Laterality in Animals: Relevance to Schizophrenia
by Patricia E. Cowell, Roslyn Holly Fitch, and Victor H. Denenberg
Despite the large and growing literature describing
behavioral, neuroanatomical, and neurophysiological
asymmetries in nonhuman species, research on animal laterality has not been well integrated into the mainstream of
human brain research. Nevertheless, a few investigators
have demonstrated success in applying animal models of
laterality to the study of human brain development and
behavioral disorders. For example, Denenberg, Fitch,
Rosen, and colleagues have used rodents to model the
anomalous laterality patterns associated with developmental dyslexia and language impairment (Rosen et al.
1989, 1995; Denenberg et al. 1991a, \99\b, 19%; Fitch et
al. 1993, 1994, 1997). In addition, many of the basic
principles involved in the normal organization and development of brain asymmetries and related behavior have
been conceptualized through the use of animal models
(Collins 1977, 1985; Nordeen and Yahr 1982; Lipp et al.
1984, 19%; Galaburda et al. 1986; Diamond 1991; Rosen
et al. 1992; Waters and Denenberg 1994; Riddle and
Purves 1995). Advancements in the areas of developmental learning disabilities and basic neuroscience strongly
suggest that the field of neuropsychiatry may also benefit
from studies of laterality in animals.
Abnormalities in behavioral and neurobiological laterality have been widely documented in studies of schizophrenia (see Flor-Henry and Gruzelier 1983; Kovelman
and Scheibel 1986; Nasrallah 1986; Takahashi et al. 1987
for reviews). Yet very few experiments have been specifically designed_to study, these phenomena injionhuman
species. Numerous animal models of schizophrenia have
been proposed and implemented in recent years (see Lyon
1990, 1991 for reviews), but most have focused on neurotransmitter systems and the behavioral pharmacology
related to this psychiatric disorder. These models have not
addressed right-left differences (e.g., Hafner et al. 1991,
1993; Lewis et al. 1992; Schwartzkopf et al. 1992; Lipska
Abstract
Anomalies in the laterality of numerous newocognitive dimensions associated with schizophrenia have
been documented, but their role in the etiology and
early development of the disorder remain unclear. In
the study of normative neurobehavioral organization,
animal models have shed much light on the mechanisms underlying and the factors affecting adult patterns of both functional and structural asymmetry.
Nonhuman species have more recently been used to
investigate the environmental, genetic, and neuroendocrine factors associated with developmental language disorders in humans. We propose that the animal models used to study the basis of lateralization in
normative development and language disorders such
as dyslexia could be modified to investigate lateralized
phenomena in schizophrenia.
Key words: Animal models, laterality in animals,
functional and structural asymmetry, language, hand
preference.
Schizophrenia Bulletin, 25(l):41-62,1999.
Throughout the history of the brain and behavioral sciences, it has been largely accepted that cerebral lateralization was a unique feature of the human brain, particularly
for functions underlying language and hand preference
(Glick et al. 1979; MacNeilage et al. 1987; Denenberg
1988). However, accumulated evidence now supports the
existence of lateralization at the structural and functional
levels in a range of species. A portion of the literature on
animal laterality will be discussed in this article, but the
reader is referred to a number of recent, comprehensive
reviews for more detailed coverage of functional, anatomical, and neurochemical asymmetries in nonhuman
species (Denenberg 1984; Diamond 1984; Gerendai 1984;
Goldman-Rakic and Rakic 1984; Bianki 1988; Springer
and Deutsch 1989; Ward 1991; Hellige 1993; Hiscock and
Kinsbourne 1995).
Reprint requests should be seat to Dr. P.E. Cowell, Dept of Human
Communication Sciences, University of Sheffield, 31 Claremont
Crescent, Sheffield, S10 2TA, United Kingdom.
41
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
P.E. Cowcll et al.
et al. 1993; Lipska and Weinberger 1994, 1995;
Moghaddam et al. 1997). Thus, connections between
investigations of laterality in nonhuman species and
research on neurobehavioral asymmetries in patients with
schizophrenia can be made only indirectly. The objective
of this article is to draw together and present the laterality
findings from the seemingly distant areas of clinical
research in humans and basic neuroscience research in
animals. Toward this end, we will review the neuropsychiatric and animal literature on laterality to lay the
groundwork for further discussion. Then, we will integrate examples of lateralized systems that have been studied in both animals and in schizophrenia patients to
demonstrate the feasibility and importance of bridging
these research fields. The topics discussed are not meant
to be exhaustive of either literature, but rather indicative
of lateralized phenomena exhibited by schizophrenia
patients, phenomena that also occur in neural or behavioral systems that have been studied in animals.
Material on human and animal laterality from three
major areas of neuroscience will be covered: (1) behavioral
and cognitive, (2) neuroanatomical, and (3) neurophysiological and biochemical. The primary emphasis will be on
behavioral laterality, although related asymmetries in brain
structure and function will be covered briefly as well. Some
of the developmental factors that affect the expression of
these neurobiological measures will also be addressed. Our
aim is to demonstrate how overlaps and links between the
study of neurobiological asymmetries in animals and
humans may inform both the study of schizophrenia and
the direction of future neuropsychiatric research.
We have attempted to be sensitive to the limitations of
cross-species comparisons and acknowledge that it is virtually impossible to operationalize the many clinical manifestations of schizophrenia into straightforward animal experiments. Conversely, we recognize that data derived from
animal models must often be applied in a conceptual rather
than in a literal sense to the study of schizophrenia. We do
not intend to suggest that lateralized neurobehavioral measures in humans and animals necessarily have common evolutionary (homologous) or functional (analogous) bases.
We designed the comparisons simply to elucidate general
issues important to the development and organization of
brain and behavior laterality in schizophrenia patients and
in nonhuman species and to point out areas of convergence
between these traditionally disparate fields of research.
tive asymmetries in patients with schizophrenia.
Lateralized disturbances in patients with schizophrenia
have been noted at many levels of behavioral analysis
(Nasrallah 1986). Some early studies of anomalous laterality found disturbances in basic cognitive, perceptual,
and motor behaviors (Flor-Henry 1976; Gur 1977, 1978;
Gruzelier and Hammond 1979), in addition to evidence
for abnormal distributions of hand preference in schizophrenia populations (Boklage 1977; Fleminger et al.
1977). These studies laid the groundwork for exploration
into the sensory (Carr et al. 1992; Mathew et al. 1993),
motor (Bracha 1987; Gorynia and Uebelhack 1992; Lohr
and Caligiuri 1995; Sakuma et al. 1996), attentional
(Posner et al. 1988; Tomer and Flor-Henry 1989; Harvey
et al. 1993; Carter et al. 1994; Bustillo et al. 1997; Evans
and Schwartz 1997), and cognitive manifestations (Saykin
et al. 1991, 1994; Green et al. 1994; Haut et al. 1996;
Sakuma et al. 1996) of behavioral asymmetry that have
continued to demonstrate striking differences between
patients with schizophrenia and normal controls. Some
studies have also been able to detect lateralized behavioral
disturbances related to a particular clinical state (Gorynia
and Uebelhack 1992; Harvey et al. 1993; Mathew et al.
