Neural Correlates of Anxiety Associated with Obsessive-Compulsive Symptom Dimensions in Normal Volunteers

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1 Neural Correlates of Anxiety Associated with Obsessive-Compulsive Symptom Dimensions in Normal Volunteers David Mataix-Cols, Sarah Cullen, Kezia Lange, Fernando Zelaya, Christopher Andrew, Edson Amaro, Michael J. Brammer, Steven C.R. Williams, Anne Speckens, and Mary L. Phillips Background: The neural correlates of anxiety associated with obsessive-compulsive symptomlike provocation in normal volunteers are unknown. Methods: Ten healthy volunteers participated in four functional magnetic resonance experiments. Subjects were scanned while viewing alternating blocks of emotional (normally aversive, washing-relevant, checking-relevant, or hoarding-relevant pictures) and neutral pictures, and imagining scenarios related to the content of each picture type. Nonparametric brain mapping analyses were used. Results: In response to the provocative pictures in all experiments, increases in subjective anxiety and activation in bilateral ventral prefrontal, limbic, dorsal prefrontal, and visual regions were demonstrated. Anxiety related to different symptom dimensions was associated with different patterns of activation: provocation of washing-relevant anxiety predominantly activated dorsal and ventral prefrontal regions; checking-relevant anxiety predominantly activated dorsal prefrontal regions; and hoardingrelevant anxiety predominantly activated ventral prefrontal regions and the left amygdala. Conclusions: Our findings support a dimensional model of obsessive-compulsive disorder (OCD) whereby 1) the brain systems implicated in the mediation of anxiety in response to symptom-related material in normal subjects are similar to those identified in OCD patients during symptom provocation, and 2) anxiety associated with different symptom dimensions is associated with differential patterns of activation of these neural systems. Further investigation of the neural basis of OCD symptom dimensions is required. Biol Psychiatry 2003 Society of Biological Psychiatry From the Division of Psychological Medicine (DM-C, SC, KL, MLP), Departments of Neuroimaging Research (FZ, CA, EA, SCRW), Biostatistics (MJB), and Psychology (AS), GKT School of Medicine and Institute of Psychiatry, London, United Kingdom. Address reprint requests to David Mataix-Cols, Ph.D., Department of Psychological Medicine, GKT School of Medicine and Institute of Psychiatry, 5th Floor Thomas Guy House, Guy s Hospital, London SE1 9RT United Kingdom. Received March 26, 2002; revised June 12, 2002; accepted June 21, Key Words: Obsessive-compulsive disorder, symptom dimensions, hoarding, neuroimaging, fmri, emotion Introduction Functional neuroimaging studies have substantially increased our understanding of the neural mechanisms underlying obsessive-compulsive disorder (OCD). Symptom provocation paradigms have used positron emission tomography (PET), single photon emission tomography (SPECT), or functional resonance imaging (fmri) to compare, in a single session, the patterns of brain activation during OCD symptom provocation and control states (Saxena and Rauch 2000). Although findings are discrepant, they strongly associate OCD symptoms with activation of the orbitofrontal cortex, with less consistent involvement of lateral frontal cortex, anterior cingulate gyrus, temporal cortex, striatum, thalamus, amygdala, and insular cortex (Adler et al 2000; Breiter et al 1996; McGuire et al 1994; Rauch et al 1994; Saxena and Rauch 2000). Obsessive-compulsive disorder is heterogeneous, with symptoms that can be summarized in a few consistent, temporally stable, dimensions (Baer 1994; Leckman et al 1997; Mataix-Cols et al 1999a, 2002a; Summerfeldt et al 1999). Despite this phenotypic heterogeneity, most previous neuroimaging studies of OCD have grouped together patients with diverse symptom patterns, although they have included patients with predominantly contamination/ washing or mixed symptoms. To our knowledge, only three functional neuroimaging studies have examined the neural correlates of different symptoms in OCD. In one PET study (Cottraux et al 1996), all patients were predominantly checkers, and symptoms were provoked using an individually tailored script-driven paradigm that prompted the urge to check. They found significant increases in orbitofrontal and superior temporal cortex activity, and-,contrary to most previous findings, lower activity in the basal ganglia compared with control subjects. In another PET study, Rauch et al (1998) found significant correla Society of Biological Psychiatry /03/$30.00 doi:10/1016/s (03)

