Behavioural Neurology (1994),7,59-66 Do young schizophrenics with recent onset of illness show evidence of hypofrontality? O. Gureje, o. Olley, R.A. Acha and B.O. Osuntokun Departments of Psychiatry and Medicine, University Col/ege Hospital, PMB 5116, Ibadan, Nigeria Correspondence to: 0 Gureje, Department of Psychiatry, at above address Young schizophrenic patients (n = 43), manic controls (n = 32), both groups diagnosed according to the Research Diagnostic Criteria and on remission from acute illness, and 53 normal subjects were given a battery of neuropsychologic tests selected to assess different functional areas in the brain. Compared with normal controls, patient groups showed evidence of impaired functioning of many cortical areas but with the schizophrenics having the worst performance. In addition, schizophrenic patients performed poorly in tests designed to assess frontotemporal cortical functioning. This pattern of deficits differentiated schizophrenics from both manic and normal subjects. The results suggest that widespread cognitive deficits are a feature of both schizophrenia and mania but that frontal lobe dysfunction may be more specific to the former. It would also appear that these impairments are not artefacts of age, chronicity or of institutionalization, and are present even in schizophrenic patients who may have an illness with putative better outcome than those studied in previous reports. Keywords: Schizophrenia - Neuropsychological assessment - Frontal lobe dysfunction INTRODUCTION The impainnents associated with schizophrenia are may suggest that the illness is somewhat less "biologi- many and varied (Shakow, 1963; Spitzer et af., cal" in the latter countries (Cooper and Sartorius, 1970; Wallace, 1984; Taylor and Abrams, 1984; 1977). The evaluation of neurobiological factors in Keefe et at., 1987). However, those relating to cogni- such societies may thus provide evidence for or tions are of particular interest to researchers. This against the possibility that the fundamental nature of is so for a number of reasons. First, cognitive defi- schizophrenia is different in these two cultural cits in schizophrenia tend to be persistent and are settings. therefore a frequent source of poor social function- Neuropsychological tests are useful in the demon- ing among patients with the disorder (Gold and stration of the biological substrate of schizophrenia Hurt, 1990). Secondly, these impairments, in view because their validity and putative regional cerebral of the assumption that they may sometimes pre- origins have been established from studies of patients date the clinical manifestation of the disorder (Neale with insults to specific brain areas. et at., 1984), may serve as pointers to the aetiological The nature of cognitive deficits in schizophrenia is origins of the disorder. Thirdly, their differential contentious. Results implicating deficits in specific association with schizophrenia is a useful valida- brain areas include those suggesting involvement of tion evidence for an illness that is still only poorly the frontal lobe (Kolb and Whishaw, 1983; Taylor delineated from some other psychotic disorders, and and Abrams, 1984; Weinberger et at., 1986; Goldberg can serve as a tool in the on-going attempt to deline- et at., 1987), and of medial temporal and hippocampal ate the clinical components of what is increasingly systems (Kolb and Whishaw, 1983; Gruzelier et af., seen as a heterogeneous disorder (Tsuang et af., 1988; Saykin et al., 1991). Both left and right hemi- 1990). sphere dysfunction have also been reported (Gur, Few people will now argue against the notion that 1978; Gruzelier et at., 1989). While some of these schizophrenia is a brain disease (Mesulam, 1990). studies would imply that focal cerebral pathology is However, the demonstration of a differential out- more characteristic of the disorder, there are other come for the disorder in developed and developing results implicating a diffuse or generalized brain countries (Sartorius et af., 1986), with the implied insult in the disorder. Recently, a group of in- salience of sociocultural factors in such differences, vestigators suggested that there may indeed be two (<:) 1994 Rapid Communications of Oxford Ltd Behavioural Neurology. Vol 7 . 1994 59 UNIVERSITY OF IBADAN LIBRARY O. GURFJE ET AL. TABLE I. Demographic features of the subjects (S.D. in parentheses) Normals Sch izoph ren ics Manics (n = 53) (n = 43) (n = 32) Sex (% female) 53 40 56 Age (years) 27.1 (7.78) 29.3 (5.59) 27.7 (6.73) Years of education 14.6 (11.89) 11.9 (3.75) 12.7 (2.71) Social class 3.6 (1.52) 3.2 (1.17) 3.1 (1.22) Age at onset of illness 26.2 (5.35) 22.9 (5.53) (years) Length of current 41.2 (18.11) 35.7 (15.08) hospitalization (days) Current neuroleptic 1008.7 (526.06) 1270.3 (880.15) dosage (chlorpromazine equivalent, mg) levels of neuropsychological dysfunction in schizo- Andreasen, 1983) and an abridged version of the phrenia: one generalized and the other involving Brief Psychiatric Rating Scale (BPRS; Overall and fronto-temporal cortical systems (Goldberg et al., Gorham, 1962). The abridged version of the BPRS 1990). consisted of items previously used by other workers In this report, we examine the nature of neuro- to rate positive symptoms: conceptual disorganiza- psychological impairments in a group of schizo- tion, grandiosity, suspiciousness, hallucinatory experi- phrenic patients with relatively short duration of ence, and unusual thought content. The interview was illness. As this is, to our knowledge, the first such administered as soon after admission as patients' attempt using exclusively black African patients, we mental status permitted. The three groups were have used two groups of controls: normals and manic matched for sex, age and years of education. This patients. We were interested in determining whether was done by ensuring that for every manic patient, schizophrenics could be differentiated from the con- there was at least one schizophrenic of same sex and trols using neuropsychological test performance and age (within 5 years) and educational level (within 2 identifying the pattern of cognitive deficits character- years), and that for every schizophrenic, there was at istic of the illness in this sample. We have also least a normal control of identical features. Thus, examined the relationship between neuropsychologi- because of unequal numbers, two schizophrenics were cal test performance and the constituent syndromes sometimes matched to a manic while two normals of schizophrenia in order to see whether distinct were sometimes matched to a schizophrenic. All the cognitive profiles could be found for these syn- patients were receiving neuroleptic medication at con- dromes. ventional doses at the time of study. While the manics tended to be on a higher level of neuroleptic medica- tion, there was no significant difference between the METHODS patient groups in respect of mean neuroleptic dosage, The study sample consisted of 43 patients with schizo- and no significant correlations were found between phrenia. Controls were 32 patients with mania and drug dosage and any of the neuropsychological tests 53 "normals". Table I gives demographic details for for either of the two groups. the subjects. All patients were in-patients on the Neuropsychological tests were administered to the psychiatric wards of the university teaching hospital patients during the index admission but when active at the time of recruitment for the study. Normal symptoms had remitted. They were carried out by a controls were junior staff members at the university research clinical psychologist who was blind to the teaching hospital. All patients fulfilled Research Diag- patients' diagnoses but not to the clinical status of nostic Criteria (RDC; Spitzer et al., 1978) following the normal subjects. Most subjects completed the assessment by a trained assistant with the use of the tests at a single sitting. All were dextral. Composite International Diagnostic Criteria (CIDI; The neuropsychological tests were grouped into Robins et al., 1988), a structured polydiagnostic five rational content areas: verbal memory, verbal interview. Patients were also rated on the Scale for fluency, design fluency, Wechsler Adult Intelligence the Assessment of Negative Symptoms (SANS; Scale (WAIS; Wechsler, 1955) performance tests, 60 Behavioural Neurology. Vol 7 . 1994 UNIVERSITY OF IBADAN LIBRARY HYPOFRONTALITY IN YOUNG SCHIZOPHRENICS and W AIS verbal tests. The verbal memory test was were made with the use of the Tukey HSD statistic conducted with the use of the Y oruba version of the to determine the source of the difference. Significance narrative contained in the Test of the Sensorium of such comparisons was set at 0.05. (Withers and Hinton, 1971) previously used by the first author (Gureje, 1989). The test is an adapta- RESULTS tion of the Logical Memory Test (Wechsler, 1945). Yerbal fluency was assessed by the use of two tests. Table II shows the means and standard deviations of The first was a verbal associative fluency test, the scores of the three groups. There was no signifi- modified from the Multilingual Aphasia Examination cant group difference in the performance of the sub- (Benton and Hamsher, 1976) in which subjects were jects in the immediate recall of the Logical Memory required to produce as many words as possible Test. Even though a difference was observed in re- beginning with a particular letter in 1 min. Based on spect of the delayed recall of the test, with the schizo- data from a pilot study, the letters A and B in the phrenic having the poorest performance, there was local Y oruba language, the language in which all however no significant difference between any two of tests were conducted, were used. The former has the groups when comparisons were made with the many associative possibilities and is therefore easy Tukey HSD test. while the latter has fewer such possibilities and There was a significant group difference in each is therefore more difficult. Subjects were instructed of the verbal fluency tests. In the case of the associa- to name as many words as