1993; Tyler et al. 1995) or subtype (Carter et al. 1994;
Green et al. 1994; Bustillo et al. 1997).
Although the presence of abnormal functional asymmetry in schizophrenia is not disputed, considerable
debate still exists as to whether laterality effects are primary characterizations or epiphenomena of the disorder.
Some authors have suggested that the study of anomalous
neurobehavioral or dermal asymmetry patterns could provide insights into which types of developmental factors or
processes may be involved in the emergence of schizophrenia (Crow 1990; Mellor 1992; Tyler et al. 1995; Crow
et al. 1996). Multiple investigations of risk factors and
early brain injury have examined atypical development in
schizophrenia (see Mednick et al. 1988; Cannon 1996;
Chua and Murray 1996 for reviews), but most of these
studies were carried out at the neuroanatomical or clinical
level and did not address laterality. In addition, the direct
methods of manipulation used in animal research are not
available to the study of neurocognitive development in
humans, so there is little purely experimental evidence to
confirm the mechanisms by which prenatal risk is
involved in the development of abnormal behavioral
asymmetry in schizophrenia. As a result, the etiology of
asymmetrical behavioral phenomena in schizophrenia and
their contributions to the disorder are still not well understood. It is at this juncture that the information derived
from animal research and early disruption in neural development may be useful in understanding the basic principles governing the development of abnormal patterns of
behavioral asymmetry.
Laterality in Animals and in
Schizophrenia Patients
Behavioral and Cognitive Laterality.
An overview of anomalous behavioral and cogni-
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Laterality in Animals
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
An overview of functional laterality in animals.
Lateralized behaviors have been studied extensively in
animals, either to model basic neurobehavioral principles
or to provide insights into pathological neurodevelopmental processes. Some of the earliest reports of functional
lateralization in nonhuman species derived from
Nottebohm's work showing that control of song production was lateralized to the left hypoglossal nucleus of
male canaries (Nottebohm and Nottebohm 1976;
Nottebohm 1977). Asymmetries have been also reported
in the sensory (Heffner and Heffner 1984; Zappia and
Rogers 1987; Rogers 1990), motor (Lehman 1980; Glick
and Ross 1981; Camp et al. 1984; Dewberry et al. 1986;
Fagot and Vauclair 1991; Waters and Denenberg 1994;
Bulman-Fleming et al. 1997), affective (Rogers 1982;
Crowne et al. 1987; Maier and Crowne 1993), and cognitive (Zimmerberg and Riley 1988; Adelstein and Crowne
1991; Crowne et al. 1992; King and Corwin 1992; Fenton
and Bures 1993; Fitch et al. 1993; Cowell et al. 1997)
aspects of avian, rodent, and primate behavior.
The hormonal and environmental conditions that
affect the organization of functional asymmetries have
been investigated in developmental studies of animals,
particularly rodents (Denenberg et al. 1978, 1986;
Sherman et al. 1980; Rogers 1982, 1990; Garbanati et al.
1983; Camp et al. 1984; Lipsey and Robinson 1986;
Zappia and Rogers 1987; Zimmerberg and Riley 1988;
Alonso et al. 1991; Fitch et al. 1993; Maier and Crowne
1993; Cowell et al. 1997). The specific measures employed and the direction of the effects often distinguish
behavioral asymmetries observed in animals from those
seen in humans, making direct comparisons across species
difficult. Despite these limitations, researchers will find it
useful to turn to the animal literature to obtain theoretical
context for, or gain better understanding of, the results
from human studies, which typically examine developmental processes indirectly (i.e., with data from interview
questionnaires or obstetric records). By looking to animal
studies of behavioral asymmetry, we hope to shed light on
some of the environmental conditions and developmental
mechanisms that influence the origins and expressions of
anomalous lateralized behaviors seen in patients with
schizophrenia.
Converging lines of research on behavioral laterality in animals and in patients with schizophrenia.
Few behavioral modalities have been studied within all
three of the following paradigms: (1) functional laterality
in patients with schizophrenia, (2) functional laterality in
animals, and (3) animal models of lateralized behavioral
systems in schizophrenia. Of the many lateralized phenomena cited in the preceding sections, research on asymmetries in motor behavior provides the broadest basis for
comparison across all of the above three research para-
digms. In addition, studies of functional asymmetries in
language and language-related processes have been examined in the first research paradigm listed above and have
been modeled in animals using tests of auditory discrimination. These studies provide another context from which
to address laterality issues in schizophrenia. Therefore,
two in-depth sections—one on behavioral motor asymmetries and the other on language, language-related
processes, and auditory discrimination—will discuss specific connections between animal laterality and schizophrenia research.
Asymmetries in motor behavior. Motor asymmetries in patients with schizophrenia. One notion that
emerged from early behavioral studies of schizophrenia
was that patients' left hemispheres appeared to be dysfunctional or "overactivated." Patients were shown to
exhibit more leftward patterns of circling behavior and
eye, foot, and hand movements than controls (Gur 1977,
1978; Bracha 1987). Results from such investigations of
motor asymmetries have been interpreted in various ways,
which were not necessarily mutually exclusive but were
certainly difficult to confirm on the basis of behavior
alone. One view was that primary disruptions in the left
hemisphere were accompanied by shifts of motor lateralization to the right hemisphere, whereas others attributed
similar results to increased activation of dopaminergic
systems in the right hemisphere (Gur 1977, 1978; also see
Gruzelier and Flor-Henry 1979; Bracha 1987). Recent
research on functional magnetic resonance imaging (MRI)
suggests that disturbances in lateralized movements
involve complex interactions of activity in both right and
left sensorimotor cortices (Wenz et al. 1994). However,
the underlying basis of even straightforward behavioral
asymmetries, such as hand preference or body movements, are still not clearly understood from a neurodevelopmental basis.
The study of individual differences in motor function
has revealed an even more complex and heterogeneous
view of laterality in schizophrenia. For example, various
studies of hand preference have shown patients with
schizophrenia to have higher, lower, or equal percentages
of non-right-handedness as compared with controls
(Boklage 1977; Fleminger et al. 1977; Taylor et al. 1980;
Torrey et al. 1993; Cannon et al. 1995; Sakuma et al.