2 Obsessive-Compulsive Symptom Dimensions BIOL PSYCHIATRY 483 tions between the obsessions and checking dimension (Leckman et al 1997) and activations in bilateral striatum and between the contamination/washing dimension and activations in bilateral anterior cingulate, left orbitofrontal, and other cortical areas. Symmetry/ordering symptoms tended to be negatively correlated with regional cerebral blood flow in right striatum; however, these patients were examined while performing a continuous performance task rather than during the presentation of relevant stimuli. More recently, Phillips et al (2000) compared OCD patients who had mainly washing or checking symptoms with normal control subjects while viewing pictures of either normally disgusting scenes or washer-relevant pictures using fmri. When viewing washing-related pictures, only washers demonstrated activations in regions implicated in disgust perception, that is, visual regions and the anterior insula (Phillips et al 1997, 1998; Sprengelmeyer et al 1998). Checkers demonstrated activations in frontostriatal regions and the thalamus. Taken together, these studies suggest that the discrepancy within findings of previous functional imaging studies of OCD may be the result of relatively small sample sizes and phenotypic variations among their subject groups. Most individuals in the general population experience normal obsessive and compulsive phenomena at some time that resemble the form and content of abnormal, pathologic phenomena (Muris et al 1997; Rachman and de Silva 1978). Furthermore, studies involving nonclinical samples have demonstrated that normal individuals with high scores on self-administered scales of obsessions and compulsions show striking similarities to OCD patients regarding clinical and personality characteristics, as well as cognitive functioning (Gibbs 1996; Mataix-Cols et al 1999b, 1999c; Sher et al 1983). To date, however, little is known about the neural correlates of anxiety associated with symptom provocation in the normal population. To our knowledge, only three symptom provocation studies in OCD have used normal control groups (Breiter et al 1996; Cottraux et al 1996; Phillips et al 2000). All three of these studies found that symptom provocation induced some degree of anxiety not only among patients but also among normal control subjects, although to a lower extent. Breiter et al (1996) found that no brain areas were significantly related to symptom provocation (contaminants) in five normal subjects. Cottraux et al (1996) found significant increases in orbitofrontal cortex in both patients and control subjects and, interestingly, greater activations in thalamus and putamen in normal subjects than in patients during symptom provocation (aggressive obsessions and checking compulsions). Phillips et al (2000) found that normal subjects activated predominantly visual and frontal regions, cerebellum, middle and inferior temporal gyri and the hippocampus in response to washing-related pictures. Differences in the technology used (fmri vs. PET), the modality of stimuli presentation (exposure in vivo vs. script-driven auditory stimulation vs. visual stimulation), and the type of provocative symptom (mainly contaminants vs. mainly aggressive obsessions) could account for the differences among these three studies. Our study aimed to examine the neural correlates of experimentally induced anxiety associated with obsessivecompulsive symptomlike stimuli in a sample of normal subjects. It also aimed to validate a novel symptom provocation paradigm that combines two modalities of stimulus presentation, verbal instructions and visual presentation of symptom-related material. We hypothesized that, in normal volunteers, 1) anxiety would be provoked in response to all types of symptom-related material (Breiter et al 1996; Cottraux et al 1996), 2) anxiety provocation would activate regions previously identified during symptom provocation in OCD patients (orbitofrontal cortex, lateral frontal cortex, anterior cingulate, temporal cortex, basal ganglia, thalamus, amygdala, insula), and 3) distinct patterns of neural response would be associated with the anxiety related to each symptom dimension. Specifically, we hypothesized that 1) provocation of contamination/ washing-related anxiety would activate predominantly areas involved in emotion and disgust perception (i.e., ventral prefrontal and limbic regions; Phillips et al 2000; Rauch et al 1998); 2) provocation of checking-related anxiety would predominantly activate regions associated with attention but not emotion perception (i.e., dorsal prefrontal cortex, thalamus, and striatal regions, but not paralimbic and limbic regions; Phillips et al 2000; Rauch et al 1998); 3) although there are no previous studies on the neural correlates of hoarding symptoms, we hypothesized that hoarding-related anxiety would also activate areas involved in emotion and disgust perception; and 4) areas involved in visual processing would be activated in response to all types of symptom-related anxiety. Methods and Materials Subjects Ten right-handed healthy volunteers (five men, five women) were recruited among colleagues and ancillary staff at the Institute of Psychiatry, Kings College London. Mean age was 27.6 (SD 5.5; range 20 36). They reported no history of neurologic or psychiatric disorder by clinical screen (DM-C) and were on no medications at the time of the study. The Maudsley Hospital ethics committee approved the study protocol, and all subjects signed an informed consent form before their participation. Stimuli Fifty color pictures of scenes rated as aversive/disgusting by normal subjects (e.g., insects, mutilated bodies, decaying food)

