Much converging evidence suggests that a specific role is played by the dorsolateral prefrontal cortex (DLPC) in schizophrenic disorders and by the orbitofrontal cortex (OFC) in obsessive-compulsive disorder (OCD). In this study, 25 schizophrenic and 25 OCD patients were evaluated with the Wisconsin Card Sorting Test and the Object Alternation Test, tests that are sensitive to DLPC and OFC damage, respectively. The patients were also given the Weigl Sorting Test and Word Fluency Test to assess global frontal functioning. The results point to a DLPC deficit in schizophrenia and an OFC lability in OCD and confirm that functional disorders of the central nervous system can be investigated using neuropsychological methods.
1.1 Converging evidence indicates that abnormalities in the frontal regions of the brain are involved in schizophrenia and obsessive- compulsive disorder (OCD). This link between frontal lobe pathology and schizophrenia and OCD has been proposed on the basis of several structural and metabolic studies.
1.2 Structural abnormalities in schizophrenia associated with frontal lobe areas have been reported from CT scan (Williamson et al., 1989) and NMR (Andreasen et al., 1990) studies. Decreased metabolic activity in the frontal cortex has been reported in schizophrenic patients using PET (Buchsbaum et al., 1984; Wolkin et al., 1988); PET studies have also reported increased metabolic activity in the basal ganglia in schizophrenia (Gur et al., 1987; Berman and Weinberger, 1990).
1.3 Structural and metabolic abnormalities of subcortical frontal regions in OCD patients have also been reported. Insofar as structural abnormalities are concerned, CT scan and NMR have revealed reduced (Luxemberg et al., 1988) or increased (Scarone et al., 1992) caudate nuclear size in OCD patients. Metabolic data (Baxter et al., 1987; Garber et al., 1989) have indicated higher levels of glucose metabolism in the head of the caudate nucleus.
1.4 From a neuropsychological standpoint, cognitive dysfunctions related to the frontal lobes have been noted in schizophrenia (Goldberg et al., 1987; Butler et al., 1989; Levin et al., 1989; Seidman, 1990; Bellini et al., 1991) and to a somewhat lesser extent in OCD (Malloy, 1987; Cattaneo et al., 1988). In schizophrenia, neuropsychological abnormalities seem to be the expression of a malfunction in dorsolateral prefrontal cortex (DLPC)-basal ganglia circuits (Weinberger et al., 1986; Berman et al., 1988; Goldberg and Weinberger, 1988).
1.5 A recent psychophysiological model of OCD (Alexander 1986; 1990; Wise and Rapoport, 1989), supported by metabolic (Baxter et al., 1987) and neuropsychological data (Malloy, 1987), suggests that a complex dysfunction in the circuits which connect the basal ganglia with orbitofrontal cortex (OFC) is at the basis of the thinking and motor abnormalities of OCD patients. Unfortunately, as far as we know, no supporting neuropsychological data are available.
1.6 In a series of recent neuropsychological experiments, Freedman (1990) was able to demonstrate that the Object Alternation Test, previously proposed as a neurofunctional probe both in primates and in humans (Mishkin, 1964; Mishkin et al., 1969), is specifically sensitive to orbitofrontal cortical malfunctioning,
1.7 This target article evaluates the neuropsychological characteristics of frontal regions in a sample of OCD patients compared with a sample of schizophrenics and a control group matched for age, sex, educational level, and handedness. Our first objective was to test further the hypothesis of global frontal lobe impairment, both in schizophrenia and OCD; for this purpose, performance on the Weigl Sorting Test (WST) and Word Fluency Test (WFT) was evaluated. Both these neuropsychological tools have been described in the literature as good indices of frontal functioning. Our second objective was to confirm the involvement of DLPC in schizophrenia and of OFC in OCD using the Wisconsin Card Sorting Test for DLPC and the Object Alternation Test for OFC dysfunction.
2.1 Seventy-five subjects (25 OCD patients, 25 schizophrenic patients and 25 controls matched for age, sex, educational level and handedness) made up the three groups investigated. Table 1 shows the clinical and demographic characteristics of the sample.
2.2 The 25 OCD patients were all recruited from the Anxiety In-patients Unit and the 25 schizophrenics from the S. Raffaele Hospital Rehabilitation In-Patients Service of the Psychiatric Branch in Milan, Italy. All the schizophrenics were chronic and classified as paranoid according to DSM III-R criteria. The diagnoses of OCD and schizophrenia were made using the computerized version of DIS-R (Robins et al., 1989) according to DSM III-R criteria (A.P.A. 1987) by two psychiatrists. In addition, OCD symptomatology was assessed by means of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (Goodman et al., 1989a, 1989b).
