Orbitofrontal cortex dysfunction in obsessive-compulsive disorder?

European Neuropsychopharmacology 9 (1999) 415–420 www.elsevier.com / locate / euroneuro

Orbitofrontal cortex dysfunction in obsessive-compulsive disorder? II. Olfactory quality discrimination in obsessive-compulsive disorder a b c d e, Haggai Hermesh , Joseph Zohar , Abraham Weizman , Hillary Voet , Ruth Gross-Isseroff * a

Anxiety Disorders and Behavior Therapy Unit, Geha Psychiatric Hospital, Petach Tikva and Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel b Division of Psychiatry, The Chaim Sheba Medical Center, Tel-Hashomer and Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel c The Geha Psychiatric Hospital, Felsenstein Medical Research Center, Beilinson Medical Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel d Department of Agricultural Economics and Management, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot, Israel e Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel Received 25 January 1999; received in revised form 16 April 1999; accepted 16 April 1999

Abstract Background: Olfactory quality discrimination is a putative marker of orbitofrontal cortex function in mammals. As this portion of the cerebral cortex was repeatedly implicated in the pathophysiology of obsessive-compulsive disorder (OCD) this study was designed in an attempt to quantify this behavioural function in OCD patients. Methods and Results: Olfactory quality discrimination was compared in OCD patients and healthy controls. Thirty two subjects participated in the study: 16 (13 women and 3 men) medication free OCD outpatients and 16 sex and age matched healthy controls. Olfactory tests consisted of determination of detection thresholds to isoamyl acetate, and a three way forced choice quality discrimination task, using isoamyl acetate, citral and eugenol as stimuli. No significant differences in sensitivity and performance of the quality discrimination task between the two groups were found. Within the OCD group the more severely affected patients (Y-BOCS.29) performed significantly better than the less severely affected (Y-BOCS,30) patients on the more difficult part of the quality discrimination task. Within this subgroup of patients the correlation between performance on the olfactory task and a previously reported alternation task tended to be negative as compared to a significantly positive correlation in the control group. Conclusions: It seems that olfactory quality discrimination may prove to be a useful noninvasive marker of prefrontal cortex function in OCD. Furthermore, the organization of functional modules within the orbitofrontal cortex, rather than a simple dysfunction, may prove to characterize OCD.  1999 Elsevier Science B.V. All rights reserved. Keywords: Olfaction; Obsessive-compulsive disorder; Orbitofrontal cortex

1. Introduction Several lines of converging evidence have implicated the orbitofrontal cortex in the pathophysiology of obsessive compulsive disorder (OCD). Thus studies using novel brain imaging techniques, have outlined a putative ‘OCD neural network’ in which the orbitofrontal cortex is implicated (Benkelfat et al., 1990; Goodman et al., 1990, *Corresponding author. Tel.: 1972-8-934-3741; fax: 1972-8-9344112. E-mail address: [email protected] (R. Gross-Isseroff)

Swedo et al., 1989; Nordahl et al., 1989). Partial surgical disconnection of prefrontal cortical areas, including the orbitofrontal cortex, from the rest of the forebrain, through anterior internal capsulotomies has been found to be beneficial in the treatment of highly resistant OCD cases (Mindus et al., 1994). A third line of evidence is based on the observation that mechanical damage to orbitofrontal structures results in OCD-like behaviour patterns (McKeon et al., 1984). And finally, OCD patients were found to be impaired in an alternation learning task (Abbruzzese et al., 1995; Gross-Isseroff et al., 1996; Zohar et al., 1999) which taps orbitofrontal cortex function in non-human primates

0924-977X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 99 )00018-8

H. Hermesh et al. / European Neuropsychopharmacology 9 (1999) 415 – 420

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(e.g. Mishkin et al., 1969). Apparently the magnitude of orbitofrontal cortex-related dysfunction on this task seems to be related to severity of OC symptoms (Gross-Isseroff et al., 1996; Zohar et al., 1996). A variety of physiological studies in non-human primates (Tanabe et al., 1975a; Tanabe et al., 1975b; Potter and Nauta, 1979; Thorpe et al., 1983; Yarita et al., 1980) as well as some behavioural studies in human subjects (Potter and Butters, 1980; Jones-Gotman and Zatorre, 1988; Zatorre et al., 1992) have lead to the hypothesis that part of the orbitofrontal cortex is involved in odour quality discrimination. In an attempt to further characterize orbitofrontal function in OCD patients we have asked whether they would be impaired in the performance of a simple odour quality discrimination task. A previous study has shown that OCD patients were impaired in the performance of an odour identification task (Goldberg et al., 1991), which finding has lead to the speculation that olfactory sensitivity was impaired in these patients. On the other hand we have failed to find impaired olfactory sensitivity in these patients when using a direct olfactory threshold assay (Gross-Isseroff et al., 1994a). It could be that the odour identification impairment was due to a higher order processing of olfactory information, independent of sensitivity. The present experiment was designed in an attempt to test this hypothesis.