3 484 BIOL PSYCHIATRY D. Mataix-Cols et al and 50 pictures of neutral scenes (e.g., furniture, nature scenes, household items) were selected from a standard set of stimuli (Lang et al 1997). These stimuli were carefully chosen to avoid resembling common triggers of OCD symptoms. In addition, pictures of washing-, checking-, and hoarding-related material (50 of each type) were obtained with a standard digital camera (Canon PhotoShot S20). For each symptom type, three clinicians with experience in OCD had previously listed the most common items that were provocative of anxiety and the urge to ritualize in OCD patients. Examples of washing-related pictures included a public telephone/toilet, money, a syringe, and an ashtray. Examples of checking-related pictures included electric appliances (computer, kettle, light switch), an open door, and a purse. Examples of hoarding-related scenes included old newspapers/ magazines, old clothes/toys, empty bottles/cans, and trash bins. Two hundred and fifty scenes were selected after an independent group of nine normal volunteers (unrelated to the study) had rated an originally larger pool of pictures according to their level of visual complexity, anxiety, and disgust on a 0 3 scale (0 nil;3 a lot). Pictures that were too simple or too complex were excluded, and an effort was made to avoid using washing-related pictures that could be perceived as very disgusting by normal individuals. The final 250 stimuli were well matched with regard to visual complexity, and, as intended, the normally aversive/ disgusting pictures induced more anxiety and disgust than the other three types of pictures (data not shown). One neutral picture of the World Trade Center in New York City was substituted with another neutral picture in the middle of the study following the terrorist attacks of September 11, Symptom Provocation Paradigm All subjects participated in four, 6-min experiments consisting of alternating blocks of emotional (normally aversive/disgusting, washing-, checking-, or hoarding-related pictures) and neutral pictures. The order in which the four experiments were conducted was fully counterbalanced, as was the order of the emotional and neutral conditions within each experiment. Before the presentation of each set of pictures, subjects were played a prerecorded voice file by means of high fidelity pneumatic headphones, instructing them to imagine being in a particular situation while looking at the scenes they were about to see (there were five slightly different recordings per type of stimuli in each experiment, to avoid monotony). Some examples of these instructions are the following: For normally aversive/disgusting pictures: Imagine that you must touch or stand by the following objects. For washing-related pictures: Imagine that you must come into contact with what s shown in the following pictures without washing yourself afterward. For checking-related pictures: Imagine that you are not sure whether you switched off or locked the following objects and it is impossible for you to go back and check. For hoarding-related pictures: Imagine that the following objects belong to you and that you must throw them away forever. For neutral scenes: Imagine that you are completely relaxed while looking at the following scenes. After each set of pictures, another prerecorded sound file of the question How anxious do you feel? was played to the subjects. Subjects had to rate their subjective anxiety by answering the question verbally with a number from 0 (no anxiety) to8 (extreme anxiety). Scanning was interrupted while both of the sound files mentioned earlier were played and while subjects gave their responses, so that scanning occurred only during picture presentation. The investigators heard these responses through the speaker system and noted them. Only one such scale was used because in previous studies, OCD and general anxiety analog scales were highly intercorrelated (Rauch et al 1994). These procedures were carefully explained and also provided in writing to all subjects before entering the scanner to make sure they fully understood the experimental procedure. Rating Scales Each participant s visual imagery ability was assessed with the Vividness of Visual Imagery Questionnaire (VIVQ; Marks 1989) before the scan. The VIVQ is a 16-item questionnaire requesting a response on a 1 5 scale. Scores range from 0 80; the lower the score, the better the ability to imagine visual scenes. In this sample, scores on the VVIQ suggested good visual imagery abilities (mean 36.3, SD 13.7, range 16 55). The Beck Depression Inventory (BDI; Beck et al 1961) and the state subscale of the State Trait Anxiety Inventory (STAI-S; Spielberger et al 1983) were also administered immediately before the scan to account for psychologic state variables. As expected, the BDI (mean 2.1, SD 2.5, range 0 7) and STAI-S (mean 32.4, SD 3.9, range 27 40) scores suggested minimal depression and moderate state anxiety levels. The presence and degree of obsessive compulsive symptoms in this sample was assessed using the Padua Inventory (PI; Sanavio 1988). The PI is a 60-item self-administered questionnaire requesting a response on a 0 4 scale regarding degree of disturbance. Scores range from Its British adaptation (Macdonald and de Silva 1999) has four subscales: impaired control over mental activities/doubting (28 items; score range: 0 112), contamination (10 items; score range: 0 40), checking (12 items; score range: 0 48), and worries about losing control over motor behavior (11 items; score range: 0 44). Scores on the PI suggested low levels of obsessive compulsive symptoms in this sample (total score: mean 14.4, SD 13.5, range 2 47; impaired mental control: mean 7.6, SD 7.4, range 1 23; contamination: mean 4.1, SD 3.0; range 1 10; Checking: mean 3.5, SD 6.8, range 0 22; worries about loosing control: mean.8, SD 1.2, range 0 3). Because the PI does not cover hoarding symptoms, the Saving Inventory Revised (SI-R; Frost et al, unpublished report) was also administered. The SI-R is a revised version of the wellvalidated Hoarding Scale (Frost and Gross 1993) and consists of 26 items, scored from 0 4, that assess various components of hoarding behavior (score range 0 104). Preliminary studies on the SI-R suggest that its psychometric properties are sound (Frost et al, unpublished report). Mean scores on the SI-R were low (mean 6.2, SD 3.8, range 0 11). Finally, sensitivity to disgust was assessed with the Disgust Scale (DS; Haidt et al 1994). It consists of 32 items, and its

4 Obsessive-Compulsive Symptom Dimensions BIOL PSYCHIATRY 485 scores range from Scores on the DS (mean 41, SD 10, range 30 58) were comparable to the published norms (Haidt et al 1994). Image Acquisition Gradient echo echoplanar (EPI) images were acquired on a GE Sigma 1.5T Neurovascular system (General Electric, Milwaukee, WI) at the Maudsley Hospital, London. One hundred T2*- weighted whole-brain volumes depicting blood oxygen level dependent (BOLD) contrast (Ogawa et al 1990) and consisting of 16 slices oriented according to the bicommissural plane (thickness 7 mm, 0.7 mm gap) were acquired over 6 min for each of the four experiments (TR 2.0 sec; TE 40 msec; flip angle 70; matrix). In each 20-sec stimulus presentation block, subjects viewed either 10 provocative or 10 neutral pictures. Each picture was presented for 1950 msec, with an interstimulus interval of 50 msec. Ten whole-brain volumes were acquired during each stimulus presentation block. Each stimulus block was followed by 1) an 8-sec period of complete silence during which subjects were asked to rate their level of anxiety; 2) a further 8-sec period during which the subjects listened to a sound file containing instructions pertinent to the next stimulus block. Four dummyvolumes were excited during this 8-sec period using exactly the same radio frequency (RF) pulses and gradient slice selection parameter, with the same repetition time of 2 sec to allow the magnetization to reach an equilibrium amplitude before the next period of data acquisition. The frequency-encoding gradient was turned off during this period to minimize acoustic noise and to ensure that the subjects heard the instructions clearly (Van De Moortele et al 1998). The four dummy volumes were later discarded from the time series. Individual brain activation maps were coregistered to a whole head gradient-recalled echo planar imaging scan of superior spatial resolution acquired on all subjects. This structural scan had the following acquisition parameters: TE 40 msec, TR 3000 msec, field of view 24 cm, image resolution , number of slices 43, slice thickness 3.0 mm, interslice gap.3 mm, number of signal averages 8. Figure 1. Differences in neural response to normally aversive, washing-, checking-, and hoarding-related stimuli. The left side of the brain is shown on the right side of the image and vice versa. OFC, orbitofrontal prefrontal cortex (BA11); MTG, middle temporal gyrus (BA37); IFG, inferior frontal gyrus (BA 44 and 45); A, amygdala; ACG, anterior cingulate gyrus (BA24/32); VLP, ventrolateral prefrontal cortex (BA47). Statistical Analyses The effects of symptom provocation on subjective ratings of anxiety were assessed using repeated-measures analyses of variance to compare the provoked and neutral conditions in all four experiments. Following motion correction (Bullmore et al 1999), periodic change in T2*-weighted signal intensity at the (fundamental) experimentally determined frequency of alternation between A and B conditions ( 1/60 Hz in all four experiments) was estimated by an iterated least squares fit of a sinusoidal regression model to the fmri time series observed at each voxel (Bullmore et al 1996). This model included sine and cosine waves at the fundamental AB frequency of the experimental input function, parameterized by coefficients {g, d}. The power of periodic response to the input function was estimated by (g2 d2); and this fundamental power divided by its SE yielded a

5 486 BIOL PSYCHIATRY D. Mataix-Cols et al Table 1. Demographic Characteristics and Mean Subjective Anxiety Ratings of 10 Healthy Volunteers Subject No. Sex Age Disgust Experiment a Washing Experiment b Checking Experiment c Hoarding Experiment d Disgust Neutral Difference Washing Neutral Difference Checking Neutral Difference Hoarding Neutral Difference 1 Male Female Female Female Male Male Male Male Female Female Mean (SD) (5.5) (1.2) (.9) (1.1) (1.5) (.6) (1.1) (1.5) (.5) (1.3) (.7) (.5) (.3) a paired t (9) 14.1, p.001 (2-tailed) b paired t (9) 5.8, p.001 (2-tailed) c paired t (9) 6.1, p.001 (2-tailed) d paired t (9) 5.6, p.001 (2-tailed) standardized test statistic, the fundamental power quotient (FPQ), at each voxel. Parametric maps representing FPQ observed at each intracerebral voxel were constructed. To sample the distribution