possible in 1 min but tive test for the letter A, this difference was due to to avoid proper nouns and names. The second test the significantly poorer performance of the schizo- of verbal fluency involved the production of as phrenics when compared with the normal controls. many words as possible belonging to a designated For the letter B, the difference was accounted for semantic category in 1 min. The category used was by the significantly better performance of the animals. manics than the schizophrenics. The group differ- Design fluency was tested by asking the subjects to ence in performance on the semantic category was draw as many designs as possible in 1 min (Jones- accounted for by the impaired performance of the Gotman and Milner, 1977). In the first trial, subjects schizophrenics in comparison with the normal sub- drew the designs without restriction as to how many jects. lines and curves could be used. In the second trial, Of the two design fluency tests, only the "re- subjects were restricted to four lines and curves for stricted" form significantly difTerentiated the groups. each design. Post-hoc pairwise comparison showed this to be en- Two tests were administered from the W AIS per- tirely due to the poorer performance of the schizo- formance subtests. These were the object assembly phrenics compared with the normal subjects. and the picture completion subtests. These two were Both of the two tests of performance intelligence chosen because they are often regarded as the most on the W AIS, the Object Assembly and Picture sensitive and also because they do not contain Arrangement tests, significantly differentiated the culture-sensitive items. Two tests were also selected three groups. While the difference in the former was from the W AIS verbal sub tests based on similar accounted for by the poorer scores of the schizophren- considerations: digit span and similarities. The ics compared with the normals, both of the patient similarities subtest was modified in this study by the groups scored significantly poorer than normals on deletion of three of the 13 items. The deleted items the latter. On both of the tests of verbal intelligence were those for which the Yoruba language lacked that differentiated the groups (i.e. Digit Span - adequate concepts for the description of similari- backwards and Similarities), each of the two patient ties between the pairs in the items. The W AIS tests groups showed impaired performance in comparison were administered according to standard specifica- with the normal controls. tions. In order to control for the potential confounding Three schizophrenics and four manics did not re- effects of age and previous level of education on the ceive the verbal fluency tests. Otherwise, every test test results and to determine the relative importance was administered to the 53 normals, 43 schizophren- of the tests at differentiating the groups, we per- ics and 32 manics. formed a multiple regression analysis in which all the Analysis of variance (ANOYA ) was carried out to neuropsychological tests, age and years of 'education compare the performance of the three groups on were forced into the equation. The results suggest each of the tests. When statistically significant differ- that only four tests significantly differentiated the ence (p < 0.05) was observed, pairwise comparisons groups or showed a trend in that direction (Table . Behavioural Neurology. Vol 7 . 1994 61 UNIVERSITY OF IBADAN LIBRARY O. GUREJE ET AL. TABLE II. Neuropsychological test performance of the groups Normals Sch izoph ren ics Manics p Tukey (ANOVA) HSD P < 0.05 Logical Memory Immediate recall 8.0 (2.77) 7.1 (2.69) 6.7 (2.36) N.S. 5 min recall 6.9 (2.85) 5.6 (2.97) 5.6 (2.22) 0.04 Verbal Fluency Letter A 9.6 (4.36) 6.3 (3.16) 7.8 (3.57) 0.0004 N>S Letter B 3.3 (1.77) 2.4 (2.25) 3.7 (2.41) 0.03 M>S Animal naming 12.0 (3.80) 10.0 (4.14) 10.3 (3.07) 0.016 N>S Design Fluency No restriction 5.4 (3.59) 3.9 (3.01) 4.2 (2.74) N.S. With restriction 5.1 (4.26) 3.0 (1.93) 3.7(3.15) 0.009 N>S WAIS Performance Object Assembly 26.6 (9.80) 20.1 (9.10) 21.4 (11.10) 0.004 N > S Picture Arrangement 14.3 (6.39) 10.4 (5.12) 11.0 (5.26) 0.003 N > S, N > M WAIS Verbal Digit forward 6.5 (1.20) 6.0 (1.40) 6.1 (1.22) N.S. Digit backward 4.4 (1.53) 3.4 (1.44) 3.5 (1.19) 0.003 N > S, N > M Similarities 12.0 (4.29) 9.6 (4.67) 9.6 (4.31) 0.01 N > S, N > M N, normals; S, schizophrenics; M, manics. TABLE III. Multiple regression analysis (forced entry)-variables making significant contribution to equation Variable B SEB fJ T P Design fluency No restriction 0.094 0.048 0.344 1.965 0.054 With restriction 0.111 0.048 -0.369 -2.299 0.025 Verbal fluency Letter A -0.076 0.032 -0.350 -2.352 0.022 Object Assembly -0.024 0.011 -0.313 -2.206 0.031 III). All the tests, except the Object Assembly, were consisting of hallucinations, suspiciousness and unu- tests of frontal lobe functioning. sual thought disorder accounted for 10.5% of the Our results suggest that there was variation in the variance. The results of the correlational analysis performance