2.3 The 25 controls were recruited from among hospital employees and the nursing staff; the inclusion criterion for recruitment was the absence of a personal history of neurological, psychiatric illnesses or alcohol abuse. Before being given the tests, all subjects were submitted to a complete physical and neurological examination to exclude any somatic illness. Furthermore, no subject had any history of documented head injuries, loss of consciousness, neurosurgical treatment or perinatal trauma.
2.4 At the time of their neuropsychological evaluation all the OCD patients had been under treatment with Fluvoxamine Maleate at a mean dosage of 234 + 35 mg/day for at least two months; the schizophrenic patients were receiving neuroleptics at a mean chloropromazine dose equivalent to 225 + 65 mg/day for at least six months. No patients had taken benzodiazepines in the two weeks preceding the tests. All subjects were right handed; handedness was evaluated using a standardized questionnaire (Raczkowskj et al., 1974). Informed consent concerning the purposes of the study was obtained from each subject before starting the test.
3.1 The tests were administered by a trained neuropsychologist in a quiet laboratory and in a single standard sequence: Weigl Sorting Test (WST), Word Fluency Test (WFT), Wisconsin Card Sorting Test (WCST), Object Alternation (OAT) Test. The complete task never took longer than 60 minutes. The examiner was not blind to the diagnosis. All the subjects completed the neuropsychological battery with no problem of fatigue or uncooperativeness.
3.2 WEIGL's SORTING TEST (WST) (Weigl, 1941; De Renzi et al., 1966). This tool assesses the subject's ability to shift from one strategy to another (patients with frontal lobe damage show impairment in sorting or shifting: Kramer and Jarvik, 1979). The subject is presented 20 wood blocks varying in shape (triangle, circle, square), colour, thickness, symbol printed on the surface, and size. The subject is requested to arrange them in homogeneous groups according to a common feature within three minutes. The possible scores, based on the number of categories the subject recognizes, range from 0 to 5.
3.3 WORD FLUENCY TEST (WFT). Many studies have confirmed that verbal fluency is strongly connected with frontal lobe damage, particularly the left frontal lobe anterior to Broca's area (Ramier and Hecaen, 1970). The controlled oral WFT (Benton and Hamsher, 1976) is a neuropsychological task in which the subject is asked to say words beginning with a particular letter of the alphabet. For each letter there is one minute in which to produce as many words as possible. The test consists of three word-naming trials; the letters F, A, and S are usually used. The score consists of the total number of words recalled, adjusted for age, sex and education, according to Benton's procedures.
3.4 The WISCONSIN CARD SORTING TEST (WCST) is a widely used tool which accurately recognizes frontal cortical dysfunction (Milner, 1963; Robinson et al., 1980), particularly the DLPC (Goldberg et al., 1987; Berman et al., 1988). The WCST was administered according to standardized criteria (Heaton, 1981). Briefly, four stimulus cards with symbols differing in color, shape and number are placed in front of the subject who is given a pack of 128 response cards, four identical to the stimulus cards. The subject is instructed to place each response card under one of the four stimulus cards and is told that the examiner will say whether his pairing criterion is right or wrong. Guided by the examiner's feedback, the subject must try to get as many cards right as possible right. After pairing ten cards with the first criterion (color) he has to shift to the second one (shape) and then to the third one (number). This procedure is repeated twice or until all 128 cards have been placed. The indices considered for the test evaluation are as follows:
(1) SN: Number of stages completed by the subject.
(2) TE: Total errors made during the task.
(3) PE: Perseverative error score: A perseverative error is one
where the subject continues to sort the cards in the same
way, for example, according to color, after the examiner
says the card is wrong or changes criteria.
3.5 OBJECT ALTERNATION TEST. The OAT is a task sensitive to orbitofrontal cortical dysfunction in nonhumans (Pribram and Mishkin, 1956; Mishkin, 1964; Mishkin et al., 1969) and humans (Freedman and Oscar-Berman, 1986a, 1986b; Freedman, 1990). The task is explained in full elsewhere (Freedman, 1990). Briefly, the investigator and the patient sit facing each other across a table; they are separated by a 60 cm wide and 60 cm high wood platform. A black curtain is anchored to the platform and can be moved to reveal the stimulus board, where there are two plaques. When the curtain is lowered, the patient can see neither the plaques nor the investigator. When it is raised, the subject can see the two objects and only the hands of the investigator. An object, such as a penny, is placed under one of the two black plaques. The subject is asked to choose one of the two. On the first trial both plaques are baited with a penny; for the other trials, the penny is put under the side which was not previously chosen. The penny remains on the same side until the subject finds it. After a correct response, it is placed under the opposite plaque. After each response the curtain is lowered (and if there has been a correct response, the investigator changes the penny's location). Each task is composed of 25 complete trials; the learning criterion is 15 consecutive correct responses. For our purposes, OAT performance was calculated as the total number of perseverative errors (OAT-PE). An error is thus recorded if the subject chooses the incorrect object two or more times consecutively before shifting his strategy.
