Structural Asymmetries of the Human Brain and
Their Disturbance in Schizophrenia
fry Richard Q. Petty
the degree of asymmetry is what misled earlier investigators to think that asymmetry of the nervous system was
not present in other organisms. (Other asymmetries—for
instance, one claw of the blue crab being larger than the
other—have long been known.) It has also become clear
that asymmetry is not found only in the cortex, but also in
many subcortical structures, presumably reflecting their
close interrelationships.
The apparent ubiquity of cerebral asymmetry among
animal species raises a number of important questions, a
detailed discussion of which lies outside the scope of this
article. Similarly, we must omit an exploration of the possible reasons for these asymmetries. For the interested
reader we recommend a recent review by Lent and
Schmidt (1993).
The objective of this article is to examine the current
evidence concerning the normal structural asymmetries of
the brain, then move to a discussion of the disturbances of
these structural asymmetries in schizophrenia. While this
review deals with the evidence concerning structural
asymmetries that have been revealed by neuroimaging, in
normal individuals and in those with schizophrenia, the
data must clearly be placed in the broader context of
asymmetries discovered from other sources, including
anatomy, paleontology, and biochemistry. We would also
stress at the outset that the unbridled enthusiasm of the
1970s for unequivocal differentiation of hemispheric
structure and function has given way to an appreciation of
the fundamental reciprocity between the hemispheres
(Gruzelier 1981; Nass and Gazzaniga 1989; Efron 1990).
Abstract
Asymmetries of the brain have been known about for
at least a century, but they have been explored in
detail only relatively recently. It has become clear
that, although different asymmetries are common
throughout the animal kingdom, they are most
marked in the human brain. Disturbances in asymmetry are particularly striking in patients with schizophrenia and perhaps all psychotic illnesses, and may
provide the neurological substrate for the etiology and
clinical manifestations of the illness.
Key words: Structural asymmetries, functional
asymmetries, laterality.
Schizophrenia Bulletin, 25(1): 121-139,1999.
The two hemispheres of the human brain and their interactions have intrigued scientists and philosophers for centuries. Although functional asymmetries—the simplest
being handedness—have been known for millennia, it is
only within the last 150 years that it has gradually become
clear that there are also structural differences between the
two sides of the brain. However, as recently as 1929, a
comparative study of endocranial casts (endocasts) of
modern and prehistoric man and of anthropoid apes found
no marked cerebral asymmetries (Weil 1929). Until relatively recently, it was usually held that only humans
exhibited structural asymmetries, but increasing evidence
indicates that structural lateralization is common among
such disparate nonhuman species as birds, monkeys, and
apes (for a review, see Bradshaw 1991). Furthermore,
there is impressive evidence that structural asymmetries
are to be found far back in evolution: studies of a 600million-year-old Cambrian fossil, the calcichordate
Gross Anatomical Asymmetries
The developing brain already shows marked asymmetries
by the second trimester of pregnancy. The cortical fissures
are consistently found to appear earlier in the right hemisphere (Dooling et al. 1983; Nowakowski 1987), and the
Placocystites forbesianus—a primitive forerunner of
some vertebrates—appear to show clear evidence of caudal asymmetry (Jefferies and Lewis 1978). Indeed, it may
be that asymmetry is the rule. However, it is also clear
that the greatest degrees of structural laterality are to be
found in the human brain. Presumably, this increase in
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Schizophrenia Bulletin, Vol. 25, No. 1, 1999
most marked asymmetry in the brain, that of the planum
temporale, has been identified in fetal brains (Wada et al.
1975; Chi et al. 1977) and in the majority of infants
(Witelson and Pallie 1973). This structure is of great
importance in health and perhaps also in schizophrenia.
The earliest studies of structural asymmetries of the
brain concentrated on indices such as the weight and volume of the hemispheres, the relative proportions of gray
and white matter, and the differences in the thickness and
folding of the cortex on the two sides. Perhaps because of
the limited technologies employed, few differences were
found. However, there were some reports of reproducible
asymmetries. Eberstaller (1884) and Cunningham (1892)
both described asymmetries in the posterior ends of the
Sylvian (lateral) fissures, the left reaching further back
and being more horizontal. These findings have been
confirmed using arteriography (LeMay and Culebras
1972) and computed tomography (CT) scanning (Rubens
et al. 1976; LeMay and Kido 1978). It has also become
clear that the distribution of this asymmetry is related to
handedness (Hochberg and LeMay 1975).