of FPQ under the null hypothesis that observed values of FPQ were not determined by experimental design (with few assumptions), all images observed in each anatomic plane were randomly permuted, and FPQ was estimated exactly as described earlier in each permuted time series. This process was repeated 10 times, resulting in 10 permuted parametric maps of FPQ at each plane for each subject. Observed and randomized FPQ maps were transformed into the standard space of Talairach and Tournoux (1988) and smoothed by a two-dimensional Gaussian filter with full width half maximum 11 mm. This filter size was chosen to accommodate regional differences in brain anatomy between subjects (Clark et al 1996) and has been employed in previous studies examining neural responses to emotional stimuli (e.g., Phillips et al 1997, 1999). The median observed FPQ at each intracerebral voxel in standard space was tested against a critical value of the permutation distribution for median FPQ ascertained from the permuted FPQ maps (Brammer et al 1997). To estimate differences in mean power of functional activation between the four experiments, we conducted six pairwise repeated measures analysis of covariance (ANCOVA) at each intracerebral voxel of the standardized power maps after their coregistration in standard (Talairach) space. We used a nonparametric model of inference on spatially informed test statistics to identify clusters of activation within brain regions that showed a significant difference (p.01) in mean power of response between experiments; for full details of this method and its validation see Bullmore et al (1999). Results Subjective Ratings Analog scale ratings reflected increased anxiety during provoked versus neutral conditions in all four experiments (Table 1). These differences were large for the normally aversive experiment and smaller, but highly significant, for the washing, checking, and hoarding experiments. Generic Brain Activation Maps ACTIVATION ASSOCIATED WITH NORMALLY AVER- SIVE STIMULI. Compared with neutral pictures, normally aversive pictures activated predominantly bilateral ventral prefrontal cortical regions (ventral anterior cingulate gyrus, orbitofrontal and ventrolateral prefrontal cortices), limbic regions (hippocampus, insula, parahippocampal gyrus, and amygdala) and regions involved in visual processing. Additional regions included bilateral dorsal and dorsomedial frontal regions (pre- and postcentral gyri, dorsolateral prefrontal cortex, and dorsal anterior cingulate gyrus), cerebellum, thalamus, caudate nucleus, and putamen (see Table 2). ACTIVATION ASSOCIATED WITH WASHING-RE- LATED STIMULI. Compared with neutral pictures, washingrelated pictures activated predominantly bilateral visual regions, bilateral dorsal and dorsomedial prefrontal regions (medial and superior frontal gyri, dorsolateral prefrontal cortex, precentral gyrus, dorsal anterior cingulate gyrus), and bilateral ventral prefrontal and limbic regions (ventrolateral prefrontal cortex, orbitofrontal cortex, medial frontal gyrus (BA10), ventral anterior cingulate, insula, and parahippocampal gyrus). Additional regions included bilateral cerebellum and right putamen (Table 3). ACTIVATION ASSOCIATED WITH CHECKING-RE- LATED STIMULI. Compared with neutral pictures, checkingrelated pictures activated predominantly bilateral visual regions and dorsal prefrontal regions (medial frontal gyrus, preand postcentral gyri, dorsal anterior cingulate gyrus, dorsolateral prefrontal cortex). There was little activation in

6 Obsessive-Compulsive Symptom Dimensions BIOL PSYCHIATRY 487 Table 2. Generically Activated Brain Regions in the Normally Aversive Experiment Brain Region Brodmann s Area(s) Side x a y a z a No. of Voxels p Value Ventral Prefrontal and Limbic Ventral anterior cingulate/ 25/11 R orbitofrontal gyrus 25 L Ventrolateral prefrontal 47 L R Ventral anterior cingulate 25/32 R L Hippocampus L R Insula R L Parahippocampal gyrus 35 L R Amygdala 34 R Visual Processing Fusiform gyrus 19 L R Inferior parietal lobe 40 L R Inferior temporal gyrus 37 R L Middle occipital gyrus 19/39 R L Precuneus 7 L R Superior parietal lobe 7 R L Dorsal/Dorsomedial Frontal Precentral gyrus 4/6 R /6 L Inferior frontal gyrus 44 L Inferior frontal gyrus 45 L R Postcentral gyrus 1/2 L Medial frontal gyrus 9 R L Anterior cingulate gyrus 24 R L Other Cerebellum L R Thalamus R L Caudate nucleus L R Putamen L R a The cluster with the largest number of voxels within each region. Talairach coordinates refer to the voxel with the maximum fundamental power quotient (FPQ) in each cluster. paralimbic and limbic regions (ventrolateral prefrontal gyrus, orbitofrontal cortex, insula, amygdala). Additional activated areas included bilateral cerebellum (Table 4). ACTIVATION ASSOCIATED WITH HOARDING-RE- LATED STIMULI. Compared with neutral pictures, hoarding-related pictures activated predominantly ventral prefrontal and limbic regions (orbitofrontal cortex, ventral anterior cingulate cortex, medial/superior frontal gyrus, anterior insula, ventrolateral prefrontal gyrus, parahippocampal gyrus, and amygdala) and visual regions. There were few dorsal prefrontal activations (middle and superior frontal gyrus, dorsolateral prefrontal cortex, precentral gyrus). Additional areas included bilateral cerebellum (Table 5).