of the schizophrenics in the neuropsycho- between the tests and the three clusters are shown in logical tests. We examined the basis for this variation Table IV. As can be seen, there was a consistent by performing a correlational analysis between the trend for the test scores to correlate more strongly test scores on the one hand and gender, duration of with the "disorganization" syndrome than with the illness and symptomatology on the other. There were other two syndromes, with two of the correlation no significant correlations between the test scores coefficients attaining statistical significance at the and either gender or duration of illness. A factor 0.01 level. analytical examination of the symptoms of the schizophrenic patients as rated on the SANS and DISCUSSION the abridged BPRS produced three clusters of symp- toms: a "negative" cluster consisting of affective Using a battery of neuropsychological tests, we have flattening, anhedonia, avolition! apathy, and alogia shown that schizophrenics are different from normal accounted for 39.2% of the total variance; a "disor- subjects and from manics in respect of cognitive ganization" cluster consisting of conceptual disorgani- functioning that reflects the integrity of specific brain zation and attentional impairment accounted for areas. We have studied a group of young Nigerian 14.8% of the variance; and a "positive" cluster patients with relatively recent onset of illness, few 62 Behavioural Neurology. Vol 7 . 1994 UNIVERSITY OF IBADAN LIBRARY HYPOFRONT ALITY IN YOUNG SCHIZOPHRENICS TABLE IV. Correlations of three syndromes of schizophrenia with neuropsychological test performance Syndromes Test Negative Disorganization Positive Logical Memory Immediate recall 0.04 -0.20 0.09 5 minute recall 0.01 -0.29 0.10 Oral Word Association Letter A 0.01 - 0.42- -0.Q7 Letter B - 0.11 -0.33 -0.27 Animal names -0.14 -0.28 -0.06 Design Fluency Unrestricted -0.05 -0.20 -0.10 Restricted -0.02 -0.22 -0.09 WAIS Performance Tests Object Assembly 0.30 -0.30 0.02 Picture Arrangement -0.01 -0.23 -0.12 WAIS Verbal Tests Forward digit span -0.16 -0.38 0.11 Backward digit span 0.07 - 0.46- 0.02 Similarities 0.10 -0.45 -0.22 - P < 0.01. hospitalizations and with no prolonged institutional stricted: r = 0.20) and the higher correlations with care. The sample thus gave us the unique opportu- the total of the letter fluency test (unrestricted: r = nity to address the questions relating to whether 0.55; restricted: r = 0.26). Poor performance in the cognitive impairment in schizophrenia is a reflection Object Assembly and the Picture Arrangement sub- of such impairment in all psychotic states, is tests of the W AIS is associated with lesions of the evidence of impoverished institutional environment right temporal lobe (McFie, 1960). Subjects with or of ageing, or whether patients with a putative lesions in the right frontal lobe also show impairment better clinical outcome would evidence such impair- on the latter (McFier and Thompson, 1972). Digit ment. Span is a test of both attention and immediate The validity and cerebral localization of the tests memory and impaired performance reflects left used in this study have been generally based on parietal or temporoparietal dysfunction (Warrington evidence derived from unilateral lesion studies. The and Shallice,. 1969; Warrington et al., 1971). The Logical Memory Test is a test of immediate recall similarities sub test is a test of abstraction which is and recent semantic memory. The left frontal and subserved by the frontal lobe system (Flor-Henry et temporal lobes, particularly the hippocampus, are al., 1983) the cerebral areas responsible for these functions There is controversy over the selection of appropri- (Geschwind, 1974; Luria, 1976). Verbal fluency tests ate control groups for the study of neuropsychologi- generally assess frontal lobe functions. While fluency cal functioning in schizophrenia. Using patients with in response to letter category is associated with fron- diagnoses other than schizophrenia assumes a degree tal impairment of either hemisphere (Benton, 1968; of specificity of the impairments to schizophrenia, a Miller, 1984), that in response to semantic category view that is hardly justified by the body of present is associated with anterior or posterior left hemi- knowledge. Using normal controls matched for educa- sphere lesions (Newcomb, 1969; Gruzelier et al., tion and socioeconomic status can lead to erroneous 1988). In this study, the existence of some functional conclusions. As pointed out by Saykin et al. (1991), independence between the two was supported by the schizophrenia could in itself impede education and low correlation between the total scores on the letter produce a downward drift in socioeconomic status. and semantic categories among the normal subjects It seems to us that using both normal and patient (r = 0.29). Design fluency tests assess right frontal control groups, and studying patients with history of lobe functioning. This is confirmed in our study by early onset, will attenuate the effects of these con- the low correlations of these tests in normals with the straints. Nevertheless, one limitation of our study semantic fluency test (unrestricted: r = 0.07; re- was our inability to more rigorously control the Behavioural Neurology. Vol 7 . 