1996) and patients with bipolar disorder (Lohr and
Caligiuri 1995). The direction and degree of various
motor asymmetries have been shown to vary as a function
of clinical subgroup, severity of illness, family history of
psychosis, and sex (Fleminger et al. 1977; Manoach 1994;
Cannon et al. 1995; Tyler et al. 1995). In general, findings support the view of Nasrallah (1986, p. 160), who
theorized that "inconsistent findings in handedness
research in schizophrenia may in large part be due to the
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Schizophrenia Bulletin, Vol. 25, No. 1, 1999
RE. Cowell et al.
different subtype and gender compositions of the various
samples reported." The effects of such differences on
variation in neurobehavioral asymmetries in schizophrenia are further complicated by "the combined effect of the
disease and the neuroleptic medication" (Wenz et al.
1994, p. 975). Therefore, animal models that allow
researchers to experimentally control or manipulate neuropharmacology, environment, genetics, and developmental conditions are particularly essential in unraveling the
intricacies of neurocognitive laterality in this disorder.
Motor asymmetries in animals. Evidence of motor
asymmetries in a variety of nonhuman species has been
clearly demonstrated (Collins 1985; Glick et al. 1987;
Bradshaw 1989; Carlson and Glick 1989). Evidence of
population bias in nonhuman species has also been studied
(Glick and Ross 1981; Alonso et al. 1991; Waters and
Denenberg 1994; see also MacNeilage et al. 1987). As is
the case with humans (Healey et al. 1986; Peters 1990,
1991), side preference appears to depend partly on the
nature of the task used for measurement (Camp et al. 1984;
Fagot and Vauclair 1991; Waters and Denenberg 1994;
Bulman-Fleming et al. 1997) and the neurobiological systems involved (Whishaw et al. 1986; Barneoud et al. 1990;
Cabibetal. 1995).
In the process of trying to investigate the basis and
role of functional laterality in schizophrenia, continued
research has uncovered a highly heterogeneous set of
behaviors with anomalous asymmetry patterns. In the
animal literature on lateralized motor behavior, the array
of asymmetries is equally broad and complex, but somewhat better understood in terms of developmental principles. Studies of open-field activity, swimming rotation, Tmaze side preference, and paw preference have revealed
that direction and degree of motor laterality are influenced
by multiple developmental factors, including early environment (Sherman et al. 1980; Camp et al. 1984; Alonso
et al. 1991), genetics (Collins 1977; Waters and
Denenberg 1994), hormonal milieu (Robinson et al. 1980;
Ross et al. 1981; Sherman et al. 1983), neuropharmacology (Brass and Glick 1981; Jerussi and Taylor 1982;
Rodriguez et al. 1994), immune status (Neveu et al. 1988;
Denenberg et al. 1991b, 1996; Neveu 1992; Delrue et al.
1994), and neonatal cortical injury (Rosen et al. 1995).
By exploring these factors, it may be possible to develop
novel frameworks for couching both conceptualizations
of, and research directions for, schizophrenia laterality
research.
and Ross 1981). It was found that many measures of
motoric and postural laterality (e.g., rotation behavior and
side bias in the open field) were different in males and
females and were affected by early environmental conditions. For example, females exhibited more amphetamine-induced rotation in adulthood and a greater degree
of lateralized spatial preference in the open field than
males (Robinson et al. 1980; Ross et al. 1981; Denenberg
et al. 1982; Rosen et al. 1983). In addition, neonatal handling was found to enhance lateralization of spatial preference differently in male and female rats (Sherman et al.
1980, 1983). Furthermore, the effects of postnatal handling (Camp et al. 1984), prenatal stress (Alonso et al.
1991), and prenatal alcohol (Zimmerberg et al. 1988) on
lateralized motor and postural behaviors were shown to
differ as a function of sex.
Convergence of human and animal motor asymmetry
research. Studies of motor behavior in patients with
schizophrenia have not focused simultaneously on sex
differences, perinatal development, and laterality. Ethical
standards for human research practice, combined with the
cost and time scale of studying human development, present major obstacles to the investigation of phenomena
routinely examined in animals. Investigators must resort
to very large-scale studies and intricate statistical methods
to pull apart the sources of variance presented to them in
clinical human data bases. Turning to the study of comparable phenomena in animals is another way to triangulate
information, and as will be described later, some of the
hormonal, environmental, and developmental factors that
appear to affect lateralized behavior in schizophrenia also
appear to play a role in the organization of motor asymmetries observed in animals.
The finding that a higher proportion of men than
women with schizophrenia were left-handed writers
(Fleminger et al. 1977), more sinistral on manual proficiency measures (Manoach 1994), and afflicted with
subtle deficits in lateralized motor function (Goldstein et
al. 1994) provides indirect evidence for sex differences in
this patient population's expression of anomalous behavioral asymmetries. Looking to research on sex differences
in animals, one finds support for the notion that the heterogeneous array of asymmetry effects observed within and
between human patient groups depends in part on the ratio
of male to female patients comprising the subject group.
Animal studies also indicate that the varied patients' perinatal histories and genetic backgrounds may contribute
further to different expressions of functional laterality and,
thus, exacerbate inconsistencies in the literature.
Examining sex differences in patients' motor asymmetries, together with reports of sex differences in similar
types of measures in animals (Fleminger et al. 1977;
Robinson et al. 1980; Brass and Glick 1981; Ross et al.
The classic work of Glick and colleagues, describing
brain asymmetries and right-sided population bias in
amphetamine-induced rotation in the rat, stimulated much
research into the factors and conditions involved in the
organization and expression of these and other similar
asymmetries in motor behavior (Glick et al. 1979; Glick
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Laterality in Animals
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
1981; Manoach 1994), supports the view that gonadal
hormones may play an important role in the prenatal
development and adult expressions of lateralized motor
functions in schizophrenia. As mentioned above, research
in animals shows that motor asymmetries in males and
females are differentially affected by exposure to a variety
of factors during early development (Sherman et al. 1983;
Camp et al. 1984; Zimmerberg et al. 1988; Alonso et al.
1991). For example, in rats bom to mothers exposed to
restraint stress during pregnancy, female asymmetries
were increased, whereas in males, asymmetries were
decreased in adulthood (Alonso et al. 1991). Perinatal
stressors and obstetric complications have been identified
as factors contributing to the adult onset of schizophrenia
(Cannon 1996). However, the animal literature suggests
that exposure to the same type of perinatal stressor may
lead to differential expression of lateralized behaviors in
men and women with schizophrenia.
The autoimmune status of the mother's uterus also
affects the development of behavioral motor asymmetry
in offspring. Embryos from an autoimmune mouse strain
were transferred into the uteri of non-autoimmune mice;
embryos from a non-autoimmune mouse strain were
transferred into autoimmune uteri; and other mice from
these two strains were not transferred (Denenberg et al.
I99\b). Females whose gestation occurred in autoimmune uteri had greater absolute paw asymmetry than
those who developed in non-autoimmune uteri, but males
were unaffected. If one views prenatal exposure to
autoimmunity as a stressor, the results of this study
together with those of Alonso et al. (1991) suggest that
the developing functional asymmetries of males and
females are differentially sensitive to stressful events during the prenatal period.
