Amygdala responses to human faces in obsessive-compulsive disorder

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Amygdala Responses to Human Faces in Obsessive-Compulsive Disorder Paul A. Cannistraro, Christopher I. Wright, Michelle M. Wedig, Brian Martis, Lisa M. Shin, Sabine Wilhelm, and Scott L. Rauch Background: To assess the amygdala response to emotional faces in obsessive-compulsive disorder (OCD) using functional magnetic resonance imaging (fMRI). Methods: Ten subjects with current OCD and 10 healthy control subjects underwent fMRI, during which they viewed pictures of fearful, happy, and neutral human faces, as well as a fixation cross. Results: Across both groups, there was significant activation in left and right amygdala for the fearful versus neutral faces contrast. Data extracted from these functionally defined regions of interest indicated that OCD subjects exhibited a weaker response than control subjects bilaterally across all face conditions versus fixation. No group-by-face condition interactions were observed. Conclusions: Contrary to findings in other anxiety disorders, there was no observed increase in amygdala responsivity to fearful versus neutral human faces in OCD as compared with healthy control subjects. Moreover, across all face conditions, amygdala responsivity was attenuated in OCD subjects relative to control subjects. Therefore, the present findings are consistent with abnormal amygdala function in OCD and are of a character that may distinguish OCD from other anxiety disorders. Key Words: Functional MRI, limbic system, anxiety disorders, neuroimaging, facial expressions


urrent neurobiological models suggest an important role for the amygdala in the neurocircuitry of anxiety. Convergent evidence suggests that the amygdala mediates states of increased arousal, as well as the fear response (Davis 1992; LeDoux 1996). While previous neuroimaging studies have implicated the amygdala in the pathophysiology of other anxiety disorders (Rauch et al 2003), there has been a relative lack of such evidence with regard to obsessive-compulsive disorder (OCD). Rather, neuroimaging studies of OCD have principally implicated orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), basal ganglia, and thalamus (Saxena et al 1998; Saxena and Rauch 2000). Although one functional magnetic resonance imaging (fMRI) symptom provocation study did show amygdala activation in OCD not found in control subjects (Breiter et al 1996), the preponderance of symptom provocation studies have not found amygdala activation in OCD (Adler et al 2000; McGuire et al 1994; Rauch et al 1994). Interestingly, recent research has revealed amygdala activation in psychiatrically healthy individuals in response to obsessive-compulsive– related stimuli (Mataix-Cols et al 2003). As a complement to provocation studies, investigators have used human face stimuli in conjunction with fMRI to probe for differences in amygdala function in both mood and anxiety disorders. In this context, amygdala hyperresponsivity to fearful faces has been observed in major depression (Sheline et al 2001) and posttraumatic From the Psychiatric Neuroimaging Research Program and The Obsessive Compulsive Disorders Program (PAC, CIW, MMW, LMS, SW, SLR), Department of Psychiatry, Massachusetts General Hospital, and Athinoula A. Martinos Center for Biomedical Imaging (PAC, CIW, MMW, LMS, SLR), Charlestown, Massachusetts; Brigham Behavioral Neurology Group (CIW), Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts; Department of Psychiatry (BM), VA Healthcare System and University of Michigan, Ann Arbor, Michigan; and Department of Psychology (LMS), Tufts University, Medford, Massachusetts. AddressreprintrequeststoScottL.Rauch,M.D.,PsychiatricNeuroimagingResearch Program, Massachusetts General Hospital, Building 149, Thirteenth Street, Charlestown, MA 02129; E-mail: [email protected]. Received June 10, 2004; revised August 31, 2004; accepted September 9, 2004.

