amygdaloid regional cerebral blood flow and subjective fear during symptom provocation in anxiety disorders. Ann NY Acad Sci 985:341–347. Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ. 1997. Psychophysiological and modulatory interactions in neuroimaging. Neuroimage 6:218–229. Fu CH, Williams SC, Cleare AJ, Brammer MJ, Walsh ND, Kim J, et al. 2004. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatry 61:877–889. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. 1989. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 46:1006–1011. Gu BM, Park JY, Kang DH, Lee SJ, Yoo SY, Jo HJ, et al. 2008. Neural correlates of cognitive inflexibility during task-switching in obsessive-compulsive disorder. Brain 131:155–164. Hamilton M. 1959. The assessment of anxiety states by rating. Br J Med Psychol 32:50–55 Hamilton M. 1960. A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62. Hariri AR, Bookheimer SY, Mazziotta JC. 2000. Modulating emotional responses: effects of a neocortical network on the limbic system. Neuroreport 11:43–48.
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
362 N. Cardoner et al. Hariri AR, Mattay VS, Tessitore A, Fera F, Weinberger DR. 2003. Neocortical modulation of the amygdala response to fearful stimuli. Biol Psychiatry 53:494–501. Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, Lopez-Sola M, Hernandez-Ribas R, et al. 2009. Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch Gen Psychiatry 66:1189–1200. Haxby JV, Hoffman EA, Gobbini MI. 2000. The distributed human neural system for face perception. Trends Cogn Sci 4:223–233. Henseler I, Gruber O, Kraft S, Krick C, Reith W, Falkai P. 2008. Compensatory hyperactivations as markers of latent working memory dysfunctions in patients with obsessive-compulsive disorder: an fMRI study. J Psychiatry Neurosci 33:209–215. Hoehn-Saric R, McLeod DR, Hipsley P. 1995. Is hyperarousal essential to obsessive-compulsive disorder? Diminished physiologic flexibility, but not hyperarousal, characterizes patients with obsessive-compulsive disorder. Arch Gen Psychiatry 52: 688–693. Holsen LM, Dalton KM, Johnstone T, Davidson RJ. 2008. Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome. Neuroimage 43:592–604. Irak M, Flament MF. 2009. Attention in sub-clinical obsessivecompulsive checkers. J Anxiety Disord 23:320–326. Ishai A, Schmidt CF, Boesiger P. 2005. Face perception is mediated by a distributed cortical network. Brain Res Bull 67: 87–93. Jung WH, Gu BM, Kang DH, Park JY, Yoo SY, Choi CH, et al. 2009. BOLD response during visual perception of biological motion in obsessive-compulsive disorder: An fMRI study using the dynamic point-light animation paradigm. Eur Arch Psychiatry Clin Neurosci 259:46–54. Lawrence NS, An SK, Mataix-Cols D, Ruths F, Speckens A, Phillips ML. 2007. Neural responses to facial expressions of disgust but not fear are modulated by washing symptoms in OCD. Biol Psychiatry 61:1072–1080. Lieberman MD, Cunningham WA. 2009. Type I and Type II error concerns in fMRI research: re-balancing the scale. Soc Cogn Affect Neurosci 4:423–428. Mataix-Cols D, Rauch SL, Manzo PA, Jenike MA, Baer L. 1999. Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder. Am J Psychiatry 156:1409–1416. Mataix-Cols D, Wooderson S, Lawrence N, Brammer MJ, Speckens A, Phillips ML. 2004. Distinct neural correlates of washing, checking, and hoarding symptom dimensions in obsessivecompulsive disorder. Arch Gen Psychiatry 61:564–576. McClure EB, Monk CS, Nelson EE, Parrish JM, Adler A, Blair RJ, et al. 2007. Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Arch Gen Psychiatry 64:97–106. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET. 2008. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev 32:525–549. Monk CS, Telzer EH, Mogg K, Bradley BP, Mai X, Louro HM, et al. 2008. Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. Arch Gen Psychiatry 65: 568–576. Muller J, Roberts JE. 2005. Memory and attention in ObsessiveCompulsive Disorder: a review. J Anxiety Disord 19:1–28. Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB. 2005. Dose-dependent decrease of activation in bilateral
amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry 62:282–288. Phan KL, Fitzgerald DA, Nathan PJ, Tancer ME. 2006. Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia. Biol Psychiatry 59:424–429. Phillips ML, Drevets WC, Rauch SL, Lane R. 2003a. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry 54:515–528. Phillips ML, Drevets WC, Rauch SL, Lane R. 2003b. Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry 54:504–514. Pujol J, Torres L, Deus J, Cardoner N, Pifarre J, Capdevila A, Vallejo J. 1999. Functional magnetic resonance imaging study of frontal lobe activation during word generation in obsessivecompulsive disorder. Biol Psychiatry 45:891–897. Pujol J, Soriano-Mas C, Alonso P, Cardoner N, Menchon JM, Deus J, Vallejo J. 2004. Mapping structural brain alterations in obsessive-compulsive disorder. Arch Gen Psychiatry 61: 720–730. Pujol J, Harrison BJ, Ortiz H, Deus J, Soriano-Mas C, Lopez-Sola M, et al. 2009. Influence of the fusiform gyrus on amygdala response to emotional faces in the non-clinical range of social anxiety. Psychol Med 39:1177–1187. Radua J, Mataix-Cols D. 2009. Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. Br J Psychiatry 195:393–402. Rauch SL, Shin LM, Wright CI. 2003. Neuroimaging studies of amygdala function in anxiety disorders. Ann NY Acad Sci 985:389–410. Remijnse PL, Nielen MM, van Balkom AJ, Cath DC, van Oppen P, Uylings HB, Veltman DJ. 2006. Reduced orbitofrontalstriatal activity on a reversal learning task in obsessive-compulsive disorder. Arch Gen Psychiatry 63:1225–1236. Rotge JY, Guehl D, Dilharreguy B, Cuny E, Tignol J, Bioulac B, et al. 2008. Provocation of obsessive-compulsive symptoms: a quantitative voxel-based meta-analysis of functional neuroimaging studies. J Psychiatry Neurosci 33:405–412. Schienle A, Schafer A, Stark R, Walter B, Vaitl D. 2005. Neural responses of OCD patients towards disorder-relevant, generally disgust-inducing and fear-inducing pictures. Int J Psychophysiol 57:69–77. Schwartz CE, Wright CI, Shin LM, Kagan J, Whalen PJ, McMullin KG, Rauch SL. 2003. Differential amygdalar response to novel versus newly familiar neutral faces: a functional MRI probe developed for studying inhibited temperament. Biol Psychiatry 53:854–862. Sergent J, Ohta S, MacDonald B. 1992. Functional neuroanatomy of face and object processing. A positron emission tomography study. Brain 115(Pt 1):15–36. Shapira NA, Liu Y, He AG, Bradley MM, Lessig MC, James GA, et al. 2003. Brain activation by disgust-inducing pictures in obsessive-compulsive disorder. Biol Psychiatry 54:751–756. Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. 2001. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry 50:651– 658. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, et al. 2005. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 62:273–281. Simmons AN, Paulus MP, Thorp SR, Matthews SC, Norman SB, Stein MB. 2008. Functional activation and neural networks in
World J Biol Psychiatry Downloaded from informahealthcare.com by Joaquin Ibanez Esteb on 01/13/12 For personal use only.
Emotional face-processing in OCD 363 women with posttraumatic stress disorder related to intimate partner violence. Biol Psychiatry 64:681–690. Soriano-Mas C, Pujol J, Alonso P, Cardoner N, Menchon JM, Harrison BJ, et al. 2007. Identifying patients with obsessivecompulsive disorder using whole-brain anatomy. Neuroimage 35:1028–1037. Stein DJ, Liu Y, Shapira NA, Goodman WK. 2001. The psychobiology of obsessive-compulsive disorder: how important is the role of disgust? Curr Psychiatry Rep 3:281–287. Stein MB, Simmons AN, Feinstein JS, Paulus MP. 2007. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry 164:318–327. Surguladze S, Brammer MJ, Keedwell P, Giampietro V, Young AW, Travis MJ, et al. 2005. A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder. Biol Psychiatry 57:201–209. van den Heuvel OA, Remijnse PL, Mataix-Cols D, Vrenken H, Groenewegen HJ, Uylings HB, et al. 2009. The major symptom dimensions of obsessive-compulsive disorder are mediated by partially distinct neural systems. Brain 132:853–868.
Supplementary material available online Supplementary Figure 1.
van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC, et al. 2005. Disorder-specific neuroanatomical correlates of attentional bias in obsessivecompulsive disorder, panic disorder, and hypochondriasis. Arch Gen Psychiatry 62:922–933. Vuilleumier P, Driver J. 2007. Modulation of visual processing by attention and emotion: windows on causal interactions between human brain regions. Phil Trans R Soc London B Biol Sci 362:837–855. Wechsler D. 1999. Wechsler Abbreviated Scale of Intelligence Manual. San Antonio, TX: The Psychological Corporation. Williams LM, et al. 2004. Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. Am J Psychiatry 161:480–489. Williams MA, McGlone F, Abbott DF, Mattingley JB. 2005. Differential amygdala responses to happy and fearful facial expressions depend on selective attention. Neuroimage 24:417–425. Yücel M, Harrison BJ, Wood SJ, Fornito A, Wellard RM, Pujol J, et al. 2007. Functional and biochemical alterations of the medial frontal cortex in obsessive-compulsive disorder. Arch Gen Psychiatry 64:946–955.
