Invited commentary on: Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk: The genetics of asymmetry and psychosis

Spence et al (2000, this issue) describe an original and incisiveapproach to the genetics of psychosis - an attempt to definebrain connectivity in patients and family members closest tothe genetic risk (‘obligate carriers’) by comparisonwith those remote from familial risk. Their findings are potentiallyimportant but I suggest an alternative interpretation: thatwords are simply less lateralised in those genetically predisposedto suffer from schizophrenic symptoms. This conclusion has,I believe, implications for understanding the organisation ofthe human brain.

The authors report three main findings: non-replication of previousreports of ‘deactivation of the left superior temporalgyrus’; significant ‘disconnectivity’ ofthe left dorsolateral prefrontal cortex (DLPFC) and anteriorcingulate cortex (ACC) in patients with schizophrenia and obligate carriers; and failure of deactivation of the precuneus in patients.

RE-INTERPRETATION

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RE-INTERPRETATION

Each of these findings (including the failure of replication)is of interest in its own right, but all may be seen as subordinateto the fact (not remarked on) that word generation activatesthe prefrontal cortex on the left side, and the fourth finding(introduced into the abstract on revision) that "qualitativelyaberrant... patterns of bi-frontal activity were exhibitedby patients and obligates", a finding that the authors qualify by saying that the aberrations were "statistically non-significant".

I return to the question of statistical significance later butI will first draw attention to the findings which arrestedmy attention as a referee.

Firstly, Fig. 1 (see page 55) shows areas of activation anddeactivation that can be associated with the generation ofwords. In normal controls there are two obvious lateralisations- activation of the DLPFC to the left, and a deactivation inthe 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 relatingto patients and obligate carriers reveals that, by contrastwith the normal comparison group, activation is present inthe DLPFC on the right (as noted in the legend) as well ason the left side, and that deactivation in the occipito-temporal region is absent posteriorly (in the area identified as thefusiform gyrus) and is bilaterally symmetrical in patientsin the region of the STG, as it is also in obligate carriers.The obvious interpretation of Fig. 1 is that patients and obligatecarriers are less lateralised than the normal comparison group.

Secondly, this impression is borne out by the correlationaldata in Fig. 3 (see page 56). Positive correlations are mostextensive in controls, relative to the other groups, on theleft side. In both patients and obligate carriers they arepresent in the DLPFC on the right side, but absent in controls. Negative correlations are conspicuous in the occipito-temporalregions on the right side in controls; they are less evidentin either patients or obligate carriers.

Thirdly, and illustrating other lateralised differences in thedata, 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 ofactivation to the right of the midline in the occipito-parietalregion.

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 schizophreniarelative to normals, the area of the ACC identified in eachcase is clearly to the right of the midline. Since the cingulategyrus is not a midline structure it is presumably the rightACC that is ‘functionally disconnected’ from theDLPFC in patients. These findings, therefore, also appear tobe susceptible to the interpretation that patients have greaterbilateral representation of word generation than controls, and the second part of Fig. 5 suggests that they may be more bilaterallyorganised than obligate carriers.

This interpretation is confirmed by Table 4 (see page 57). Ifmy reading of the location of the ACC in Fig. 5 is correct,all of the differences in connectivity between patients andthe other two groups are lateralised, with a relative decreasein connectivity to areas including Broca's in the left frontallobe, and an increase in connectivity to the right DLPFC. These findings are all significant at the P < 0.05 level correctedfor multiple comparisons.

LATERALISATION IN THE HUMAN BRAIN

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LATERALISATION IN THE HUMAN...

Although the authors have de-emphasised the importance of thefindings portrayed in Fig. 1 by describing the "aberrant patternsof bi-frontal activity" as "statistically non-significant",I believe that this reflects their having overlooked the factthat all their positive findings (with the possible exceptionof that relating to the precuneus) are lateralised, and thatthis oversight follows from their failure to recognise thesignificance of lateralisation of word generation itself. As we have known since the work of Broca (1861) and Dax (1865),some component of language is lateralised, and this may bethe distinguishing feature of the human brain. The latter possibilityis suggested by two recent findings. The population-based directionalhandedness that is present in Homo sapiens (and is a correlateof the anatomical torque of the brain (Bear et al, 1986)) is absent in chimpanzees (Marchant & McGrew, 1996; McGrew & Marchant, 1997),and the asymmetries of spacing of pyramidalcell columns that are present in the human (left being greaterthan right) are absent in the chimpanzee brain (Buxhoeveden & Casanova, 2000).Cerebral asymmetry may therefore bethe characteristic that distinguishes us from our nearest survivingprimate relative, and this characteristic may be crucial toour ability to generate words and, from words, to generatelanguage.

ASYMMETRY AND PSYCHOSIS

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ASYMMETRY AND PSYCHOSIS

The possibility that cerebral asymmetry may be related to psychosiswas first considered by Crichton-Browne (1879); the possibilitythat it is genetically determined was first investigated inrelation to handedness by Jordan (1911) and Ramaley (1913),and has been the subject of recent work and theories by Annett (1978, 1985) and McManus (1985). I proposed (Crow, 1984)that the genetics of psychosis and of cerebral asymmetry wererelated, on the basis that Brown et al (1986) had found astructural change in post-mortem brain (thinning of the parahippocampalgyrus) that was lateralised to the left. Since no aetiological factor other than a genetic one was plausible at this time,it appeared that a genetic explanation was required. The mostparsimonious was that the genes for psychosis and cerebralasymmetry are the same. Subsequent anatomical studies (e.g.Crow et al, 1989a,b) strengthened the case that the structuralchanges are indeed related to the dimension of asymmetry (forreviews see Crow (1990, 1997a) and Petty (1999), for critiquessee Weinberger et al (1991) and Bartley et al (1993), andfor counter-critiques see Crow et al (1995)).

