Is Schizophrenia a Lateralked Brain Disorder?
Editor's Introduction
by Raquel E. Qur
Abstract
Laterallzation of brain function was established on the
basis of clinical-pathological correlations over a century ago. In the past two decades, this line of research
has attempted to link the complex behaviors evident in
schizophrenia to the failure to develop and maintain a
normal pattern of hemispheric activity. This issue of
Schizophrenia Bulletin reviews and presents data from
multiple perspectives of methods applied to the study
of laterality in schizophrenia. Brain disorders affecting
systems that modulate complex behavior are commonly related to laterality. Therefore, this dimension
of brain function merits further investigation in schizophrenia.
Key words: Laterality, hemispheric activity, functional imaging.
Schizophrenia Bulletin, 25(l):7-9,1999.
This issue of Schizophrenia Bulletin is devoted to an
overview of laterality. Hemispheric asymmetry of brain
function has been of interest to neurologists ever since
Broca (1863), Dax (1865), and Hughlings-Jackson (1876)
demonstrated the profound differences between the effects
of unilateral lesions on language and on other cognitive
functions. For psychiatrists and psychologists, the phenomena of laterality have not presented in such a compelling fashion in the clinic. Perhaps as a consequence,
the concept of laterality has been slow to influence the
mainstream of psychiatric thinking, even within neurobiological theory. Nonetheless, laterality hypotheses of schizophrenia were proposed more than two decades ago
(Gruzelier and Venables 1974; Flor-Henry 1976; Gur
1977, 1978) and have since been tested using increasingly
powerful neurobehavioral, neuroanatomic, and neurophysiologic methods.
As this issue will show, the hypothesis has not been
consistently examined, even in studies that were in a posi-
tion to do so. Yet, almost surprisingly, this dimension has
fared quite well in the turbulence of empirical testing. It
has been reformulated and modified, to be sure, but the
evidence continues to grow that schizophrenia, like many
other brain disorders, is related to lateralized brain dysfunction. On the other hand, it is also becoming clear that
the question of whether schizophrenia is characterized by
dysfunction of one or the other hemisphere is simplistic
and needs to be reformulated. Some authors have tried
such formulations, and common to all of them is the
belief that complex behavior requires the participation of
neural networks. In this context, laterality can explain in
only a limited fashion one gradient or dimension that
modulates such networks.
Understanding lateralization of brain function in
health and disease, however, provides a heuristic hypothesis for building a neuropsychiatric perspective of schizophrenia (Crow 1990). The neuropsychiatric dimension
needs to converge with careful dissection of the neurobehavioral dysfunction evident in schizophrenia and pursuit
of the underlying mechanism that regulates it. By examining schizophrenia within the context of other brain disorders, we will be able to assess the nature and extent of
aberrant behavior and the brain systems affected that
stimulate or may control such behavior. For example, the
recognition that memory impairment is prominent in
schizophrenia has led to productive lines of research
attempting to tease apart the specific memory systems
involved. This research has applied structural and functional imaging methods to investigate memory-related
neural tissue and processes, and conducted animal work
to advance the understanding of the molecular basis for
memory. Likewise, comparing the memory deficit in
schizophrenia to other brain disorders, such as epilepsy
(see Hyde and Weinberger 1997), can give a perspective
Reprint requests should be sent to Dr. R.E. Gur, 10th Floor Gates
Bldg., University of Pennsylvania Hospital, Philadelphia, PA 19104.
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
and stimulate hypotheses on the pathophysiology of
schizophrenia. The study of laterality of brain function
provides an opportunity to apply both research strategies.
The review by Harris (1999, this issue) details some
of the history of the theory and research on hemispheric
specialization and how pathological behavior, or "madness," has received some cursory notation. Early and careful documentation of neurobehavioral dysfunction following brain lesions is the foundation for experimental
paradigms applied in cognitive neuroscience and in functional imaging studies today. Reading some of the theoretical arguments of our predecessors can be a humbling
experience. With all the advanced tools at our disposal
now, has our understanding increased commensurately?
Lateralization of brain structure and function, initially
considered unique to humans, is evident in other species.