tion free for at least 2 weeks. Some were cigarette smokers, and the amount of smoking was recorded for each. All patients were diagnosed as suffering from OCD according to DSM-III-R (APA, 1987) criteria, by two independent psychiatrists, using an unstructured interview. Patients with other comorbid psychiatric disorders were not included in the study. Full concordance on diagnoses was required. Severity of OC symptoms was assessed using the ten item modified Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Goodman et al., 1991). Severity of depression was assessed using the 17 item Hamilton Psychiatric Rating Scale for Depression (Hamilton, 1967). Only patients with a Y-BOCS score of 16 and higher and a depression score of 16 and below were included in the study. All patients had normal cellular blood count (CBC), urea, electrolytes, liver function, prolactin, ECG and none were pregnant or using oral contraceptives.

2.2. Procedure All subjects were tested once during a single session lasting 40–60 min. Each subject’s threshold for isoamyl acetate was assessed first, and then he performed the odour discrimination task. Subjects were not given feedback on their performance; intertrial intervals were 1 min. No smoking and no intake of food or flavoured beverages were allowed for 1 h prior to testing. All tests were conducted in a well-ventilated temperature controlled, odourless room.

2. Methods

2.3. Odourants 2.1. Subjects Thirty two subjects participated in the study. Sixteen (13 women and 3 men) were diagnosed as OCD, and 16 (13 women and 3 men) healthy controls. Patients were recruited from a series of consecutive admissions to the OCD outpatient clinic of the Division of Psychiatry, at the Chaim Sheba Medical Center, Tel Hashomer, Israel, and the healthy controls were recruited among staff personnel, after screening for neuropsychiatric and respiratory disorders. Table 1 presents demographic and epidemiological data on all subjects. All subjects were unpaid volunteers, and they all signed an informed consent form. At the time of testing all subjects were completely drug and medicaTable 1 Demographic variables a Variable

Control

OCD

Sex (F / M) Age (years) Y-BOCS HAM-D

13 / 3 33.462.3 (18–52) – –

13 / 3 33.462.5 (22–60) 26.761.3 (19–34) 6.461.4 (0–14)

a

Table presents mean6SEM (range) of demographic variables in the two groups of subjects. Y-BOCS, Yale-Brown Obsessive Compulsive Scale; HAM-D, Hamilton Depression Scale.

For the threshold determination isoamyl acetate (Aldrich, Milwaukee, Wisconsin) was diluted in heavy mineral oil (Sigma, St Louis, MA). Five-millilitre solutions were prepared in 20 ml dark glass bottles capped with odourless plastic screw caps. For threshold determination, serial dilutions of half decimal log steps were prepared, with the highest concentration being 1:2 (v / v) of the pure odourant. The highest concentration in the series was designated no. 1 and the lowest no. 10. For the quality discrimination task isoamyl acetate (Aldrich, Milwaukee, Wisconsin), citral (Aldrich, Milwaukee, Wisconsin) and eugenol (Aldrich, Milwaukee, Wisconsin) were similarly diluted in heavy mineral oil (Sigma, St Louis, MA) at a concentration of 1:2 (v / v) of the pure odourant.

2.4. Threshold measurements Thresholds were measured by a three-way forced choice technique previously described (Gross-Isseroff et al., 1994b). Briefly, subjects were presented with three bottles, one of which contained the odourant and the other two an identical volume of solvent. They were asked to identify the bottle containing the odourant by indicating which one

H. Hermesh et al. / European Neuropsychopharmacology 9 (1999) 415 – 420

smelled different. An ascending series of concentrations was presented, and threshold was defined as the lower of two consecutive concentrations for which four consecutive correct detections were obtained. The higher the number designating a given subject’s threshold, the higher his or her sensitivity to isoamyl acetate.

2.5. Quality discrimination We devised a three way forced choice task, in which the subject was presented with one bottle containing a given odourant and two containing a second odourant. The subject was asked to identify the one smelling different. Eighteen trials were given to each subject. Six trials for each of the three possible combinations of the three odourants used. Of the six trials three were of the type ABB and three of the type BAA. Order of bottles and of trials was randomised within and between subjects so as to avoid order effects. Scoring of performance on this task was as following: the twelve trials of discrimination between citral and eugenol and isoamyl acetate and eugenol were designated ‘easy’, and the six trials of discrimination between citral and isoamyl acetate were designated ‘difficult’. For each subject we computed four scores: percent correct responses on the easy task (‘easy’), percent correct responses on the difficult task (‘difficult’), percent correct responses on all 18 trials (‘total’) and the difference between performance on the easy task and the difficult task.