7 488 BIOL PSYCHIATRY D. Mataix-Cols et al Table 3. Generically Activated Brain Regions in the Washing Experiment Brain Region Brodmann s Area(s) Side x a y a z a No. of Voxels p Value Visual Processing Precuneus 7/31 R L Fusiform gyrus 37 R Cuneus 19 L R Occipital gyrus 19 R L Middle occipital gyrus 18/19 L R Inferior temporal gyrus 19 L R Dorsal/Dorsomedial Frontal Medial frontal gyrus 6 R Inferior frontal gyrus 44 L R Inferior frontal gyrus 45 R L Middle frontal gyrus 6 L R Precentral gyrus 6 L R Precentral gyrus 4 L R Middle frontal gyrus 9 R L Anterior cingulate gyrus 24/32 R Medial frontal gyrus 8 L R Ventral Prefrontal and Limbic Ventrolateral prefrontal 47 R L Orbitofrontal gyrus 11 R L Medial frontal gyrus 10 L R Ventral anterior cingulate 24/32 L R R Insula L Parahippocampal gyrus L Other Cerebellum L R Putamen R a The cluster with the largest number of voxels within each region. Talairach coordinates refer to the voxel with the maximum fundamental power quotient (FPQ) in each cluster. Differences in Neural Response to Normally Aversive, Washing-, Checking-, and Hoarding- Related Material Results of the repeated measures ANCOVAs comparing all possible combinations of two experiments are shown in Table 6 and Figure 1. Normally aversive pictures induced significantly more activation in right middle temporal gyrus and right orbitofrontal cortex than washing-related pictures and in those same areas plus right inferior frontal gyrus compared with checking-related pictures. There were no significant differences between normally aversive pictures and hoarding-related pictures. Hoarding-related pictures induced significantly greater activation in the left amygdala and right inferior frontal gyrus compared with checking-related pictures. Checking-related pictures induced significantly greater activation in the left dorsal anterior cingulate gyrus compared with hoarding-related pictures. Washing-related pictures induced significantly greater activation in bilateral

8 Obsessive-Compulsive Symptom Dimensions BIOL PSYCHIATRY 489 Table 4. Generically Activated Brain Regions in the Checking Experiment Brain Region Brodmann s Area(s) Side x a y a z a No. of Voxels p Value Visual Processing Fusiform gyrus 19 L R Precuneus 7 R L Cuneus 18/19 L Inferior temporal gyrus 19 L Middle occipital gyrus 37/19 L R Inferior occipital gyrus 18 R Middle temporal gyrus 21 L Occipital gyrus 19 L R Superior temporal gyrus 22 L Superior temporal gyrus 38 L Superior occipital gyrus 19 R Cuneus 31 R Dorsal/Dorsomedial Frontal Medial frontal gyrus 6 R Precentral gyrus 6/4 L /4 R Anterior cingulate gyrus 24 R L Inferior frontal gyrus 44 L R Middle frontal gyrus 46 R L Postcentral gyrus 40 L R Ventral Prefrontal and Limbic Ventrolateral prefrontal 47 R Insula L Orbitofrontal gyrus 11 R Amygdala R Ventrolateral prefrontal 47 R L Other Cerebellum R L a The cluster with the largest number of voxels within each region. Talairach coordinates refer to the voxel with the maximum fundamental power quotient (FPQ) in each cluster. inferior frontal gyri compared with checking-related pictures. On the right side, this activation extended to the ventrolateral prefrontal cortex. Finally, washing-related pictures induced significantly greater activation in the left inferior frontal gyrus compared with hoarding-related pictures. In these analyses, the expected number of false positive activated clusters was 2.91 and the observed number of activated clusters, 12. a z score but is used in this context because in nonparametric tests, none of the data distributional assumptions are made that underlie the use of a z score. There were no significant correlations between fmri signal intensity within the clusters of interest and subjective anxiety ratings (data not shown). Likewise, there were no significant correlations with scores on any of the questionnaire measures (VIVQ, BDI, STAI-S, PI, SI-R, DS). Correlations between Clinical Scales and Patterns of Neural Response Post hoc analyses were conducted correlating the intensity of activation within the two largest clusters of activation in each of the four experiments. In these analyses, the FPQ was averaged over each cluster. Note that the FPQ is analogous to Discussion Our findings demonstrate that OCD symptomlike anxiety can be reliably induced by appropriate, provocative stimuli in normal volunteers. As expected, presentation of normally aversive stimuli was associated with significant