Before these contemporary confirmations, it had been
assumed that the longer left Sylvian fissure was a consequence of larger temporal and parietal opercula, which
form, respectively, the floor and roof of the posterior fissure. This was partially confirmed by Pfeiffer (1936),
who demonstrated a larger left temporal operculum.
Additionally, he made the observation that the left planum
temporale (PT) was larger on the left The PT is a triangular area lying on the superior surface of the superior
temporal gyrus, between Heschl's transverse gyms (the
primary auditory area) and the most posterior portions of
the Sylvian fissure. This finding was confirmed in elegant
studies that also showed the left PT to be larger on the left
side in 65 percent of brains, approximately equal in 24
percent and larger on the right in 11 percent (Geschwind
and Levitsky 1968). This distribution of PT asymmetry
has since been confirmed many times (Teszner et al. 1972;
Witelson and Pallie 1973; Wada et al. 1975; Kopp et al.
1977).
With the advent of sophisticated neuroimaging techniques, it has proven possible to identify the PT on magnetic resonance imaging (MRI) scans, and once again the
asymmetry has been confirmed (Steinmetz et al. 1989),
together with the new observation that the relative dimensions of the PT on the two sides are related to handedness
(Steinmetz et al. 1991; Barta et al. 1997). The left PT may
be as much as 10 times larger than the right, greater than
any other asymmetry anywhere else in the human brain
and far outstripping any asymmetries observed in other
species so far examined. There are other differences in the
PT on the two sides, the most striking being the existence
of one or more additional transverse gyri (Pfeiffer 1936;
Campain and Minckler 1976). These findings have been
confirmed in the fetus: The PT develops between the 29th
and 31st weeks of gestation (Chi et al. 1977),
There is ample reason for taking a special interest in
this region of the brain. Not only is it the most highly lateralized so far identified, but it also contains a portion of
the heteromodal association cortex responsible for the
comprehension and generation of language (Galaburda et
al. 1978, 1987, 1990; Galaburda and Sanides 1980;
Leinonen et al. 1980; Galaburda 1993). This same system
is involved in a number of other major cognitive functions, including working memory (Mesulam 1985;
Goldman-Rakic 1987, 1990). The PT is also the typical
site of injury in patients with Wernicke's aphasia.
Taken together, these observations suggest an intimate association between the anatomical asymmetry of
this discrete region of the brain and the functional localization of much language activity to the left hemisphere.
Attention has also been drawn to the incidence of asymmetries of the PT and the incidence of hand skill in the
population (Annett 1992). It is of note that similar asymmetries in this region have been identified in the chimpanzee (Yeni-Komshian and Benson 1976). One major
problem remains, however, that is of general importance
in any discussion of sizes and volumes of structures in the
brain. It is the problem of generating a precise definition
of what constitutes the PT. This point has recently been
explored in some detail (Galaburda 1993; Barta et al.
1995).
In the frontal lobe, the size of the regions involved in
language are, in both fetal and adult brains, paradoxically
smaller in the left hemisphere than in the right, if measured only according to the visible surface area (Wada et
al. 1975). However, over a century ago, Eberstaller
(1884) noted that regions around the frontal operculum, a
component of Broca's (the anterior language) area, are
more convoluted—hence, probably larger—on the left.
These findings have received support using contemporary
methodologies (Falzi et al. 1982).
A number of other asymmetries have been noted in
the brain, particularly through the use of radiological
methods. Furthermore, the study of "endocasts"—the
impression that the brain leaves on the inner surface of the
skull—has made it possible to make inferences about the
shape of the brain of ancient man and nonhuman anthropoids. Thus it has become feasible to make deductions
about the evolution of cerebral dominance. This is significant, because the structural organization of the brain is of
greater importance than just its size (Holloway 1968).
The endocast of a Neanderthal dated at approximately
50,000 years old showed the pattern of Sylvian fissure
asymmetry characteristic of modern man (Boule and
Anthony 1911; LeMay and Culebras 1972). More re-
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"balanced asymmetry" in the horizontal plane. Apart
from the association of the normal torque pattern and
handedness and the "balanced asymmetry," other gross
morphological asymmetries are associated with some
measures of functional asymmetries, notably speech lateralization and handedness both in vivo (Ratcliff et al.
1980) and at postmortem (Witelson 1983; Witelson and
Kigar 1992).
