ON THE PRESENTATION AND RELEVANCE OF LATERALITY: A STUDY OF PSYCHOSIS By Stuart John Leask MA MB BChir (Cantab) Thesis submitted to the University of Nottingham for the degree of Doctor of Medicine University Department of Psychiatry Duncan Macmillan House Porchester Road Nottingham NG3 6AA TITLE: On the Presentation and Relevance of Laterality: A Study of Psychosis SUBTITLE: Exploring the concepts that associate handedness, lateralization of function and psychosis in two UK birth cohorts. AUTHOR: Dr Stuart John Leask, MA, MB, BChir (Cantab), MRCPsych DEGREE: Doctorate of Medicine (DM) UNIVERSITY: University of Nottingham DIVISION: Psychiatry and Community Mental Health SUBMITTED TO: Faculty of Medicine, University of Nottingham SUBMITTED IN: HEAD OF UNIVERSITY DEPARTMENT: Professor Chris Hollis, Professor of Child Psychiatry, University of Nottingham SUPERVISORS: Professor Peter Jones, Professor of Psychiatry, University of Cambridge Professor Tim Crow, Professor of Psychiatry, University of Oxford 1 TABLE OF CONTENTS Page Preface 4 Introduction 7 Structured Summary 10 1. What is lateralization? 12 2. What is handedness? 29 3. Lateralization and psychological function 44 4. The thesis 60 5. The cohorts 63 6. The casefinding exercise 79 7. Two papers, but more problems 93 8. Cognition and lateralization 101 9. Adult outcomes and lateralization 147 10. Conclusions 172 References 187 Appendices 193 A CDROM accompanies this manuscript. The 3D figures in chapters 8 and 9 are quite complex, and it is recommended that these are examined by the reader in 3D, in order to fully appreciate their shapes. The CDROM contains the figures as VRML v1.0 models, and a compact viewer. CDROM Inside back cover 3 Abstract A discussion of concepts of lateralization and handedness is followed by an examination of the three-way relationships between lateralization of brain function, level of function, and schizophrenia. It is proposed that conventional examinations of such relationships, using lateralization indices, can be unenlightening or even misleading, and that alternative approaches are preferable. Support for this thesis is sought in analyses of data from two UK national birth cohorts. The author's process of gathering data on psychiatric outcomes is presented in detail. Previously-published findings in this data, employing laterality indices, are presented and their shortcomings discussed. Several alternative approaches to examining the relationships between measures of functional lateralization and level of function are developed, including a novel application of the method of principal curves, and a three-dimensional presentation of function as height over a 'laterality surface'. This latter approach is applied to a number of measures of function in the cohort datasets, including measures of cognitive ability, social success and psychiatric illness, including schizophrenia. The benefits of this method of presentation over previously-published presentations are discussed in the context of several contemporary hypotheses that touch upon the relationships between functional lateralization, cognitive function and schizophrenia. 8 Preface Statement of Authorship The discussion on the nature of lateralization, the critique of how it has been quantified in the past and how it may be quantified without recourse to indices, how the measure relates to central and peripheral functions, and how this might be associated with outcome have emerged from numerous discussions of these topics with colleagues and associates since 1996. Their synthesis is my own work. The 1958 National Child Development Study (NCDS) is a large general population birth cohort that has been followed continuously since its inception in 1958. The 1970 British Births cohort study (BCS70) is a similar study. The databases on the two birth cohorts that are drawn on are the work of thousands of individuals over many decades. Their origins, constitution, and data used in this thesis are described in chapter 5. An identification of individuals in these cohorts with schizophrenia was initially undertaken in the NCDS cohort alone in the mid-1980's by Dr John Done, Professor Tim Crow and Professor Eve Johnston. A repeat of the exercise of case identification, in order to increase numbers of cases of schizophrenia to allow for analyses of sex differences, was planned in the early 1990's. Between 1995 and 1997, under the supervision of Drs Crow & Done I developed a database of admissions, pursued those regionally-held lists of psychiatric admissions not yet obtained by Dr Done, and then obtained casenotes of the individuals on these lists. I examined the notes to obtain clinical data and entered these into the OPCRIT computerised multi-classification diagnostic programme for psychosis. I also used the casenotes to derive 'clinical' DSMIV diagnoses in a parallel effort with Dr Mike Blows, each blind to the others' diagnoses. Differences were then resolved in a three-way discussion between Dr Blows, Dr Crow and myself. This process is documented in chapter 6. In the first paper in chapter 7 I was responsible for a