More recent work has found that the profile of lateralized behavior, and whether sex differences were present,
depended on the specific strain of mouse examined.
Denenberg et al. (1996) showed that absolute asymmetry
in swimming rotation was increased in two autoimmune
strains of mice (different strains from those used in
Denenberg et al. 1991ft), which had been transferred and
developed in the uteri of non-autoimmune mothers.
Overall, the animal literature suggests that the development of anomalous motor asymmetry patterns seen in
patients with schizophrenia may be influenced by a complex interaction between genetic background and other
perinatal factors, including stress levels, hormonal milieu,
and immune status of the mother and developing fetus.
The animal literature reviewed earlier may provide
clues for designing future studies in humans that investigate the neurodevelopmental basis of motor asymmetries
in patients with schizophrenia. Future research would
include collecting detailed information on family and
medical history, plus considering demographic variables
such as sex and age. Multiple measures of behavioral laterality would also need to be assessed, since animal studies indicate that measures of motor laterality, such as paw
preference and swimming rotation, are associated with
asymmetries in different brain areas (Whishaw et al.
1986; Bameoud et al. 1990; Cabib et al. 1995). Applying
a research approach similar to the one described above
would allow heterogeneity in motor asymmetries to be
studied with respect to variation in specific developmental
and neurobiological characteristics seen in patients with
schizophrenia.
Language asymmetry in neurodevelopmental disorders: Research links to the study of behavioral asymmetry in schizophrenia. Language and languagerelated processes in patients with schizophrenia. Many
measures of lateralized language processing have been
shown to differ between patients with schizophrenia and
controls. Verbal memory deficits indicating dysfunction in
left temporal and frontal regions are notable neuropsychological characteristics of schizophrenia (Saykin et al. 1991,
1994; Cannon et al. 1994; Harper Mozley et al. 1996).
Language dysfunction is present early in the course of the
disease (Saykin et al. 1994) and has been shown to be
related to formal thought disorder and atypical patterns of
behavioral asymmetry (Manoach 1994; Sakuma et al.
1996). Reversal or absence of the normative patterns of
left-hemispheric lateralization in verbal processing has
been noted in the visual and auditory modalities (Gur
1978; GUT et al. 1983, 1985, 1994). Decreased left frontal
and increased left temporal lobe activity have also been
reported during verbal fluency activation in patients
(Yurgelun-Todd et al. 1996). Furthermore, tests of
dichotic listening have revealed that abnormal patterns of
language asymmetry are associated with auditory hallucinations in schizophrenia (Green et al. 1994). It appears
that disruptions in functional language asymmetry have
important associations to cognitive and clinical aspects of
schizophrenia.
.
_
The investigation of normative sex differences in language asymmetry has contributed greatly to the general
understanding of lateralized functions in the human brain.
This research also has the potential to reveal which factors may be involved in the anomalous development and
the expression of the functional laterality associated with
schizophrenia. Early evidence for sex differences in functional asymmetry of language processing was derived
from research showing that women exhibited significantly
better recovery of language following damage to the left
hemisphere than men (Kimura and Harshman 1984).
These findings supported the view that there may be a
greater degree of functional language symmetry in the
brains of women (see McGlone 1980, for review). Sex
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Schizophrenia Bulletin, Vol. 25, No. 1, 1999
P.E. Cowell ct al.
Animal models of laterality in language-related
differences have also been reported in the interhemispheric patterns of cerebral blood flow during the performance of verbal tasks (Wood et al. 1991), in neurophysiological asymmetry as measured by functional MRI
during verbal tasks (Shaywitz et al. 1995), and in structural asymmetry as measured by right and left planum
temporale size in men and women (Kulynych et al. 1994).
These results support the notion of sex differences in the
cerebral organization of language and are consistent with
long-standing, although somewhat controversial, evidence
of normative sex differences in the magnitude of the right
ear advantage (REA) for discriminating verbal material in
tests of dichotic listening (Lake and Bryden 1976; Bryden
1979; Hiscock et al. 1994).
The normative data suggest that controversy over the
presence of REA reversal or attenuation in patients with
schizophrenia (Gur 1978; Colbourn and Lishman 1979;
Bruder 1983; Ragland et al. 1992; Grosh et al. 1995;
Sakuma et al. 1996) may be due in part to the confounding
effects of sex. Recent findings from neuropsychological
studies reveal sex differences in performance on verbal
memory and other language-related measures of performance (Goldstein et al. 1994; Gruzelier 1994; Lewine et al.
1996). Using latent class analysis, Goldstein et al. (1994)
identified a subgroup of patients characterized by previous
history of developmental learning problems. This subgroup, subsequently found to exhibit deficits in neuropsychological tests of verbal function, consisted entirely of
male patients. This research provides further supporting
evidence for unique profiles of lateralized cognitive ability
and impairment in men and women with schizophrenia.
Research has demonstrated that functional lateralization for speech is directly dependent on the temporal (i.e.,
time-relevant) parameters of acoustic stimuli, regardless
of linguistic content, both at the behavioral level, as measured by dichotic listening (Schwartz and Tallal 1980), and
at the neurophysiological level, as measured by positron
emission tomography activation during verbal, phonological, and nonverbal discrimination tasks (Fiez et al. 1995).
These findings are consistent with evidence of language
dysfunction in children with auditory discrimination
deficits (Tallal et al. 1993), a population shown to exhibit
atypical cerebral asymmetry (Jernigan et al. 1991).
Conceptualizing language in terms of discrete auditory
stimuli has enabled researchers to operationalize both language processing and language-processing deficits into
tests suitable for animal studies. The following sections
will explore how animal research on behavioral laterality
has informed the study of developmental language disorders in humans and how it may also provide clues to some
of the anomalous patterns of functional asymmetry in
patients with schizophrenia.
processes. The notion that lateralization of speech depends on left-hemisphere specialization for the processing
of rapidly changing auditory information is consistent, in
turn, with animal studies demonstrating left-hemisphere
specialization for auditory temporal processing (Dewson
et al. 1970; Dewson 1977; Petersen et al. 1978, 1984;
Heffner and Heffner 1984; Ehret 1987; Gaffan and
Harrison 1991). Thus, monkeys, mice, and rats appear to
exhibit patterns of lateralization for complex auditory discrimination similar to those seen for speech and complex
nonspeech auditory processing in humans.
It has also been shown that male, but not female, rats
exhibit an REA for the processing of rapidly presented
tone sequences (Fitch et al. 1993), a finding that is consistent with studies of humans (Brown et al., in press). These
data support the view that there are parallels between
human and animal species with respect to lateralized gender differences in the neurobiological systems underlying
language. As such, using animal models to address these
and similar issues opens the door to research questions that
are sometimes impossible to address in human clinical
research. For example, in human research it is often difficult to demonstrate directly that sex differences in behavioral laterality result from perinatal hormonal exposure.