Similar asymmetries are also seen in apes and to a
lesser degree in some monkeys (LeMay 1976; Holloway
and De La Coste-Lareymondie 1982). In a study of photographs of 28 higher apes, the human pattern with a
higher right Sylvian fissure was present in 16 and the
higher left in only 1 (LeMay and Geschwind 1981).
Similarly, an examination of ape and monkey endocasts
has shown that the apes resemble humans, as, to a lesser
extent, did Old World monkeys. However, there were few
asymmetries in New World monkeys, with the exception
of the protrusion of the left occipital region relative to the
right (LeMay 1976).
With the advent of radiological techniques, it has
become clear that there are a number of asymmetries in
the brain. The first to be identified were ventricular asymmetries, shown by pneumoencephalography (PEG). The
left lateral ventricle is usually (in ~ 70%) wider than the
right, particularly anteriorly and in the tips of the temporal
horns (LeMay 1984). Earlier observations derived from
casts of the ventricles made after death had shown the left
lateral ventricle to be larger in only 48 percent (Last and
Thompset 1953). However, for purely technical reasons it
is likely that the higher value would be correct. Indeed, a
study of computed tomography (CT) scans of 100 normal
adults again showed the left lateral ventricle to be wider
than the right in 62 percent, with the right wider in 32 percent. In addition, males showed a greater difference
between the measurements on the two sides (Gyldensted
1977).
Both the shape and the size of the lateral ventricles,
particularly the occipital horns, show a correlation with
the shape and size of the brain and the skull (Bailey 1936;
Berg and Lonnun 1966). When fetal brains were examined at post mortem, it was found that the occipital horns
occupied a much larger proportion of the overall ventricular volume than they do later in life (Curran 1909). It
appears that as the brain increases in size, even after birth,
the occipital horns become relatively smaller and more
asymmetrical. Ventricular asymmetries are quite clear by
the end of the first year of life (Lodin 1968), although
there are no data on whether there are gender differences
in the magnitude or timing of the development of this
asymmetry. In a PEG study of 100 right-handed adults,
the left occipital horn was longer in 60 percent, and the
right in 31 percent (McRae et al. 1968). When the same
markable still is a similar finding in Peking Man dated
over 500,000 years ago (Shellshear and Smith 1934). If
we remember that the common explanation for the differences between the two sides is that it resulted from the
growth of areas of the brain responsible for language, a
possible implication is that language may have developed
earlier in evolution than is normally assumed
(Kochetkova 1978).
There are no clear effects of ethnic origin on brain
asymmetries (Hrdlicka 1907). In a study of 297 East
African skulls, the right frontal and left occipital regions
of the brain protruded beyond the corresponding structures on the opposite sides (Gundara and Zivanovic
1968). These protrusions are known as petalias. The
most characteristic pattern, a more protruding right frontal
lobe, is termed right fronto-petalia. It is typically associated with a greater protrusion and width in the left occipital lobe—left occipito-petalia. This protrusion in normal
adults is a reflection that the left occipital lobe and the
right frontal lobes are larger than their counterparts in the
opposite hemisphere (LeMay and Kido 1978; Pieniadz
and Naeser 1984). This is referred to as "counterclockwise" or "Yakovlevian" torque, and it is most marked in
right-handers. These characteristics are certainly present
at 32 weeks gestation (LeMay 1984) and are reflected in
gross volumetric measures of the frontal and occipital
regions (Weinberger et al. 1982). In studies of the brains
of early humans, it appears that this characteristic pattern
was also present 100,000 years ago.
The most marked asymmetries of the cerebral hemispheres are found posteriorly. This is the major component of the normal torque. Associated with this is usually
a greater protrusion of the outer margin of the left occipital bone, compared with the right (Smith 1907). In association with this greater left-sided posterior extension, the
ipsilateral thalamus and choroid plexus (when it can be
seen due to calcification of the glomus) also lie posterior
to those on the right (LeMay 1976). The left occipital
petalia is associated with a more posterior positioning of
the splenium, longer temporal horn, and cerebellar protrusion, all on the same side (Hadziselimovic 1980). Since
the early part of this century, attempts have been made to
relate the shape of the head, and particularly of the petalias, to handedness (Smith 1907, 1908), but with only limited success. The development of progressively more
sophisticated methods of analyzing MRI data (e.g., Falk
et al. 1991) is revealing a number of patterns that appear
to be typical. In addition to the now familiar counterclockwise torque, there appears to be a leftward asymmetry of the temporal back of the caudal portion of the infraSylvian surface. This is balanced by a rightward
asymmetry of the parietal bank (Loftus et al. 1993). The
pattern can be best visualized in three dimensions as a
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R.G. Petty
investigators examined a group of patients with epilepsy,
they found a striking deviance from the normal pattern,
with equal lengths in 60 percent of right-handers and 38
percent of left-handers, suggesting an abnormality of
brain development or possibly some other insult to the
brain. Similar findings were reported in young children.