0006-3223/04/$30.00 doi:10.1016/j.biopsych.2004.09.029

stress disorder (PTSD) (Rauch et al 2000) but not in specific phobia (Wright et al 2003). However, to date, to our knowledge, no published studies have employed emotional faces as probes to specifically test for amygdala dysfunction in OCD. Of note, facial expressions of disgust have been used to demonstrate exaggerated insular responses in OCD (Shapira et al 2003). In the current study, we used fMRI in conjunction with fearful, happy, and neutral face stimuli to determine whether the amygdala is hyperresponsive to fearful faces in OCD.

Methods and Materials Subjects This study was approved and conducted in accordance with guidelines established by the Partners Human Research Committee. Written informed consent was obtained from each subject. The study included 10 subjects with OCD (4 male subjects, 6 female subjects, mean age ⫽ 26.8 years, SD ⫽ 5.2, range ⫽ 21–37, mean education 15.3 years, SD ⫽ 1.6, range ⫽ 13–18) and 10 healthy control (HC) subjects (4 male subjects, 6 female subjects, mean age ⫽ 24.9 years, SD ⫽ 7.8, range ⫽ 19 – 45, mean education 15.2 years, SD ⫽ 1.1, range ⫽ 13–16), group-matched for sex, age, and years of education (all p ⬎ .5). All subjects were right-handed, as assessed by the Edinburgh Inventory (Oldfield 1971). All subjects were without confounding neurologic or medical disease by history. The Structured Clinical Interview for DSM-IV (First et al 1995) was used to confirm the diagnosis of OCD in the OCD group and absence of Axis I diagnoses in the HC group. At the time of study, all OCD subjects had a Yale-Brown Obsessive-Compulsive Scale (YBOCS) (Goodman et al 1989a, 1989b) score of greater than 15 (mean score ⫽ 26.3, SD ⫽ 6.3, range ⫽ 17–38). All of the major OCD symptom dimensions (Leckman et al 1997) were represented in this sample; subjects endorsed specific obsessions and/or checking symptoms (n ⫽ 4), symmetry and/or ordering symptoms (n ⫽ 4), contamination and/or washing symptoms (n ⫽ 7), and hoarding symptoms (n ⫽ 2). The OCD group was free of any other current Axis I diagnosis, except for one subject who had comorbid generalized anxiety disorder and body dysmorphic disorder. Lifetime Axis I diagnoses in the OCD group were limited to major depression (n ⫽ 4), alcohol abuse (n ⫽ 1), and substance abuse (n ⫽ 1). With the exception of selective serotonin reuptake BIOL PSYCHIATRY 2004;56:916 –920 © 2004 Society of Biological Psychiatry