However, a considerable literature revealing the importance of early hormonal milieu in establishing sexually
dimorphic neurobehavioral asymmetries in animals has
accumulated (Robinson et al. 1980; Brass and Glick 1981;
Ross et al. 1981; Camp et al. 1984; Zimmerberg et al.
1988; Alonso et al. 1991; Denenberg et al. 1991fc; Fitch et
al. 1993). Thus, animal models can help us understand
how and why the brains of men and women differ and
moreover may help us understand the mechanisms that
underlie the development of anomalous patterns of lateralized behavior in schizophrenia.
Convergence of human and animal research on language-related processes. Crow and colleagues have
explored the notion that disruptions of neurobiological
asymmetries during fetal life are related to the emergence
of schizophrenia in adulthood (Crow et al. 1989; Crow
1990). It has been suggested (Crow 1990, p. 433) that
there is an "intimate relationship between the disease
process and the mechanisms that determine asymmetrical
brain development." Although epidemiological studies
have demonstrated relationships between environmental
and genetic risk factors and schizophrenia (Lewis and
Murray 1987; Cannon et al. 1989; Bracha et al. 1992;
Susser and Lin 1992; Verdoux and Bourgeois 1993), the
connections between these developmental influences and
atypical patterns of laterality have not been clearly established. Preliminary evidence suggests that certain devel-
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Schizophrenia Bulletin, Vol. 25, No. 1, 1999
Laterality in Animals
opmental delays in neurobehavioral laterality may be integrally linked to the emergence of schizophrenia (Crow et
al. 1996). However, other aspects of anomalous asymmetry, such as delays in neural processing of auditory stimuli
(Javitt et al. 1993), may not be unique to schizophrenia,
but may also accompany neurodevelopmental language
and learning disorders (Stein 1994).
That neurobehavioral asymmetries in verbal memory
and language comprise the essential core of the disease
process in schizophrenia seems unlikely. However, animal and normative human research indicate that asymmetries of language and language-related processes in
patients with schizophrenia may provide the backdrop for,
and interact with, numerous other complex cognitive and
clinical characteristics. The use of animal models, such as
those used by Fitch and colleagues (1993, 1994, 1997) to
study language disorders, could provide the field of schizophrenia research with information on the contributions
of sex hormones to developing asymmetries in language.
Further research could also shed light on the degree of
shared developmental history between language laterality
and other neurobiological traits specific to the etiology of
this disorder.
severity of auditory hallucinations (Barta et al. 1990) and
thought disorder (Shenton et al. 1992; Petty et al. 1995).
Additionally, Turetsky et al. (1995) showed a correlation
between severity of negative symptoms and asymmetry of
the temporal lobe.
Sex differences have been reported in the expression
of several neuroanatomical asymmetries in patients with
schizophrenia. Cowell et al. (1996) found that degree of
deviation from the normal pattern of anatomical asymmetry was sexually dimorphic and due primarily to decrements in left temporal lobe volume in male patients.
Other laboratories have reported that the normal leftgreater-than-right asymmetry of the Sylvian fissure was
present in men, but not women, with first-episode schizophrenia (Hoff et al. 1992; DeLisi et al. 1994). By contrast, Falkai et al. (1992) showed that the left Sylvian fissure was more symmetrical relative to the right in male,
but not female, patients with schizophrenia whose average
duration of illness was 20 years. Several groups have
failed to find any disturbances in the structural laterality
patterns of their patient samples (Bartley et al. 1993;
Kleinshmidt et al. 1994; Kulynych et al. 1995; Becker et
al. 19%). As seen in the review of behavioral and cognitive asymmetries, inconsistencies in the neuroanatomical
literature suggest that complex interactions among sex
hormones and the other developmental factors contributing to variation in clinical severity and subtype may lead
to real differences in lateralized brain structure across
samples of patients with schizophrenia.
An overview of neuroanatomical asymmetries in
animals. One of the best known studies of neuroanatomic asymmetry in nonhumans is Diamond's report
of laterality in the cortical thickness of the rat (Diamond
et al. 1981). Specifically, this study reported that certain
regions of the cerebral cortex were significantly thicker in
the right hemisphere than in the left. Kolb and colleagues
provided evidence of similar patterns of cortical thickness
asymmetry in rats (Kolb et al. 1984) and in other species,
including cats and rabbits (Kolb et al. 1982).
Asymmetries have also been shown in the medial and
orbital prefrontal cortex of the rat (Van Eden et al. 1984).
Galaburda (1985a) reviewed cortical asymmetries in nonhuman primates, based on skull size and other attributes.
Length of the Sylvian fissure in monkeys appeared to
show a left-greater-than-right asymmetry (Galaburda
1985a), and asymmetry of the Sylvian fissure in cats has
more recently been shown to vary as a function of sex and
paw preference (Tan and Kutlu 1993). It is interesting to
note that sex differences in associations between Sylvian
fissure asymmetry and hand preference have been
reported in humans as well (Witelson and Kigar 1992).
Early in the study of neuroanatomical asymmetries in
animals, researchers noted that the asymmetry patterns
Neuroanatomical Asymmetries.
An overview of neuroanatomical asymmetries in
patients with schizophrenia. Abnormalities in neuroanatomical asymmetries have been found to differentiate the brains of schizophrenia patients from those of controls (Barta et al. 1990, 1997; Young et al. 1991; Breier et
al. 1992; Falkai et al. 1992; Hoff et al. 1992; Rossi et al.
1992; Shenton et al. 1992; Bilder et al. 1994; Seidman et
al. 1994; Petty et al. 1995; Wible et al. 1995; Pearlson et
al. 1997), and to distinguish among clinical subtypes of
schizophrenia patients (Turetsky et al. 1995). Some of the
most reliable effects have been decrements in the size of
structures within the left temporal lobe, including the hippocampus and amygdala (Barta et al. 1990; Young et al.
1991; Breier et al. 1992), the parahippocampal region
(Young et al. 1991), and the superior temporal gyms,
Sylvian fissure, and planum temporale (Barta et al. 1990,
1997; Falkai et al. 1992; Hoff et al. 1992; Rossi et al.
1992; Shenton et al. 1992; Petty et al. 1995; Pearlson et
al. 1997). Recent reports have also begun to focus on the
contribution of the larger right planum temporale area in
patients to the reversed asymmetry effects observed in
this region (Petty et al. 1995; Barta et al. 1997).
Clinical (Barta et al. 1990; Shenton et al. 1992; Petty
et al. 1995) and cognitive measures (Hoff et al. 1992;
Seidman et al. 1994; Nestor et al. 1995) have been correlated with anatomical features in an asymmetric fashion.
Most notably, decrements in left superior temporal gyrus
and left planum temporale were found to correlate with
47
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
RE. Cowell et al.
differed between males and females. The right-thickerthan-left pattern observed in rats was seen only in the
male cortex, whereas a trend toward asymmetry in the
opposite direction was seen in females (Diamond et al.