2.6. Statistical analyses Statistical analyses were performed using SAS version 6.06 routines. a was preset at 0.05. We used t-tests for independent samples, Pearson coefficients of correlation and x 2 and Fisher exact probability tests.

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3. Results In order to test for sensitivity differences between the two groups we performed a two tailed t test for independent samples on the threshold values to isoamyl acetate. There was no significant difference (t,1.0). Using the same test we failed to find differences between the groups on the odour quality discrimination task (t,1.0 for all four scores). Results are summarised in Table 2A. As sex differences in olfactory function have been documented (Doty et al., 1981; Lehrner, 1993) with women performing better, we examined the data obtained by the female subjects separately. Results are summarized in Table 2B. None of the differences between the groups are significant, but there is a slight tendency for the difference between performance of the difficult task and performance on the easy task to be bigger in the control group than in the OCD group. There was no correlation between age and smoking habits and scores on either olfactory test in any of the groups. Correlating the scores of the olfactory tests with YBOCS scores revealed a significant negative correlation, between the difference in performance on the easy and difficult parts of olfactory quality discrimination and severity of symptoms (Table 3A). The same correlation in the subgroup of women in the OCD group revealed an even higher coefficient of correlation (Table 3B). Since these correlations may be explained by a high proportion of perfect performance on the difficult olfactory discrimination task among the most severely affected patients we have subdivided the OCD group into two groups, Y-BOCS.29 and Y-BOCS,30 (i.e. cutoff point of 29.5). As shown in Table 4 the two resulting groups are well matched for age and sex, are significantly different in the proportion of subjects performing perfectly on the difficult task, have a borderline difference in mean score on the difficult task and are significantly different on the

Table 2 Results of olfactory tests in the two groups a Variable A. Whole sample (N516 in each group) Threshold Quality Discrimination Easy Difficult Total Difference

Control

OCD

9.860.6(9–11)

110.360.2(7–14)

85.465.5 (50–100); 14 79.166.0 (33–100); 13 82.963.8 (33–100); 14 7.365.3 (242–42)

88.064.0 (25–100); 14 78.165.4 (33–100); 11 85.065.1 (25–100); 13 8.965.4 (225–50)

9.660.5 (9–11) 88.465.9 (50–100); 11 76.866.5 (33–100); 10 83.265.2 (33–100); 12 9.766.7 (242–42)

110.260.2 (7–14) 86.564.8 (25–100); 12 80.766.1 (33–100); 10 85.864.3 (25–100); 11 7.766.4 (225–50)

B. Females only (N513 in each group)

a

Table presents mean6SEM, the range of scores in parentheses and frequency of subjects with performance .66.67%.

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Table 3 Correlations between olfactory measures and measures of symptom severity in the OCD group a Obsessions

Compulsions

Total Y-BOCS

(N514) 20.11 0.08 0.48 0.23 20.45

(N514) 0.18 20.33 20.06 20.26 20.28

(N516) 20.05 0.00 0.48 0.19 20.53*

(N511) 0.18 20.25 0.32 20.06 0.17

(N511) 0.24 20.47 20.12 20.40 20.31

(N51 3) 0.22 20.30 0.36 20.08 20.62**

A. Whole sample Threshold Easy Difficult Total Difference B. Females only

a

Table presents Pearson coefficients of correlation. *, P,0.05. **, P,.0.01.

mean difference between performance of the easy and the difficult tasks.

4. Discussion We have shown that OCD patients apparently do not differ from healthy controls on two independent measures of olfactory function. The present quality discrimination task failed to reveal differences between OCD patients and healthy controls, due to large variances. The results of the threshold measurements replicate our previous results (Gross-Isseroff et al., 1994a) but seem to be in apparent contradiction to a previous report which has