9 490 BIOL PSYCHIATRY D. Mataix-Cols et al Table 5. Generically Activated Brain Regions in the Hoarding Experiment Brain Regions Brodmann s Area(s) Side x a y a z a No. of Voxels p Value Ventral Prefrontal and Limbic Orbitofrontal gyrus 11 R L Ventral anterior cingulate 24/32 R L Medial/superior frontal gyrus 10 L Insula R Parahippocampal gyrus 28 L Ventrolateral prefrontal 47 R L Amygdala L Visual Processing Precuneus 7/18 L R Cuneus 19 L R Fusiform gyrus 37/19 R /19 L Middle occipital gyrus 18/19 L R Lingual gyrus 18 L Superior temporal gyrus 38 R L Dorsal/Dorsomedial Frontal Middle frontal gyrus 9 L Inferior frontal gyrus 44 L R Inferior frontal gyrus 45 R L Precentral gyrus 4 L Other Cerebellum R L a The cluster with the largest number of voxels within each region. Talairach coordinates refer to the voxel with the maximum fundamental power quotient (FPQ) in each cluster. increases in subjective anxiety. In addition, the presentation of OCD symptomlike material (washing, checking, and hoarding experiments) was also associated with significant increases in anxiety. Previous OCD studies that included normal control groups have reported similar findings (Breiter et al 1996; Cottraux et al 1996). Overall, anxiety in response to all types of provocative stimuli was associated with activation in three main neural systems: 1) bilateral ventral prefrontal (orbitofrontal and ventrolateral prefrontal cortex, ventral anterior cingulate gyrus) and limbic regions (anterior insula, amygdala, parahippocampal gyri), 2) dorsal prefrontal regions (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, pre- and postcentral gyri), and 3) regions involved in visual processing (fusiform gyrus, cuneus, precuneus, middle occipital gyrus, middle and superior temporal regions). Additional areas included cerebellum, thalamus, putamen, and caudate nucleus. These activations were most significant in response to normally aversive pictures but were also present in response to the washing-, checking-, and hoarding-related pictures. These areas have also been consistently activated in previous neuroimaging studies of patients with OCD (for a review, see Saxena and Rauch 2000). Few previous studies have examined the neural correlates of anxiety associated with OCD symptomlike provocation in normal individuals. Breiter et al (1996) failed to report activations in any brain regions in five healthy volunteers, but their study may have been insufficiently powered. In support of findings from other studies (Cottraux et al 1996; Phillips et al 2000), areas previously identified as dysfunctional in OCD (including the orbitofrontal cortex, lateral prefrontal cortex, anterior cingulate gyrus, and limbic regions) were activated during OCD symptomlike anxiety in our normal subjects. Many of these areas have also been associated with the induction of emotional states in normal subjects (e.g., George et al 1995; Mayberg et al 1999; Pardo et al 1993; Reiman et al

10 Obsessive-Compulsive Symptom Dimensions BIOL PSYCHIATRY 491 Table 6. Repeated Measures Analyses of Covariance Comparing Generic Brain Activation Maps among the Normally Aversive, Washing, Checking, and Hoarding Experiments in 10 Normal Volunteers Comparison Region (Brodmann s Area) Side x y z No. of Voxels p Normally Aversive Washing-related Middle temporal gyrus (37) R Orbitofrontal gyrus (11) R Normally Aversive Checking-related Middle temporal gyrus (37) R Orbitofrontal gyrus (11) R Inferior frontal gyrus (45) R Normally Aversive Hoarding-related No significant differences Hoarding- Checking-related Amygdala L Inferior frontal gyrus (45) R Checking- Hoarding-related Anterior cingulate gyrus (24/32) L Washing- Checking-related Inferior frontal gyrus/ventrolateral R prefrontal (45/47) Inferior frontal gyrus (44) L Washing- Hoarding-related Inferior frontal gyrus (44) L ; Teasdale et al 1999). Our findings suggest that the anxiety associated with both pathologic and normal obsessional states involves a pattern of neural response previously shown to be important for the perception and generation of emotional states. Therefore, our findings indicate the presence of a dysfunctional emotional regulatory system in OCD whereby exaggerated emotional responses occur in inappropriate contexts. The second important finding of this study is that different OCD symptom dimensions are associated with differential patterns of activation in these neural systems. Provocation of washing-related anxiety was predominantly associated with a pattern of activation within bilateral dorsomedial prefrontal cortices, ventral prefrontal cortex/limbic regions, and visual regions. Checking-related pictures induced activations mainly in dorsal prefrontal and visual regions, with less activation in ventral prefrontal or limbic regions. These findings are consistent with those of Phillips et al (2000), who found a differential response to washing-related pictures between OCD washers and checkers; only the former perceived these pictures as disgusting and activated areas normally involved in disgust perception (i.e., insula and visual regions; Phillips et al 1997, 1998; Sprengelmeyer et al 1998). Our findings of predominant activation within dorsal prefrontal cortical regions, regions that previously have been associated with performance of attentional, nonemotional tasks (for a review, see Drevets and Raichle 1998), during checkingrelated anxiety