1981). The association between hormonal exposure and
laterality was further supported by animal research showing that patterns of cortical asymmetry were affected by
manipulations of gonadal steroids in early development
(see Diamond 1984 for review; Stewart and Kolb 1988),
and were further differentiated by exposure to prenatal
stress (Fleming et al. 1986; Stewart and Kolb 1988).
Recent research with animal models of neurodevelopmental disorder has shown that microgyric lesions performed
in infancy disrupt auditory temporal processing in adult
male, but not female, rats (Fitch et al. 1994, 1997). This
finding further supports an association between hormonal
exposure and brain injury in disabilities involving language impairment.
Convergence of neuroanatomlcal research in animals and in human populations with neurodevelopmental disorders including schizophrenia. The etiology and developmental processes underlying the various
manifestations of neuroanatomical laterality in men and
women with schizophrenia are not well understood.
However, there are many studies of both normal and
abnormal neurodevelopmental processes in humans and
animals from which general principles can be extrapolated to the study of laterality in schizophrenia. For
example, injury of the left temporal lobe during development has been put forth as an important etiologic feature
in dyslexia (Geschwind and Galaburda 1985a, 1985b;
Galaburda 1993). Similar hypotheses have been put forth
to account for the relationship between anomalous neurobehavioral asymmetries and schizophrenia (Crow 1990;
Stein 1994). To outline possible parallels between the
development of anomalous structural asymmetries in language disability and schizophrenia, the body of human
and animal research devoted to the understanding of laterality in normal and disordered language development is
discussed below.
As observed in many studies of patients with schizophrenia, normal asymmetries in the brain structures subserving language (Geschwind and Levitsky 1968;
Witelson and Pallie 1973; Wada et al. 1975; Aboitiz et al.
1992; Kulynych et al. 1994) appear to be absent or even
reversed in the majority of adult dyslexics (Galaburda et
al. 19856, 1994; Humphreys et al. 1990; Larsen et al.
1990; Duara et al. 1991) and language-impaired children
(Hynd and Semrud-Clikman 1989; Jernigan et al. 1991;
Filipek 1996 for review). Observations comparing
dyslexic and nondyslexic brains revealed a greater incidence of symmetry in the planum temporale, a part of the
temporal lobe normally found to show a left-greater-than-
right asymmetry (Geschwind and Levitsky 1968;
Kulynych et al. 1994). The notion that disruptions in the
early organization of cerebral asymmetries were central to
the pathology of development dyslexia was a primary
tenet of Geschwind's theory. He proposed that systematic
variation in the size of the left temporal lobe during normal development, mediated in part by prenatal exposure
to testosterone, determined the degree of this structure's
asymmetry (Geschwind and Behan 1982; Geschwind and
Galaburda 1985a, 1985*).
Through a combination of human and animal studies,
it was determined that the total volume of asymmetric cortical regions was smaller than the total volume of symmetric brain regions, not larger as would have been predicted
by Geschwind's theory. Re-examination of previously collected human data determined that in the normally developing planum temporale, asymmetries were more closely
related to systematic variation of the "smaller" (usually the
right) rather than the "larger" (usually the left) side
(Galaburda et al. 1987). Studies in rodents uncovered a
similar phenomenon whereby more symmetry was associated with larger total volume of cortical regions (Rosen et
al. 1989). However, mice with neurodevelopmental abnormalities failed to show this systematic relationship, revealing important clues as to possible mechanisms involved in
the development of anomalous neuroanatomical asymmetries (Rosen et al. 1989). Thus, in patients with clinical
disorders involving dysgenesis of the left hemisphere, the
disrupted relationship between brain asymmetry and brain
volume may be developmentally linked to the presence of
other more focal neural anomalies, including aberrations in
early neuronal migration patterns (Rosen et al. 1992;
Galaburda 1993).
The research of Galaburda, Rosen, and colleagues
has focused on dyslexia, but its theoretical framework and
experimental hypotheses may be applicable to other disorders, such as schizophrenia, that involve aberrant neurodevelopmental histories and abnormal neuroanatomical
asymmetries. Indeed, researchers in the field of schizophrenia are turning to concepts that were used to explain
anomalous cerebral lateralization in developmental language disorders. For example, Barta et al. (1997, p. 666)
have adopted Galaburda's (1991) notion of "lack of elimination [of neurons]" to explain phenomena such as the
larger right planum temporale area that contributed to the
reversed asymmetry in their sample of patients with schizophrenia.
The existence of focal neural anomalies in the cerebral cortex and thalamic nuclei has been demonstrated in
adults with dyslexia (Galaburda et al. 1985ft; Humphreys
et al. 1990). Particularly noteworthy is the fact that
ectopias were found more frequently in the left than in the
right cerebral hemisphere of dyslexics (Galaburda et al.
48
Laterality in Animals
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
1985i»). Focal and laminar cytoarchitectural abnormalities, representative of disturbances in neural migration
during development, have also been found in the brains of
patients with schizophrenia (Benes et al. 1986; Jakob and
Beckman 1986; Arnold et al. 1991; Benes 1995; Arnold
and Trojanowski 1996). Consistent with Galaburda et
al.'s study of dyslexics (19856), Jakob and Beckman
(1986) found more disturbances in the distribution of cortical neurons of the left hemisphere than in the right in
postmortem specimens of patients with schizophrenia.
Current animal research is addressing the questions
of how focal neural anomalies arise, how they relate to
atypical asymmetry, why behavioral deficits associated
with language impairment and dyslexia occur more frequently in males than females, and how the neural anomalies translate into behavioral deficits. For example,
ectopias that naturally occur in the brains of certain inbred
mouse strains and that have been surgically induced in
neonatal rodents have been related to patterns of spatial
navigation performance (Denenberg et al. 1991a, 1991fc;
Rosen et al. 1995; Waters et al. 1997), lateralized paw
preference (Rosen et al. 1995), and sex differences in
auditory processing similar to those observed in humans
with developmental reading and language impairments
(Fitch et al. 1994, 1997). This body of animal research
supports the generalizations that (1) at least some neurodevelopmental disorders are characterized by perinatal
insult to the brain, (2) the incidence of focal injury may in
turn influence or be associated with atypical asymmetry,
and (3) males appear to be at greater risk for these insults
and their behavioral consequences (Gualtieri and Hicks
1985; Liederman and Flannery 1993; Goldstein et al.
1994).
Thus, considerable overlap between the constellations of neurobehavioral traits associated with developmental language disorders and schizophrenia can be seen
(e.g., elevated incidence of perinatal brain insult, sex differences in the expression of the disorder, cytoarchitectural and neuromigrational disturbances, anomalous symmetry in language regions of the brain, and abnormal
patterns of lateralized brain activity in language regions).