P.A. Cannistraro et al inhibitors (SSRIs), all subjects were required to be free of all psychotropic medications for at least 4 weeks or in the case of neuroleptics for at least 1 year. With regard to this study sample, eight of the OCD subjects were entirely psychotropic mediation naïve. One OCD subject had a remote history of fluoxetine use (off medication for 9 years prior to the study), and one was on a stable dose of sertraline 50 mg daily at the time of image acquisition. Procedure We used an emotional faces paradigm that we had previously demonstrated to reliably activate the amygdala (Wright et al 2003). All subjects viewed two runs (4 min 40 s/run) of human faces chosen from a well-characterized set of emotionally expressive face stimuli (Ekman and Friesen 1976). Each face stimulus was presented for 200 milliseconds with a 300-millisecond interstimulus interval. These runs consisted of three alternating 28-second blocks of fearful (F) and happy (H) faces, bracketed by 28-second blocks of neutral (N) face and fixation (⫹) conditions. Each subject viewed 2 runs: ⫹NFHFHFHN⫹ (i.e., fearful followed by happy) and ⫹NHFHFHFN⫹ (i.e., happy followed by fearful). The order of conditions was counterbalanced across subjects. The face stimuli were displayed using standardized software (MacStim 2.5.9; White Ant Occasional Publishing, West Melbourne, Australia) and a Sharp XG-2000V color liquid crystal display projector (Osaka, Japan). Image Acquisition We used a Symphony/Sonata 1.5 Tesla whole body highspeed imaging device equipped for echo planar imaging (EPI) (Siemens Medical Systems, Iselin, New Jersey) with a three-axis gradient head coil. Head movement was restricted with expandable foam cushions. After an automated scout image was acquired and shimming procedures were performed to optimize field homogeneity (Reese et al 1995), high-resolution threedimensional (3-D) magnetization-prepared rapid acquisition gradient-echo (MPRAGE) sequences (repetition time [TR]/echo time [TE]/flip angle ⫽ 7.25 ms/3 ms/7°) with an in-plane resolution of 1.3 mm and 1 mm slice thickness were collected for spatial normalization and for positioning the slice prescription of the subsequent sequences. Then, a T1-weighted (TR/TE/flip angle ⫽ 8 s/39 ms/90°) and a T2-weighted (TR/TE/flip angle ⫽ 10 s/48 ms/120°) sequence were gathered. Functional MRI images (blood oxygenation level dependent [BOLD]) (Kwong et al 1992) were acquired using a gradient echo T2*-weighted sequence (TR/TE/flip angle ⫽ 2.8 s/40 ms/90°). Prior to each scan, four timepoints were acquired and discarded to allow longitudinal magnetization to reach equilibrium. The T1, T2, and functional images were collected in the same plane (24 coronal slices angled perpendicular to the anterior commissure-posterior commissure [AC-PC] line) with the same slice thickness (7 mm, skip 1 mm; voxel size 3.125 x 3.125 x 8 mm), excitation order (interleaved), and phase encoding (foot-to-head). Image Processing Data in each functional run were spatially smoothed (full width half maximum ⫽ 7 mm) using a 3-D Gaussian filter (, normalized to correct for global signal intensity changes and motion corrected to the first run using Analyses of Functional Neuroimages (AFNI) ( afni/index.html). The spatially smoothed, normalized, motioncorrected functional images were then aligned to the 3-D structural image created by motion correcting and averaging the

BIOL PSYCHIATRY 2004;56:916 –920 917 high-resolution 3-D sagittal images. As part of the alignment procedure, the raw functional data from each subject were visualized over the high-resolution 3-D image from that individual to ensure that the BOLD signal in the amygdala, our a priori region of interest (ROI), was not obscured by susceptibility artifact. Individual subject functional data were subsequently spatially normalized with an optimal linear transformation method (Fischl et al 2002). For the linear transformation, an automated spatial normalization procedure was used (Fischl et al 2002) that maximizes the likelihood that anatomic structures of individual subjects will overlap with each other across subjects. For consistency across studies, we displayed group statistical maps on a group-averaged Talairach brain and presented Talairach coordinates that are based on registration of the images from the optimal linear transformation with the Talairach atlas (Talairach and Tournoux 1988). Data Analyses The standard processing stream of the Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Martinos Center for Biomedical Imaging, FreeSurfer Functional Analysis Stream (FS-FAST) ( Data_Processing_STD3.html), was used for the fMRI image analysis. After spatial normalization, the functional data were averaged across subjects according to condition (⫹, N, F, and H). Using a fixedeffects model, group statistical maps were then computed for the contrast of interest on a voxel-by-voxel basis. We chose to focus our attention on the F versus N contrast, as this has previously shown robust and reproducible amygdala activation (e.g., Wright et al 2003). For this analysis, we assessed amygdala responses across all 20 subjects combined (OCD and HC), with the motivation of defining ROIs for further analysis. Note the amygdala search territory was defined by visual inspection of structural MRI data guided by the Talairach atlas (Talairach and Tournoux 1988). The following landmarks were used to operationally define the search volume for the amygdala: anterior ⫽ anterior commissure; posterior ⫽ prominence of the temporal horn of the lateral ventricle; inferior ⫽ entorhinal cortex; superior ⫽ base of the basal forebrain; medial ⫽ uncus; lateral ⫽ ventral claustrum. At the resolution limits of the current study, the dorsal boundary of the amygdala is difficult to discern. Recent anatomical evidence suggests that neurons of the central and medial nuclei extend dorsally into the substantia innominata (SI) of the basal forebrain, comprising neurons of the bed nucleus of the stria terminalis, which is a component of the so-called extended amygdala. Cholinergic neurons of the nucleus basalis of Meynert are also intermingled in this region (see Whalen et al 1998 for a more detailed discussion of amygdala/SI functional contiguity). The statistical significance threshold for the amygdala, our a priori ROI, was p ⱕ 7 x 10 ⫺4, reflecting Bonferroni-type corrections for multiple comparisons, based on the voxel size (8 x 3.125 x 3.125 mm) and the average total volume of the amygdala (5.5 cm3 ⬇ 71 voxels) in healthy adults (Filipek et al 1994). A cluster of three or more contiguous voxels above threshold was required as the criterion for a significantly activated area. The F versus N contrast was used to define the functional ROIs in the amygdala. Next, for each individual subject, values for each condition (F, N, and H) versus fixation were extracted from the functional ROI, used to calculate percent BOLD signal change, and entered into a repeated measures analysis of variance (ANOVA). We then tested for a main effect of group across all face conditions (versus the baseline fixation condition)