series of exploratory analyses of the data using a variety of techniques, before producing the lowess analysis (figure 3). This was felt to most succinctly and clearly demonstrate the relationships between sex, performance and laterality, which were more difficult to grasp in the 'by bins' figure (figure 2), where the dip is off to one side (by virtue of the group sampling employed). The 'discovery' of the misinterpretation of laterality index data described in the second paper in chapter 7 was mine, Tim Crow providing a valuable sounding-board on the implications of the corrected findings. The development and application of the relatively novel two- and three-dimensional data analysis and presentation techniques in chapters 8 and 9 is mine. 5 Acknowledgements My thanks go to Tim Crow and John Done, without whose help and encouragement I would not have undertaken the casefinding, nor developed an interest in demonstrating associations between psychological function and measures of right-left difference. I also thank Peter Jones, whose helpful and supportive comments and insights kept this manuscript on track. I am grateful to Peter Shepherd at City University for his support for the use of the cohort datasets, to Dr Tim Croudace, Dr Bert Park and Professor Ian Dryden at Nottingham University for statistical advice, Chinlyn U at Nottingham University and Dr Walter Barker at the University of Bristol for advice on the use of BCS70 data, and Dr John Coulthard at the University of British Columbia for support with VRML. Dr Catherine Gordon and Dr Bert Park read draft versions of this thesis and suggested improvements. All remaining errors are mine. 0 Introduction What does handedness have to do with psychiatry? One of the influential notions in the field of research into psychosis aetiology over the last 20 years has been Tim Crow's hypothesis that psychotic illness occurs at the point of 'hemispheric indecision'. It was during attempts to investigate this phenomenon that it was discovered that methods commonly employed to present such laterality data were flawed, and that fundamental issues relating to the distribution of lateralization required clarification. The work presented in this thesis consists for the most part of an exploration of these issues, and the seeking out of methods that might resolve these. These new methods are then re-applied to laterality measures in psychosis, to see whether any new light is shed on the field. The main area under consideration can be conceptualised in terms of figure 1; each association is reviewed in chapter 3, but what is chiefly under consideration are the conceptual uncertainties in the apex of the figure, and ultimately how these influence observations of association opposite. Lateralization* Function Schizophrenia Figure 1: A Triangle of associations *The spelling lateralize, lateralization etc. is used throughout, as ”lateral‘ is of Latin, and not French origin. While those words of French origin ending in œise retain the s, for all others the Greek ending -ize is correct, notwithstanding either use being generally acceptable. The human brain has two superficially similar halves, and appears to be 'wired up' as a huge network of neurons. If we think of the brain in this way, it suggests that any function it wishes to perform could be carried out by any part of this network. Studies of brain-damaged individuals strongly suggest that when some areas specialized to given tasks are destroyed, some if not all of their function can be taken up by other brain areas. Exactly how the brain parcels up the tasks of daily living, where it performs what, has a potential for variation between individuals. As well as functional specialization, there is also structural specialization within the brain. From specific lobes and tracts of ”wiring bundles‘, to the finest details of cellular ultrastructure, the brain shows an enormous variety of specialization. It is hard to imagine this specialization is not a consequence of selective pressures to improve brain function. So there is a tension œ the brain is hugely interconnected in a manner best modeled by repeated units of generalized function, and on the other hand there is a degree of consistency between brains, in patterns of specialization seen in specific areas. A synthesis is needed to understand how such anonymous generality and such anatomical specificity combine. 7 In a generalised network, the notion of a task being performed better or worse depending on where (and to what extent) it is localized, is illuminated by what we see around us. Small working-groups get on with tasks better than over-worked individuals or sprawling committees; manufacturing industry does better if design decisions are made closer to the shop floor. Computers function more efficiently when they can pass parts of a task to a specialised sub-processor. Thus a plastic system will interact with external and internal constraints (degrees of autonomy, the need for information, propagation delays and so forth) to arrive at an optimum degree of localisation for a given task in a given circumstance.