Therefore, animal models used to study these phenomena
in language disabilities could be modified to shed much
light on the study of neurodevelopmental processes specific to disrupted laterality in schizophrenia.
potential neurofunctional correlate of previously studied
behavioral asymmetries. With the development of modern neuroimaging techniques, researchers have access to
an even broader methodological base from which to collect data on neurochemical and neurophysiological laterality. Lateralized neurophysiological disturbances have
been noted from the level of blood flow and brain metabolism (Calabrese et al. 1992; Siegel et al. 1993; AlMousawi et al. 1996; Harper Mozley et al. 1996) to the
level of neurotransmitter binding (Joyce et al. 1992; Pedro
et al. 1994; Pilowsky et al. 1994). Consistent with evidence from behavioral studies that suggested dysfuctionality of the left temporolimbic system (Flor-Henry 1976;
GUT 1977, 1978; Bracha 1987; Cannon et al. 1994; Saykin
et al. 1994), much neurophysiological work has also
demonstrated abnormalities in left temporal lobe structures (Reynolds and Czudek 1987; Calabrese et al. 1992;
Faux et al. 1993; Javitt et al. 1993; Nishino et al. 1993;
Siegel et al. 1993).
Studies of neurotransmitter function have located
abnormal asymmetries in striatal dopamine D 2 receptor
binding in male patients with schizophrenia (Pilowsky et
al. 1994). Pedro et al. (1994) demonstrated that asymmetry of striatal D 2 receptor binding levels was correlated
with neuropsychological measures of stereotypy in
patients with schizophrenia, but not in controls. In addition to lateralized abnormalities in resting brain activity
(Early et al. 1987; DeLisi et al. 1989; Gur et al. 1989;
Wilson and Mathew 1993), abnormal patterns of asymmetry in task-activated blood flow have also been demonstrated (Gur et al. 1983, 1985, 1994; O'Leary et al. 1996).
Studies have revealed abnormal patterns of asymmetrical
brain activity in language regions of patients experiencing
hallucinations (Cleghorn et al. 1992). In addition, anomalous lateralized brain activity has been associated with
measures of clinical severity (Mathew et al. 1982; Gur et
al. 1989; Shenton et al. 1989), verbal ability (Harper
Mozley et al. 1996), auditory attention deficits (O'Leary
et al. 1996), and therapeutic response to clozapine
(Molina Rodriguez et al. 1996). As with the behavioral
and neuroanatomical asymmetries, there appears to be
evidence of complex clinical and cognitive relationships
among lateralized neurophysiological phenomena in
schizophrenia. Not surprisingly, sex differences have
been found in lateralized brain activity using measures of
task-activated blood flow (Gur et al. 1983, 1985; Gur and
Gur 1990) and MRI (Reite et al. 1997).
An overview of neurochemical and neurophysiological laterality in animals. A broad range of lateralized neurochemical and neurophysiological phenomena
have been investigated in animals. Asymmetries in brain
dopaminergic systems have been studied with respect to
various dimensions of lateralized behavior in rodents
Neurochemical and Neurophysiological Asymmetries.
An overview of neurochemical and neurophysiological asymmetries in patients with schizophrenia.
Analysis of postmortem brains showed that dopamine
concentrations in the left amygdala of patients with schizophrenia were elevated compared with controls (Reynolds
1983; Reynolds and Czudek 1987), thus providing a
49
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
RE. Cowell et al.
(Robinson et al. 1980; Jerussi and Taylor 1982; Camp et
al. 1984; Whishaw et al. 1986; Cabib et al. 1995; Carlson
al. 1996). For example, higher dopamine concentrations
were found on the side of the striatum contralateral to the
direction of amphetamine-elicited circling behavior in
female rats when neurochemical assays were performed
directly (Glick et al. 1979; Robinson et al. 1980), but not
at 1 month after behavioral testing (Camp et al. 1984).
Cabib et al. (1995) studied mice and found that patterns of
lateralized paw reaching for food were also associated
with asymmetries in dopamine function, but in the
nucleus accumbens. Additional asymmetries have been
noted in the neurotransmitter (Rosen et al. 1984; Guarneri
et al. 1988; Mclntyre et al. 1988; Barneoud et al. 1990;
Rodriguez et al. 1990) and neuroendocrinological systems
(Nordeen and Yahr 1982; Sholl and Kim 1990; von
Ziegler and Lichtensteiger 1992) of the mammalian brain.
Much of the research on asymmetries of neurotransmitter systems in the animal brain has been directed
toward the investigation of sex differences (Robinson et
al. 1980; Ross et al. 1981; Denenberg and Rosen 1983;
Camp et al. 1984; Lipsey and Robinson 1986). The
brains of male and female rats have consistently been
found to differ with respect to the neurochemical substrates of behavioral laterality. For example, Camp et al.
(1984) found that asymmetries of motor behavior and
measures of brain dopamine were different in males and
females and that early handling experience affected both
brain and behavioral asymmetries in a sexually dimorphic
fashion. In addition, direct evidence for the effects of
gonadal hormones on the activation of amphetamineinduced rotational asymmetries and related neurochemistry has been demonstrated in the female rat. Becker and
colleagues (Becker and Cha 1989; Castner and Becker
1990) reported that endogenous, or exogenously administered, pulsatile estrogen potentiated the dopaminergic and
behavioral response to amphetamine in female, but not
male, rats. This sex difference appeared to emerge at
puberty through changes in the response of female striatal
tissue to estrogen and provides some insight as to the possible mechanisms that may contribute to sex differences
seen in lateralized neurocognitive relationships in patients
with schizophrenia.
The interactive effects of sex hormones on dopamineinduced behaviors and D 2 receptor sensitivity have also
been studied in rats to specifically model mechanisms
underlying sex differences in patients with schizophrenia
(Hafner et al. 1991, 1993). The authors showed a strong
modulatory effect of estrogen on dopamine and related
behaviors in female rats (Hafner et al. 1991, 1993) but did
not investigate the relationships between these effects and
behavioral and neurochemical asymmetries. Hafner's
model would provide an excellent animal preparation for
studying the effects of hormones on the behavioral and
neuropharmacological asymmetries associated with schizophrenia.
A convergence of neurochemical and neurophysiological asymmetry in animals and in patients with
schizophrenia. The studies of the Gurs and their colleagues have focused on how asymmetries in resting and
task-activated blood flow vary as a function of sex in
schizophrenia (Gur et al. 1983, 1985; Gur and Gur 1990).
They found that verbal and spatial processing differentially activated the left and right hemispheres in male and
female patients. In anterior cortical regions, men with
schizophrenia had higher left-hemisphere activity than
control men at rest and during a verbal task. Male
patients also lacked the overall increase and right-hemisphere lateralization in brain activity during a spatial task.