918 BIOL PSYCHIATRY 2004;56:916 –920

Figure 1. Amygdala functional regions of interest.

and for group-by-condition interactions at a significance threshold of p ⬍ .05. A whole brain, voxel-wise analysis of the between-group maps was also performed to determine whether regions of the amygdala or other brain areas demonstrated significant effects of group or group x condition interactions. This analysis was conducted using a random effects model. For this betweengroup analysis, we again focused on the F versus N contrast, using the same significance threshold for the amygdala as in the other voxel-wise analysis.

Results Across both groups, voxel-wise analysis revealed a significant response to the F versus N faces contrast in the amygdala bilaterally. Two functional ROIs, one containing three voxels in the left amygdala (peak activation at -24, -8, -16) and the other comprised of seven voxels in the right amygdala (peak activation at 27, -6, -23), were created in accordance with the significance threshold criteria already discussed (see Figure 1). The presence of these clusters confirmed that the paradigm reliably activated the amygdala bilaterally. Data extracted from the functional ROIs did reveal a main effect of group, in that OCD subjects exhibited an attenuated response in comparison with control subjects across all facial expressions versus fixation in left (p ⫽ .008) as well as right (p ⫽ .0234) amygdala (see Figure 2). Post hoc t tests further indicated that for both left and right amygdala, the between-group difference in response to each individual face condition versus fixation was significant, with the exception of the fear condition in the right amygdala (p ⫽ .058) (see Figure 2). No group-by-condition interaction was observed in the ROI analysis. Further, a whole brain voxel-wise between-group comparison for the F versus N contrast likewise showed no groupby-condition interactions within or beyond the amygdala. Finally, to address the potentially confounding influences of comorbidity or medication effects, we repeated the analyses while serially excluding the OCD subject with generalized anxiety disorder as well as the subject on sertraline. The exclusion of these subjects did not significantly alter the results of our analyses.

