Prince of Wales International Centre, University Department of Psychiatry, Warneford Hospital, Oxford OX37JX. e-mail: tim.crow{at}psychiatry.ox.ac.uk
See pp. 5260, this
issue.
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INTRODUCTION |
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The authors report three main findings: non-replication of previous reports of deactivation of the left superior temporal gyrus; significant disconnectivity of the left dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in patients with schizophrenia and obligate carriers; and failure of deactivation of the precuneus in patients.
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RE-INTERPRETATION |
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I return to the question of statistical significance later but I will first draw attention to the findings which arrested my attention as a referee.
Firstly, Fig. 1 (see page 55) shows areas of activation and deactivation that can be associated with the generation of words. In normal controls there are two obvious lateralisations - activation of the DLPFC to the left, and a deactivation in the posterior occipito-temporal cortex that encompasses the fusiform gyrus and may extend into the superior temporal gyrus (STG) lateralised to the right. Inspection of the figures relating to patients and obligate carriers reveals that, by contrast with the normal comparison group, activation is present in the DLPFC on the right (as noted in the legend) as well as on the left side, and that deactivation in the occipito-temporal region is absent posteriorly (in the area identified as the fusiform gyrus) and is bilaterally symmetrical in patients in the region of the STG, as it is also in obligate carriers. The obvious interpretation of Fig. 1 is that patients and obligate carriers are less lateralised than the normal comparison group.
Secondly, this impression is borne out by the correlational data in Fig. 3 (see page 56). Positive correlations are most extensive in controls, relative to the other groups, on the left side. In both patients and obligate carriers they are present in the DLPFC on the right side, but absent in controls. Negative correlations are conspicuous in the occipito-temporal regions on the right side in controls; they are less evident in either patients or obligate carriers.
Thirdly, and illustrating other lateralised differences in the data, patients in Fig. 2 (see page 56) differ from normals (but not from obligate carriers) in overactivation of the precuneus (as noted in the abstract) but also in a conspicuous area of activation to the right of the midline in the occipito-parietal region.
Fourthly (and also illustrating further lateralised differences), in Fig. 5 (see page 58), which presents the data on disconnectivity from the left DLPFC and reciprocal disconnectivity from the anterior cingulate cortex (ACC) in patients with schizophrenia relative to normals, the area of the ACC identified in each case is clearly to the right of the midline. Since the cingulate gyrus is not a midline structure it is presumably the right ACC that is functionally disconnected from the DLPFC in patients. These findings, therefore, also appear to be susceptible to the interpretation that patients have greater bilateral representation of word generation than controls, and the second part of Fig. 5 suggests that they may be more bilaterally organised than obligate carriers.
This interpretation is confirmed by Table 4 (see page 57). If my reading of the location of the ACC in Fig. 5 is correct, all of the differences in connectivity between patients and the other two groups are lateralised, with a relative decrease in connectivity to areas including Broca's in the left frontal lobe, and an increase in connectivity to the right DLPFC. These findings are all significant at the P < 0.05 level corrected for multiple comparisons.
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LATERALISATION IN THE HUMAN BRAIN |
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ASYMMETRY AND PSYCHOSIS |
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Given this background (and their interest in word generation and the genetics of schizophrenia), one can ask whether Spence et al (2000, this issue) might not have considered that the genetics of asymmetry and psychosis are linked as a prior hypothesis. Had they done so the range of predictions would have been reduced and the correction for number of comparisons curtailed. The statistical significance of the finding of bilateral activation of the DLPFC in patients and obligate carriers would appear quite different from that presented in the abstract. Spence et al may point to ignorance of this literature as their defence. However, two of Spence's co-authors are also co-authors of a paper of similar experimental design (Sharma et al, 2000) which examines exactly this hypothesis in relation to anatomical asymmetries. The fronto-occipital torque, assessed as brain widths, was reduced in patients and in obligate carriers. Moreover, a further study with common authorship (Orr et al, 1999) reports that mixed handedness, another index of reduced asymmetry, is increased in patients and first-degree relatives compared with the general population.
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THE WIDER CONTEXT |
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Revision of the concept of general intelligence is required. It is not that there are a number of components of some mysterious overall cerebral capacity, but rather that variation in the genetic mechanism that enabled the evolution of the (species-defining) capacity for language is associated with variation in its component functions, including particularly the ability to attach words to categories. This ability is lateralised and there are degrees of lateralisation. Once the significance of lateralisation is grasped the concept of general intelligence can be discarded and the phenomena of psychosis as manifestations of a failure of lateralisation acquire new significance. Huxley et al (1964) were the first to ask what advantage balances the disadvantage associated with the genetic predisposition to psychosis. The answer that I have given is that schizophrenia is the price that Homo sapiens pays for language (Crow, 1996, 1997b). A corollary of this claim is that the symptoms of schizophrenia can be considered as deviations in the neural basis of language, as "language at the end of its tether" (Crow, 1998c). Seen from this viewpoint, Spence et al's failure to take into account the dimension of lateralisation overlooks the critical feature of the human brain (the principle around which its connectivity must be organised) and subjugates the principal clues that we have regarding the neural basis of language (the nuclear symptoms of schizophrenia) to the questionable categorical concept of a disease entity - the DSM-IV diagnosis of schizophrenia (American Psychiatric Association, 1994).
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COMPETING HYPOTHESES |
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Received for publication September 7, 1999. Accepted for publication September 8, 1999.