In the posterior cortical regions, control women had symmetric resting activity, greater left activity for the verbal
task, and greater right activity for the spatial task, whereas
women with schizophrenia had higher activity in the left
hemisphere for all three conditions. Furthermore, lateralized effects of medication were noted only in men (Gur et
al. 1985). The complexity of results from such studies
demonstrates the need for animal experiments that
address and manipulate the neurodevelopmental and neuropharmacological factors underlying sexually dimorphic
asymmetries in the brain-behavior relationships associated with schizophrenia.
Many of the behavioral and cognitive measures used
to study lateralized brain function in men and women
with schizophrenia have parallels in the study of neurobehavioral asymmetries in animals. The following studies
elucidate behaviors that could be applied toward the
development of animal models for investigating lateralized neurocognitive function in human patients. With
respect to lateralized verbal processing, research with
nonhuman primates has shown left-hemisphere specialization for discriminating species-specific coo sounds
(Petersen et al. 1978, 1984; Heffner and Heffner 1984)
and matching noise and tone bursts of varying duration
and spoken words to visual stimuli (Dewson et al. 1970;
Dewson 1977; Gaffan and Harrison 1991). In mice, a
left-hemisphere advantage for discriminating ultrasonic
pup calls from ultrasonic noise bursts has been reported
(Ehret 1987), and in rats, left-hemisphere specialization
for discriminating two-tone sequences has been demonstrated for males but not females (Fitch et al. 1993). With
respect to visuospatial processing, preliminary evidence
of right-hemisphere specialization has been found in monkeys by using tachistoscopic tests of line abstraction
(Hopkins et al. 1990) and in dolphins by using reaction
time to objects presented to the right versus the left eye
(MoiTel-Samuels et al. 1990). Furthermore, superior per-
50
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
Laterality in Animals
formance in spatial navigation has been associated with
use of the right hemisphere in male rats (Crowne et al.
1992; King and Corwin 1992; Maier and Crowne 1993;
Cowell et al. 1997). These primate and rodent experiments could be adapted to model the lateralized task-activated brain activity seen in humans. The obvious advantage of animal studies is that the effects of early brain
insult, perinatal risk, genetics, immune status, and hormone exposure could be systematically altered. Such
studies would be ideal for gaining insight into the developmental, hormonal, and neurochemical factors that differentiate the lateralized patterns of task-activated brain
activity in schizophrenia patients from those of normal
controls.
With respect to neurochemical correlates of schizophrenia, most animal models have not addressed the issue
of laterality. One study that did study right-left differences
found that haloperidol had asymmetrical effects on rotation-related nigrostriatal dopamine metabolite concentrations in rats (Jerussi and Taylor 1982). These authors suggested that by "dampening excess dopaminergic activity
in the dominant hemisphere or increasing activity of the
other, neuroleptics may restore a normal balance, or
imbalance, between the two halves of the brain" (Jerussi
and Taylor 1982, p. 73). A similar notion has been
applied to interpret the influences of drug treatment on the
brain-activation patterns of patients with schizophrenia.
For example, clozapine has been shown to normalize striatal and frontal lobe asymmetries in resting glucose
metabolism by increasing activity of the right basal ganglia and by decreasing the activity of the left frontal lobe
(Potkin et al. 1990). Also, regional brain perfusion patterns of patients who responded to clozapine treatment
differed in a lateralized fashion from their own pretreatment patterns and also from perfusion patterns of normal
controls and clozapine nonresponders (Molina Rodriguez
et al. 1996). Rodent models have been used to study the
neuropharmacology of haloperidol and clozapine (Lipska
and Weinberger 1994; Moghaddam 1994) and would provide ideal preparations for investigating the lateralized
effects of such drugs.
1995). The findings of this research suggest that medial
prefrontal involvement after puberty is a delayed effect of
neonatal hippocampal lesions. However, laterality effects
were not systematically examined (Lipska et al. 1993;
Lipska and Weinberger 1994, 1995).
The paradigms used by Lipska and colleagues, which
model schizophrenia using a developmental design and
multidimensional biobehavioral approach, could serve as
the basis for future investigations of laterality. Such
research would involve prepubertal and postpubertal
assessments of lateralized behavior and brain function in
rats that were given left, right, or bilateral hippocampal
lesions in early life. The results could then be used to draw
parallels with patterns observed in samples of patients with
schizophrenia. The behavioral battery might incorporate
techniques used by researchers such as Cabib, Carlson,
and colleagues (Cabib et al. 1995; Carlson et al. 1996),
who have investigated the contributions of asymmetries in
brain dopamine systems to both lateralized and nonlateralized behaviors. This type of detailed study could help elucidate some of the complex relationships among the various measures of abnormal behavioral asymmetry seen in
schizophrenia (Sakuma et al. 1996). Lipska and colleagues' developmental lesion model could be further
applied to the study of the lateralized "language-related"
and visuospatial processing measures discussed earlier in
this section. Groups of animals that varied as a function of
sex, early hormone manipulations, prenatal stress, early
environment, and genetic factors could be systematically
studied. Neuropharmacological manipulations, such as
those applied by Lipska and Weinberger (1994), could
then be examined with respect to laterality, developmental
history, and individual differences.
Conclusions
The animal literature strongly supports the view that both
normal and disrupted patterns of functional and structural
laterality observed in adulthood have their basis in early
development. Given the parallels between the anomalous
laterality patterns in the brains and behaviors of patients
with schizophrenia, and animals exposed to certain early
environmental conditions, it is surprising that animal
models have not been used more frequently to study the
lateralized neurobehavioral systems involved in this disorder. Changes in neurobehavioral laterality may seem trivial in comparison to the vast number of complex clinical
and neurobiological disturbances associated with schizophrenia. Despite the possibility that basic neurobiological
asymmetries may have profound influences on other more
complex functions, many researchers continue to examine
higher order neurocognitive functions in patients with
Lipska and colleagues (1993) have used rats to study
the development of the neurochemical, neuropharmacological, and behavioral phenomena that emerge after puberty
following neonatal lesions to the ventral hippocampus.
These experiments were designed to investigate a "constellation of major phenomena associated with schizophrenia"
(Lipska et al. 1993, p. 67) by modeling the anomalous
development of behavioral hyperresponsiveness to stress,
related changes in the mesocorticolimbic dopaminergic
system, and the differential effects of genetic background,
haloperidol, and clozapine on these neurobehavioral measures (Lipska et al. 1993; Lipska and Weinberger 1994,
51
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
RE. Cowell et al.
schizophrenia without regard for the influence of laterality
effects. Although our understanding of the interactions
between laterality, hormonal exposure, genetics, immune
status, and neurodevelopmental disorders is by no means
complete, the research described herein demonstrates that
animal research can provide important insights into some
of the environmental conditions and developmental mechanisms that may influence the origins and expressions of
anomalous lateralized phenomena seen in patients with
schizophrenia.
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Conformation of reduced temporal limbic structure volume on magnetic resonance imaging in male patients with
schizophrenia. Psychiatry Research:
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67:135-143,1996.
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