Measurement, Classification and Conceptualisation of Atypical Handedness in Schizophrenia Candidate: Milan Dragovic This thesis is presented for the degree of Doctor of Philosophy University of Western Australia School of Psychiatry and Clinical Neurosciences 2004 ABSTRACT Atypical handedness is found to be more prevalent in schizophrenia patients than in psychiatric and normal controls, suggesting atypical brain lateralisation, particularly of regions associated with language. This ‘behavioural aberration’ is commonly considered as a marker of disturbed neurodevelopment, which is usually indexed by minor physical abnormalities. A prevailing view in the literature is that the atypical lateralisation of hand preference provides an additional index for the neurodevelopmental hypothesis of schizophrenia. Consistent with this hypothesis, an atypical lateralisation of hand preferences can also be considered as a consequence of environmental agents that might have interfered with early embryonic development. Notwithstanding the above, an atypical lateralisation of hand preferences can occur as a result of genetic factors as well as an interaction between genetic and environmental factors. The overall objective of this thesis was to advance existing knowledge on atypical laterality in schizophrenia by addressing its various (though related) aspects, including measurement, classification and conceptualisation. Atypical lateralisation of hand preferences in schizophrenia patients was approached by five separate studies. The aim of the first study was to provide a new insight in the prevalence of various atypical handedness categories in patients suffering from schizophrenia. A critical review of existing empirical data suggests that, in contrast to the prevailing view of increased mixed-handedness in schizophrenia patients, the shift in the handedness distribution is leftward, including an increased prevalence of left-handedness. A clear leftward shift implies either unilateral cerebral insult or disrupted genetic mechanism for development of cerebral asymmetry. The findings from this study are at variance with an extended concept of pathological left-handedness (early developmental and 2 bilateral cerebral insult), which has been proposed as the casual mechanism for atypical handedness in schizophrenia. The second study addressed an overarching issue in laterality research in schizophrenia, namely the classification of handedness and the definition of cut-off points for defining different handedness categories. Due to the lack of clear and uniform handedness categorisation, many studies in laterality research have depended on ad hoc and non-standardised cut-offs, thus generating considerable inconsistency between studies. In contrast to the over-categorisation of hand preferences (eg. eight handedness categories), this study found that a three-way classification of handedness (left-, mixed-, and right-handedness) is sufficient to describe the variety of manifest handedness patterns. In addition, this study investigated which cut-offs ‘best’ separate mixed- handedness from clear left- and right-handedness. The third study investigated the relationship between atypical lateralisation of hand preferences and schizotypal personality structure (hereafter schizotypy). Study results indicated that these two phenomena are independent in the general population, but not in the population of schizophrenia patients. As expected, there was a small but statistically significant association between mixed-handedness and the schizotypy factor of Cognitive Perceptual Dysfunction in schizophrenia patients. The fourth study of this thesis was a multivariate modelling of several laterality indices in patients with schizophrenia, their unaffected and biologically unrelated siblings, and unaffected and unrelated controls. The laterality phenotypes derived in all groups were also investigated with regard to multiple cognitive measures, personality traits, and, for patients only, clinical variables such as number of admissions and length of stay in hospital. The results of this study showed a weak but consistent association between the two laterality subtypes (‘left’ and ‘mixed’) and poorer cognitive performance in schizophrenia patients. These two laterality phenotypes in schizophrenia 3 patients were differently associated with parental left-handedness, ‘left’ with mothers’ left-handedness and ‘mixed’ with fathers’ left-handedness. These findings indicate that a multivariate integration of laterality measures and familial cofactors into complex laterality phenotypes might increase the likelihood of discovering the genetic, developmental, and environmental basis of cerebral and behavioural lateralisation. The fifth and final study was concerned with the measurement of handedness by the most widely used instrument for the assessment of handedness, the Edinburgh Handedness Inventory. The specific objective of this study was to emphasise the importance of measurement issues in this area of research and to provide an improved measurement model. With regard to the latter, this study provided a psychometrically improved alternative to the standard form of the Edinburgh Handedness Inventory. Overall, this thesis argues that the causes of atypical lateralisation of hand preferences are due to combined genetic and environmental factors and that its use as a marker of vulnerability to schizophrenia is limited. A cautious interpretation of various associations between the laterality and other measures, particularly cognitive measures, is advised until a broad agreement on the true nature of handedness is reached. 4 Table of Contents ABSTRACT ................................................................................................................................................... 2 TABLE OF CONTENTS.............................................................................................................................. 5 LIST OF TABLES AND FIGURES............................................................................................................ 7 ACKNOWLEDGMENTS ............................................................................................................................ 9 PREFACE .................................................................................................................................................... 11 PART I.......................................................................................................................................................... 13 INTRODUCTION AND LITERATURE REVIEW ............................................................................... 13 1. HANDEDNESS........................................................................................................................................ 13 1.1 DEFINITION, MEASUREMENT, CLASSIFICATION AND INCIDENCE ......................................................... 13 1.2 INHERITANCE OF HANDEDNESS............................................................................................................ 22 1.2.1 The Right-Shift Theory................................................................................................................. 26 1.3 HANDEDNESS AND CEREBRAL LATERALISATION ................................................................................. 31 1.4 HANDEDNESS AND COGNITION ............................................................................................................ 36 1.4.1 Balanced polymorphism hypothesis ............................................................................................ 36 1.4.2 Crow’s hypothesis........................................................................................................................ 41 1.4.3 Knecht’s hypothesis...................................................................................................................... 43 1.4.4 Intermediate summary ................................................................................................................. 45 1.5 DEPARTURES FROM THE TYPICAL HANDEDNESS DISTRIBUTION – HOW TO EXPLAIN IT? ..................... 46 1.5.1 Developmental instability model ................................................................................................. 48 1.5.2 Pathological left-handedness (PLH) ........................................................................................... 51 1.5.3 Birth stress model......................................................................................................................... 53 1.5.4 Geschwind-Behan-Galaburda (GBG) model .............................................................................. 54 1.6 SUMMARY ............................................................................................................................................ 58 2. HANDEDNESS AND SCHIZOPHRENIA .......................................................................................... 60 2.1 DESCRIPTION OF SCHIZOPHRENIA........................................................................................................ 60 2.2 REVIEW OF THE LITERATURE ON HANDEDNESS IN SCHIZOPHRENIA .................................................... 64 2.2.1 Prevalence studies of atypical handedness in schizophrenia ..................................................... 72 2.2.2 Atypical handedness and schizotypy............................................................................................ 74 2.2.3 Relationship between