4.1 The row data obtained from the tests were transformed to normalize their distribution before statistical analysis. Data transformation was performed by means of a Spread-level examination of the all variables (SPSS, 1987). Z-scores were used for the three WCST indices (SN, PE, TE). A Square-root transformation was performed for the OAT-PE to reduce the great dispersion of data relative to the between-group variance. Furthermore, because of the presence of many scores of 0, a correction of the OAT score was made to transform x=0 to x=0.5. WST and WFT results were also square-root transformed. Three One-Way Analyses of Variance were performed with WST, WFT and OAT indices as the dependent variables and with diagnosis and sex the independent ones. Sheffe's procedure was performed in the post-hoc comparison between means. A Multivariate Analysis of Variance (MANOVA) was performed on the three WCST indices; SN, TE and PE were the dependent variables, diagnosis and sex the independent ones.
5.1 Table 2 shows the mean values of the WST, WFT and OAT-PE indices after transformation and summarizes the results of the One-Way Analyses of variance and the post-hoc comparison between means (Scheffe's procedures) according to the diagnosis. Diagnosis significantly affects test performance. Schizophrenic patients were significantly impaired on WST compared to OCD patients and controls; OCD patients had significantly poorer test outcomes on the OAT-PE when compared with schizophrenics and controls. The post-hoc comparison between means also revealed that schizophrenic patients showed significantly worse performance on the WFT compared to controls. Neither the effect of sex nor the interaction diagnosis by sex was found to be significant.
5.2 Table 3 shows the mean values of WCST-SN, WCST-TE and WCST-PE after transformation and summarizes the results of the MANOVA according to diagnostic categories. Diagnosis shows a significant effect. The post-hoc Univariate F-tests showed that the effect is due to the WCST-PE and to WCST-TE. The t-test for post-hoc multiple comparisons between means shows that the effect is due to the schizophrenic and controls groups. No significant differences were found between the three groups on WCST-SN. Neither the effect of sex nor the interaction between diagnosis and sex was found to be significant.
6.1 To the best of our knowledge, this is the first attempt to make a neuropsychological evaluation profile of frontal lobe functioning in both OCD and schizophrenic patients. Schizophrenics exhibited poorer performance on WFT and WEIGL. These results agree with similar findings reported in frontal lobe damaged neurological patients (Kramer and Jarvik, 1979) and in schizophrenics (Penati et al., 1978). Our attention was particularly focused on the functional differences between two regions, dorsolateral prefrontal cortex (DLPC) and orbitofrontal cortex (OFC).
6.2 The OCD patients were significantly impaired on OAT-PE compared to schizophrenic patients and controls. In contrast, schizophrenic patients made a significantly greater number of perseverative errors on WCST (compared with the other two groups) whereas no significant differences were found in WCST-PE between OCD and Controls.
6.3 Perseveration is an important consequence of frontal lobe damage (Robinson et al., 1980; Fuster, 1989). Nevertheless, two different aspects of perseveration are shown by OAT and WCST tests. In the OAT, the subject is required to establish the set of alternate responses from one object to another immediately but is not required to change this strategy afterwards. In the WCST, the subject must establish the set, maintain it for a certain time, and then shift to a new set after the first is completed. Since WCST performance has mainly been related to dorsolateral frontal lesions (Milner, 1963) and OAT performance has been considered to be strictly associated with orbitofrontal damage (Mishkin, 1964; Freedman, 1990), our results are in agreement with the hypothesis of two distinct neurofunctional and neuroanatomical circuits involving mainly the DLPC in schizophrenia (Goldberg et al., 1989; Goldberg et al., 1990; Weinberger et al. 1986; Braff et al., 1991) and the OFC in OCD (Modell et al., 1989).
6.4 The importance of the WCST and OAT in discriminating orbitomedial vs. dorsolateral dysfunction in the frontal area is also reconfirmed by our results. Such results agree with recent NMR (Baxter et al., 1987) and metabolic findings (Kellner et al., 1990; Nordahl et al., 1989; Scarone et al., 1992) that suggest a relationship between OCD and neuroanatomical and functional abnormalities involving the basal ganglia (mainly the caudate nucleus) and their connection with the orbitomedial areas of the frontal lobe. This relationship has also been hypothesized in neuropharmachological (Flament et al., 1987), biochemical (Pazos et al., 1985 Insel et al., 1985), behavioral (MacLean, 1978; Brooks, 1986) and neuropsychological studies reporting a link between Tourette's Syndrome and OCD (Bornstein et al., 1983; Bornstein, 1991). The 1989 model of Wise and Rapoport is the most recent and and informative.