Co well et al. (1999, this issue) examine the evidence for
cerebral lateralization in animals. They point out the lack
of integration between animal and human work. Animal
studies strongly support the critical role of early development for achieving healthy adjustment and accounting for
dysfunctional states. This line of investigation is pivotal
as we advance translational research.
Manual preference, or handedness, has been considered an index of lateralization with the majority of the
population being right-handed. For most right-handers the
left hemisphere specializes in language and the right
hemisphere in spatial abilities. Satz and Green (1999, this
issue) review the evidence for a leftward shift, or mixedhandedness, in schizophrenia and consider neurodevelopmental factors that may underlie the shift. Features of
schizophrenia in the symptomatic, neurocognitive, neuroanatomic, and genetic domains are examined in relation
to the possibility of a neurodevelopmental insult affecting
lateralized brain organization.
Ragland et al. (1999, this issue) examine laterality
indices in a range of neurobehavioral parameters including motor and sensory measures, as well as the neurocognitive domains of language and spatial abilities, and verbal and spatial memory. Patients with schizophrenia from
a large prospective sample show meager indication of lateralized disturbances in sensory processing and motor
speed. They do, however, have more language than spatial deficits, implicating relative left hemispheric dysfunction in regions needed for complex cognitive behavior.
Laterality effects in performance were mediated by sex
differences, and the results underscore the importance of
examining sex differences in laterality research.
Multiple psychophysiological measures have been
applied in the study of brain lateralization in schizophrenia. Gruzelier (1999, this issue) examines the evidence for
the association between laterality imbalance and disease-
R.E. Gur
related variables, including clinical syndromes and medication. The hemispheric basis for positive and negative
syndromes in schizophrenia and personality dimensions in
schizotypy is evaluated across diverse measures, including eye movements, lateral inattention, cardiac vagal tone,
motoneuron excitability, the P300, and other evoked
potential components. It is proposed that syndrome differences may relate to hemispheric function, interhemispheric connectivity, and neurotransmitters.
Neuroanatomic investigations permit examination of
structural asymmetries of the brain that may underlie neurobehavioral parameters. A recent issue of Schizophrenia
Bulletin examined the neuropathology of schizophrenia
(Buchanan and Carpenter 1997). Neuroimaging methods
have provided in vivo measures of brain anatomy. Petty
(1999, this issue) presents an overview of neuroanatomic
asymmetries from ah evolutionary outlook and describes
findings in healthy people and schizophrenia patients.
This provides a multilevel vista from gross anatomy to
cellular and neurochemical studies.
Functional imaging has been applied in the study of
schizophrenia more than in any other neuropsychiatric
disorder. A range of methods for evaluating cerebral
metabolism and blood flow as well as neuroreceptor functioning, is reviewed by Gur and Chin (1999, this issue).
Laterality has not been tested directly in the majority of
studies; however, the laterality dimension seems to interact with specific brain systems that modulate neurobehavioral domains that are dysfunctional in schizophrenia.
One may vacillate, after reading this diverse set of
contributions, between being overwhelmed by the amount
of data that have converged on the issue of laterality in
schizophrenia and feeling some exasperation at the
paucity of solid answers for questions that seem quite
rudimentary. Our hope is that these seven articles will
induce investigators of schizophrenia to include laterality
as a focus of inquiry. As a guiding hypothesis, laterality
can facilitate the design of studies and data analysis plans
around a dimension with established neural substrates.
As an angle on the symptoms and pathophysiology of
schizophrenia, laterality can assist researchers, clinicians,
and patients in efforts to conceptualize facets of the manifestations of this disabling and complex disorder.
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Is Schizophrenia a Lateralized Brain Disorder?
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Acknowledgments
This research was supported in part by National Institute
of Mental Health grants, P30 MH-43880, KO5 MH01336, and R37 MH-42191. The author thanks Joanne
Kuloszewski and Helen Mitchell-Sears for assistance in
various phases of this project.
The Author
Raquel E. Gur, M.D., Ph.D., is Professor of Psychiatry,
Neurology, and Radiology and Director of Neuropsychiatry and the Schizophrenia Center, Department of
Psychiatry, University of Pennsylvania, Philadelphia, PA.