P.A. Cannistraro et al uated amygdala responses bilaterally across all face conditions. Though in the present study, OCD subjects exhibited general amygdala hyporesponsivity to face stimuli, the differential response among expression conditions did not significantly differ between OCD and HC subjects; prior studies of OCD indicate amygdala hyperresponsivity to disorder-specific stimuli. Limitations of the current study include the modest number of subjects and the use of a passive viewing paradigm that does not provide behavioral data. Furthermore, as with essentially all fMRI studies that utilize noncontrast methods, we relied on measures of percent signal change with no absolute index of baseline regional activity. Conversely, the strengths of this study include a relatively well-characterized cohort of subjects and the use of a previously established paradigm for measuring amygdala responsivity. In contrast to evidence for amygdala dysfunction found in the other anxiety disorders (Rauch et al 2003), leading theories of OCD have not typically emphasized a central role for the amygdala. Rather, the preponderance of evidence implicates corticostriatal circuitry in the pathophysiology of OCD. Resting state positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) studies (Baxter et al 1988; Machlin et al 1991; Nordahl et al 1989; Perani et al 1995; Swedo et al 1989) have found greater activity in OFC, ACC, and striatum in OCD subjects in comparison with healthy control subjects. Likewise, provocation studies (Adler et al 2000; Breiter et al 1996; McGuire et al 1994; Rauch et al 1994) have shown an accentuation of hyperactivity within these same brain regions during a symptomatic state. Furthermore, treatment response studies have demonstrated normalization of the hyperactivity in these structures following successful behavioral or pharmacological therapy for OCD (Baxter et al 1992; Benkelfat et al 1990; Perani et al 1995; Schwartz et al 1996; Swedo et al 1992). There is, however, some theoretical appeal to the notion that the amygdala plays a role in OCD. For instance, it has been hypothesized that the beneficial effects of extinction-based behavioral therapies for OCD are mediated by frontal-amygdala interactions (Rauch et al 1998). Furthermore, given the intimate connections between the amygdala and striatum, activation of the amygdala during a state of fear or anxiety could perhaps

Discussion We sought to determine whether, compared with HC subjects, OCD subjects would demonstrate exaggerated amygdala responsivity to fearful versus neutral faces. Rather, we found that in comparison with HC subjects, OCD subjects exhibited

Figure 2. Percent signal change for facial expressions versus fixation in left and right amygdala for OCD and HC groups. OCD, obsessive-compulsive disorder; HC, healthy control.

P.A. Cannistraro et al induce the repetitive behaviors observed during striatal activation (Rauch et al 1998). Nonetheless, the empirical evidence of a role for the amygdala in OCD remains limited. Findings from several recent studies are consistent with amygdala involvement in OCD. Szeszko et al (1999) have described decreased amygdala volumes in OCD. As stated previously, Breiter et al (1996) have reported amygdala activation in OCD subjects not found in control subjects during symptom provocation. In a PET 18fluorodeoxyglucose (FDG) study, Horwitz et al (1991) observed a pattern of intercorrelations between regional rates of glucose utilization in OCD subjects that differed significantly from that of control subjects in an anterior medial temporal region encompassing the amygdala. The recently reported evidence for a reciprocal relationship between indices of function in the amygdala and medial prefrontal cortex (Shin et al 2004) as well as ventral prefrontal cortex (Dougherty et al 2004), along with previous findings of increased ACC and OFC activity in OCD, would appear to be consistent with our current findings of attenuated amygdala responsivity in OCD. The amygdala hyporesponsiveness seen in this study might be related to exaggerated frontal cortical inhibitory influences that could be phasic or tonic. We found no evidence of greater phasic frontal cortical activity in the OCD group, in that the voxel-wise analysis for all face conditions versus fixation yielded no significant between-group differences in frontal cortex. Due to the limitations of fMRI, testing hypotheses regarding the relationship between tonic frontal cortical activity and amygdala responsivity to face stimuli will require further investigation using other methods (e.g., positron emission tomography). Though generally hyporesponsive in the present study, in OCD the amygdala appears to be hyperresponsive to disorder-specific stimuli in some instances (Breiter et al 1996). Additional investigation is warranted to further explain the present findings and to better understand the extent of the amygdala’s involvement in OCD. In particular, the focus of future research might include functional imaging paradigms that probe: 1) the functional interactions between the amygdala and other key structures (e.g., striatum and ventromedial prefrontal cortex); 2) amygdala responsivity to disorder-specific versus general threat-related stimuli; and 3) the relationship between frontal amygdala interactions and extinction or response to extinction-based therapies.

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