1994 63 UNIVERSITY OF IBADAN LIBRARY o. GUREJE ET AL. groups for premorbid functioning. It would have and concept formation in their affected twins and been desirable, for example, to control the groups for suggested that impairment was more pronounced in premorbid reading IQ. Unfortunately, such informa- the frontotemporal cortex. Even though Saykin and tion is not routinely collected in the Nigerian educa- colleagues (1991) could not demonstrate selective im- tional system. pairment on tests related to frontal system function The overall results of our study support those of in their sample, they observed a pattern of dysfunc- earlier investigations that show two levels of neuropsy- tion that was consistent with greater involvement of chological deficits in schizophrenia, one generalized the temporohippocampal system. The hypofrontality and the other specific. Generalized dysfunction is hypothesis in schizophrenia has received support implicit in the fact that schizophrenics performed from studies using various neuropsychological tests, significantly poorer than normal subjects in many cerebral blood flow (Weinberger et al., 1986), various functional areas. An earlier study of 16 monozygotic scanning techniques (Andreasen et al., 1986), and twin pairs discordant for schizophrenia and seven mapping of brain electrical activity (Morihisa and normal monozygotic twin pairs found that affected McAnulty, 1985). twins tended to perform worse than their unaffected The observation of a significantly poorer perform- counterparts on most of the items in a battery of ance of the patient groups compared with the normal neuropsychological tests (Goldberg et al., 1990). The subjects may suggest that there was a common pat- authors showed that the deficits were related pri- tern of impaired effortful memory among the pa- marily to the clinical disease process and not to tients. However, and consistent with other reports genetic or non-specific environmental factors by dem- (Gruzelier et aI., 1988), we observed patterned deficits onstrating no significant differences in the perform- in the performance of the patients. Such an observa- ance of discordant unaffected twins and the sample tion rules out the possibility that the impaired per- of seven pairs of normal twins. In the present study, formance of the schizophrenics was due to poor the pattern of deficits in the manic patients would motivation or to distractions from the test procedure tend to suggest that this generalized dysfunction is, as a result of hallucinatory experience. Indeed, as the at least in part, a common effect of the psychotic result of correlations between neuropsychological test state even though schizophrenics may be the most scores and clinical symptomatology shows, there was affected. little association between the intensity of negative or A second level of deficits in schizophrenia may be positive symptoms and test performance. Rather, the more circumscribed. In our sample, the evidence syndrome complex characterized by conceptual disor- seems to implicate frontal lobe, possibly frontotempo- ganization and attentiona1 impairment had a dis- ral, dysfunction. The poorer performance of the tinctly higher negative correlation with neuropsycho- schizophrenics than the controls in fluency tests is logical test scores. Even though others have suggested suggestive of frontal lobe dysfunction. However, that attentional deficit may be central to the psychopa- since schizophrenics also had the poorest perform- thology of schizophrenia (Shakow, 1963), our find- ance on tests such as Object Assembly and the Digit ings suggest that such a deficit may characterize only Span, a case for the broad involvement of frontotem- a subgroup of patients with a form of the illness poral structures can be made. While it can however (Gur et aI., 1991; Peralta et aI., 1992). Thus, while be argued that the general drop in performance our observation provides partial support for the view shown by subjects with schizophrenia could also ex- regarding schizophrenia as consisting of at least three plain the specific differences observed, particularly if syndromes (Liddle, 1987; Gur et al., 1991; Peralta et the fluency tests are assumed to be more sensitive al., 1992), it also suggests that the group of patients than the other tests, the result of our multivariate that is particularly more likely to show cognitive analysis suggests that a case can still be made for the impairment is that characterized by thought disorder presence of a specific frontal or frontotemporal defi- and attentional disturbance. cit. Even so, our observation has to be interpreted with caution since we employed a relatively small number of tests designed to assess frontal lobe func- REFERENCES tioning. 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