suggests that this type of anxiety and checking symptoms of OCD may be associated with increased attention to detail rather than an exaggerated perception of emotion. The provocation of hoarding-related anxiety was associated with activation predominantly in ventral prefrontal, limbic, and visual structures, with less activation in dorsal prefrontal areas. In fact, there were no significant differences in activation within any regions in response to normally aversive and hoarding-related pictures. Interestingly, hoarding-related pictures were associated with significantly greater activation in the left amygdala compared with checking-related pictures. Our findings suggest that hoarding symptoms are associated with strong emotional reactions. Studies with both nonclinical and clinical populations have suggested that hoarding is associated with a fear of loosing important things that may be needed later and overemotional attachment to possessions (Frost and Steketee 1998). In addition, recent studies have suggested that patients with hoarding symptoms present a higher prevalence of personality disorders, especially from the anxious-fearful cluster, compared with patients with other OCD symptoms (Frost et al 2000; Mataix-Cols et al 2000) and also have poorer treatment outcomes with serotonergic agents and behavior therapy (Black et al 1998; Mataix- Cols et al 1999a, 2002b; Saxena et al 2002; Winsberg et al 1999). If our demonstration of increased involvement of the amygdala during hoarding-related anxiety is replicated in OCD patients with predominantly hoarding symptoms, this may provide a neurobiological basis for these previous findings. We speculate that hoarding and checking symptoms represent two extremes of a continuum of activation in two neural systems: a ventral prefrontal/limbic system and a dorsal frontal system. We predict that hoarding symptoms would be associated with most significant activation within ventral prefrontal cortex and limbic regions but not within dorsal prefrontal cortical regions, whereas checking symptoms would be associated with most significant activation within the dorsal prefrontal cortex, rather than

11 492 BIOL PSYCHIATRY D. Mataix-Cols et al ventral prefrontal cortex and limbic regions. We predict that washing symptoms would be associated both with significant ventral prefrontal cortical/limbic activation but also with activation within dorsal prefrontal cortical regions, the latter possibly associated with attention to symptom-provoking material or attempts to suppress the anxiety. Limitations of our study include the lack of a structured screening instrument and the relatively small sample size. We found no correlations between fmri magnitudes and anxiety scores or scores on any of the questionnaires. It is possible that these negative results are due to small score ranges and standard deviations in these measures among our healthy volunteers. In OCD patients, it will be interesting to correlate scores on each of the quantitative symptom dimensions derived from the Yale Brown Obsessive Compulsive Scale (Mataix-Cols et al 1999a) and patterns of brain activity. Another limitation is that only anxiety ratings were obtained after each block of pictures. Other forms of discomfort (e.g., disgust) may have been induced by the images; however, our design did not permit longer silence periods between blocks of stimuli. This study has important methodologic differences compared with previous symptom provocation studies in OCD. First, it combined two modalities of stimulus presentation, verbal instructions and symptom-related stimuli. Second, it used a priori selected provocative stimulus material instead of stimuli individually tailored to each subject s symptoms. Although OCD is heterogeneous, there are only a limited number of themes that normally trigger symptoms in these patients, and these symptoms tend to cluster in a consistent manner, as factor-analytical studies have shown (Baer 1994; Leckman et al 1997; Mataix-Cols et al 1999a; Summerfeldt et al 1999). The employment of a large number of pictures representative of each symptom dimension therefore allowed the inclusion of the triggers relevant to most patients (and also normal control subjects). One obvious advantage of this paradigm is that identical experimental stimuli are presented to all subjects, so that interindividual differences in patterns of activation are unable to be related to the experience of different stimuli. The results of our study provide support for a dimensional model of OCD whereby 1) the brain systems implicated in the mediation of anxiety in response to symptom material in normal subjects are similar to those previously identified during symptom provocation in OCD and 2) anxiety associated with different symptom dimensions is associated with differential patterns of activation of these neural systems. 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