6.5 The results of the present investigation seem to be further supported by the frontal lobe dysfunction in OCD as well as in schizophrenia. Nevertheless, besides a global impairment of frontal lobe functioning, it seems that quite distinct neurofunctional pathways are specifically involved in the two diseases. Biochemical and psychopharmacological treatment differences can partially explain the complexity of the pathophysiological pathways involved: different circuits are involved, both being related to the basal ganglia. Such results may contribute to a better understanding of the model that has been proposed for OCD and may clarify the role played by different frontal lobe areas in psychiatric illnesses.
TABLE 1. Clinical and demographic characteristics of the sample.
----------------------------------------------------------------
OCD Schizophrenics Controls
(n=25) (n=25) (n=25)
M (SD) M (SD) M (SD)
---------------------------------------------------------------
Age (years) 29.5(8.8) 29.9(6.9) 28.8(5.6) *
Education (yrs) 10.4(3.5) 9.8(2.6) 11.3(3.6) **
Age at onset 22.5(8.2) 22.9(3.6) $
Duration of
Illness 7.9(7.7) 7.3(5.5) $$
Sex M=14 F=11 M=18 F=7 M=11 F=14 #
BOCS(Total score) 18.4(5.5)
---------------------------------------------------------------
* anova : F(2,72) = 0.12, p=n.s.
** anova : F(2,72) = 1.35, p=n.s.
$ anova : F(1,48) = 0.04, p=n.s.
$$ anova : F(1,48) = 0.05, p=n.s.
# Chi-square= 4.03 with 2 d.f., p=.13
---------------------------------------------------------------
TABLE 2. WST, WFT and OAT-PE: mean (SD) values by diagnosis
(Square-root transformed scores)
OCD Schizophrenics Controls
(n=25) (n=25) (n=25)
---------------------------------------------------------------
Mean SD Mean SD Mean SD
---------------------------------------------------------------
WST 1.97 0.30 1.73 0.38 2.02 0.21
WFT 6.12 0.76 5.92 1.17 6.66 0.86
OAT-PE 1.40 0.71 0.88 0.47 1.00 0.41
---------------------------------------------------------------
One-way ANOVAs summary table.
---------------------------------
Indices df F p
---------------------------------------------------------------
WST (2,72) 6.25 < 0.01 *
WFT (2,72) 4.40 < 0.05 **
OAT-PE (2,72) 5.84 < 0.005 ***
---------------------------------------------------------------
Post-hoc comparison between means (Scheffe's statistics):
* Schizophrenics vs OCD and Controls
** Schizophrenics vs Controls
*** OCD vs Schizophrenics and Controls
---------------------------------------------------------------
TABLE 3. WCST mean and SD values. MANOVA Summary Table.
OCD Schizophrenics Controls
(n=25) (n=25) (n=25)
---------------------------------------------------------------
Mean SD Mean SD Mean SD
---------------------------------------------------------------
WCST-PE 6.80 6.45 11.44 12.93 4.12 5.00
z-scores -0.07 0.70 0.43 1.40 -0.36 0.54
WCST-TE 14.12 11.54 19.96 18.05 10.56 10.35
z-scores -0.05 0.81 1.28 0.25 -0.30 0.73
WCST-SN 5.56 1.26 5.60 0.63 5.84 0.37
z-scores -0.15 1.50 -0.01 0.75 0.17 0.45
---------------------------------------------------------------
Source MANOVA
------------------------------
df F p
---------------------------------------------------------------
Diagnosis 6,142 2.02 0.05
---------------------------------------------------------------
Univariate F-test with df= 2,72.
---------------------------------------------------------------
Indices Variable
------------------------------
F p
---------------------------------------------------------------
WCST-PE 4.40 0.01
WCST-TE 2.90 0.05
WCST-SN < 1.0 n.s.
---------------------------------------------------------------
Multiple Comparison *
------------------------------
1 2
---------------------------------------------------------------
WCST-PE 2.76 $ -0.45
WCST-TE 2.26 $$ -0.33
WCST-SN -0.09 -0.97
---------------------------------------------------------------
* Post-hoc multiple comparisons between means (t-tests):
1= schizophrenics vs controls
2= OCD vs controls
$ p= .007
$$ p= .02
---------------------------------------------------------------
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