demonstrated that OCD patients perform significantly worse on the University of Pennsylvania Smell Identification Test (UPSIT) (Goldberg et al., 1991). This apparent discrepancy could be reconciled by the assumption that the UPSIT taps higher order olfactory processing than the present threshold measurement. Memory and verbal aptitudes are probably involved in performance on this test, as well as olfactory sensitivity. On the other hand, within the OCD patient group, the more difficult odour discrimination task could differentiate between moderately and severely affected patients, as measured by the Y-BOCS. This preliminary finding warrants replication as the present sample of patients was small, a trend towards older patients was observed in the high severity group, and the relevant quality discrimination task too easy. It is nevertheless tempting to speculate that olfactory quality discrimination could, in the future, be used as an independent marker in OCD much in the way that olfactory sensitivity is used as an independent marker in Alzheimer disease (Peabody and Tinklenberg, 1985; Serby et al., 1985; Doty et al., 1985). In spite of the small size of the sample perfect performance of the more difficult discrimination task seems to have reliably subdivided it into severely affected (YBOCS.29) and moderately affected (Y-BOCS,30) patients. Thus of the seven perfect performers five belonged to the severely affected group and two to the moderately affected group (P,0.03, Fisher exact probability test). Numerous attempts have been made to subtype OCD. Among the more prominent sub classifications proposed until now are pure compulsives vs pure obsessives, age of onset (e.g. Swedo et al., 1989), comorbidity with Tourette or other tic disorders (e.g. Pauls et al., 1986), severity (e.g. Black et al., 1992) and resistance to common pharmaco-

Table 4 Comparison between severely affected and less severely affected OCD patients a

SEX (M / F) AGE TOTAL Y-BOCS Obsessions Compulsions OLFACTION Thresholds Quality Discrimination Easy Difficult Easy-Difficult Perfect performance b a

Y-BOCS,30 (N510)

Y-BOCS.29 (N56)

Statistics

2/8 30.562.3 23.561.1 9.461.2 14.160.3

1/5 38.264.4 32.060.5 16.260.5 15.460.2

t51.72, P50.11 t57.3, P50.0001 t55.1, P50.0004 t53.2, P50.007

9.860.3

9.860.2

t,1.0, ns

88.365.6 70.067.4 18.465.8 2/8

80.6611.9 91.768.3 211.265.1 5/1

t,1.0, ns t51.9, P50.08 t53.5, P50.004 x 2 56.1, P50.01

Table presents means6sem. Proportion between number of subjects performing 100% on the difficult olfactory discrimination task and number of subjects scoring less than 100% on the same task. b

H. Hermesh et al. / European Neuropsychopharmacology 9 (1999) 415 – 420

logical treatment (e.g. Princhep et al., 1993). Some of these subclassifications have been at least partially corroborated by behavioural genetic analyses (Pauls et al., 1995) and electrophysiological methods (Princhep et al., 1993) while others still await convergent validation by either genetic, neurochemical, neurophysiological or independent behavioural methods. The most convincing neurochemical subtyping so far has been the response to mCPP challenge (Gross-Isseroff et al., 1994b), which has hitherto been corroborated by regional cerebral blood flow studies (Hollander et al., 1995) and response to serotonin reuptake inhibitors (Zohar et al., 1995). The present olfactory results could, if replicated, constitute an additional way of validating OCD subtyping according to severity, substantiating thereby involvement of orbitofrontal cortex and possibly anterior temporal cortex in the pathophysiology of this disorder. As some of the subjects participating in the present experiment have also participated in the experiment described in the companion article (Zohar et al., 1999), we have looked at the relationship between the two different orbitofrontal tasks: alternation learning and olfactory quality discrimination. These are summarized in Table 5. As obvious from this table there is a difference between the control group and the highly severe patients in the relation between the performance on these tasks. While in healthy subjects this correlation is negative, it is positive in the severely affected patients. However, it should be noted that our results are limited due to the small number of OCD patients included in the study. The implications of our results need to be further elucidated. We speculate, though, that they may reflect expression of different components of the orbitofrontal cortex functioning in relation to each other. If corroborated, this speculation would imply differential neural modulation (e.g. serotonergic) of different brain structures in OCD. This assumption merits further investigation.

Table 5 Interrelationships between orbitofrontal tasks and severity of OC symptoms in female subjects a Correlation

Control (N57)

Y-BOCS,30 (N58)

Y-BOCS.29 (N55)

Easy-Alt Difficult-Alt Total-Alt Easy-Y-BOCS Difficult-Y-BOCS Total-Y-BOCS Alt-Y-BOCS

20.56 (0.19) 20.91 (0.004) 20.73 (0.06)

20.44 (0.38) 0.20 (0.69) 20.07 (0.89) 0.54 (16) 0.20(0.63) 0.37 (0.37) 20.97 (0.001)

0.57 0.38 0.52 0.09 0.09 0.09 0.74

(0.32)b (0.53) (0.37) (0.88) (0.89) (0.88) (0.15)c

a Table presents Pearson coefficients of correlation (p) between easy, difficult and total olfactory quality discrimination scores, alternation (alt) learning scores and Y-BOCS scores. b Z51.21, P50.11 for for high and low Y-BOCS comparison; Z51.44, P50.07 for high Y-BOCS and control comparison. c Z53.33, P50.0004 for high and low Y-BOCS comparison.

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