Given this background (and their interest in word generationand the genetics of schizophrenia), one can ask whether Spenceet al (2000, this issue) might not have considered that thegenetics of asymmetry and psychosis are linked as a prior hypothesis.Had they done so the range of predictions would have been reducedand the correction for number of comparisons curtailed. The statistical significance of the finding of bilateral activationof the DLPFC in patients and obligate carriers would appearquite different from that presented in the abstract. Spenceet al may point to ignorance of this literature as their defence.However, two of Spence's co-authors are also co-authors ofa paper of similar experimental design (Sharma et al, 2000) which examines exactly this hypothesis in relation to anatomicalasymmetries. The fronto-occipital torque, assessed as brainwidths, was reduced in patients and in obligate carriers. Moreover,a further study with common authorship (Orr et al, 1999) reportsthat mixed handedness, another index of reduced asymmetry, is increased in patients and first-degree relatives compared withthe general population.

THE WIDER CONTEXT

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THE WIDER CONTEXT

The central issue is the genetic determination of asymmetry.Following Crow (1984, 1990, 1993), Annett (1997, 1999),Klar (1999) and Yeo et al (1999) have each discussed a geneticrelationship between asymmetry and psychosis, but no gene foreither has yet been located (see DeLisi & Crow (1999)for progress in genome scans in psychosis and Crow (1999)for theories of asymmetry). The question can be placed in awider context. Annett's (1985) hypothesis that variation indegrees of handedness is associated with variation in academic ability is supported, in a modified form, by observations onthe National Child Development Study (Crow et al, 1998). In12 000 11-year-olds, academic ability was predicted by degreesof handedness in a square-checking task. Those at the extremeswere disadvantaged relative to those less strongly lateralised(as predicted by Annett, 1985) but those who were most delayedin verbal ability were those who were closest to having equalhand skill (i.e. ambidexterity). These findings are consistent with the theories of Orton (1937) and Zangwill (1960) thatfailure to lateralise or delay in lateralisation is a majordeterminant of reading skill and academic ability; they arealso relevant to psychosis, as children who later develop aschizophrenic illness have been shown to be slow in learning to read (Crow et al, 1995) and closer to the point of equalhand skill at the ages of seven and eleven years (Crow et al,1996). Genetic variation related to psychosis is thus alsorelated to the development of verbal ability and reading skill.

Revision of the concept of ‘general intelligence’is required. It is not that there are a number of componentsof some mysterious overall cerebral capacity, but rather thatvariation in the genetic mechanism that enabled the evolutionof the (species-defining) capacity for language is associatedwith variation in its component functions, including particularlythe ability to attach words to categories. This ability islateralised and there are degrees of lateralisation. Once thesignificance of lateralisation is grasped the concept of generalintelligence can be discarded and the phenomena of psychosisas manifestations of a failure of lateralisation acquire new significance. Huxley et al (1964) were the first to ask whatadvantage balances the disadvantage associated with the genetic predisposition to psychosis. The answer that I have given isthat schizophrenia is the price that Homo sapiens pays forlanguage (Crow, 1996, 1997b). A corollary of this claim isthat the symptoms of schizophrenia can be considered as deviationsin the neural basis of language, as "language at the end of its tether" (Crow, 1998c). Seen from this viewpoint, Spenceet al's failure to take into account the dimension of lateralisationoverlooks the critical feature of the human brain (the principlearound which its connectivity must be organised) and subjugatesthe principal clues that we have regarding the neural basisof language (the nuclear symptoms of schizophrenia) to thequestionable categorical concept of a disease entity - theDSM-IV diagnosis of schizophrenia (American Psychiatric Association, 1994).

COMPETING HYPOTHESES

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COMPETING HYPOTHESES

One can ask whether there is any other hypothesis which canaccount for the findings and relate them to the genetics ofpsychosis. Spence et al's own hypotheses were simply that therewas a failure of left superior temporal gyrus ‘deactivation’(this hypothesis was falsified by their findings) and that‘fronto-temporal disconnectivity’ provides a traitmarker for schizophrenia. But what genes would one expect togovern fronto-temporal (or fronto-frontal) connections andat what stage in evolution might variation relating to thesegenes have arisen? A merit of the asymmetry/cerebral dominancetheory is that it specifies a change (deviation across the fronto-occipitalaxis) that is simple, that according to the evidence cited aboveoccurred recently in the hominid lineage, and that can be related,at least in principle, to the functional capacity that hasto be explained, namely language. The theory can also be relatedto the evidence for deviations in anatomical asymmetry (Crow, 1990, 1997a; Highley et al, 1998, 1999; McDonald et al,2000) as well as to the time course of development of componentsof language (Crow et al, 1998; Crow, 1998a,b). It specifiesa single change that relates to occipito-parieto-temporal hetero-modalassociation cortex as well as to the fronto-occipital torque which is diminished in those who develop schizophrenic symptoms (Bilder et al, 1994). For this reason I suggest that reappraisalof the important findings of Spence et al is necessary forprogress in the genetics of psychosis to be made.

REFERENCES

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