The left occipital horn was longer in 60 percent, but in
those who had developed epilepsy before the age of 1
year, the two sides were either symmetrical or the right
was longer (Strauss and Fitz 1980).
The association of structural and functional asymmetries has received increasing attention. We have already
referred to the typical Yakovlevian torque being more
accentuated in right-handers and to the interactions
between handedness and the structure of the corpus callosum (Witelson 1989) and the Sylvian fissure (Witelson
and Kigar 1992). Frequently, however, there have been
limitations in the analysis of handedness (Chapman and
Chapman 1987; Bryden and Steenhuis 1991), in the interpretation of structural data, or in controlling for gender or
for the presence of diseases that might affect the brain.
Clearly, there are also individual differences in brain
asymmetries and fiber composition in the corpus callosum, implying the need for large studies to segregate the
relationships between handedness and callosal structure
(Abbitiz et al. 1992). A CT study of children, 71 percent
of whom had epilepsy, clearly demonstrated significant
structural asymmetries, but these did not correlate with
measures of handedness (Deuel and Moran 1980).
However, examination of the presented data reveals technical difficulties in the interpretation of the scans, and as
we have already seen, epilepsy may be associated with a
disturbance of the normal pattern of brain asymmetry.
doubt, A more challenging question is whether hormones
themselves or the sex chromosomes may affect the structure of the brain. In 1879, Crichton-Browne wrote that
"the tendency to symmetry in the two halves of the cerebrum is stronger in women than in men" (p. 53). Although
there are wide variations, there does indeed seem to be a
true sexual dimorphism in the asymmetry of the brain
(Bear et al. 1986). The hypothesis that prenatal exposure
to testosterone could be responsible for differential rates of
brain maturation and asymmetry has, as intended, generated considerable interest and debate, although no firm
conclusions (Geschwind and Galaburda 1984).
The gross structure of the brain appears to be the
same in males and females, with the exception of size differences, which appear themselves to be a function of
height rather than gender (McGlone 1980; Janowsky
1989). However, a number of lines of evidence indicate
gender differences in the maturation of the fetal and
young child's brain. Furthermore, there is some evidence
of gender differences in a number of neuropsychological
tasks ascribed to different hemispheres (for a review see
Halpern 1992). There is evidence in favor of these differences being genetically determined. On tests of intelligence, patients with Turner's syndrome (XO) have performance deficits relative to verbal, which are consistent
with right hemisphere dysfunction (Netley and Rovet
1982), and maldevelopment of heteromodal association
cortex in the right hemisphere (Christensen and Nielsen
1981). By contrast, patients with an extra X chromosome—Klinefelter's syndrome—and triple X syndrome
have verbal deficits or delays, while their performance IQ
tends to be in the normal range, suggesting left hemisphere dysfunction (Netley 1986).
The most important conclusion from a number of
studies has confirmed Crichton-Browne's observation that
the male brain is indeed more symmetrical than the
female. It has also become clear that the corpus callosum
is larger in women, particularly in its more posterior parts
(Witelson 1989; Kimura 1993), and that there are, in the
callosum, marked interactions between gender and handedness (Cowell et al. 1993). It has been suggested that a
larger corpus callosum is associated with better interhemispheric transfer of information, which might contribute to
the statistically superior verbal fluency in women (Hines
1990). This gender difference in the corpus callosum may
be relevant to the symptomatology of schizophrenia and
the different clinical expressions of the disease in men and
women. There are structural abnormalities in the corpus
callosum in schizophrenia (Woodruff et al. 1993),
although it is not yet known whether these abnormalities
are modulated by gender. Several authors have found evidence of abnormalities in callosal transfer in schizophrenia, but the precise nature of this remains the subject of
In addition to these regional differences, there are
more generalized interhemispheric differences. The ratio
of gray to white matter is smaller in the right hemisphere.
The greater amounts of gray matter on the left are primarily in the motor, premotor, and primary sensory area (Gur
et al. 1980). These findings are consistent with the assertion that the left hemisphere is focally organized, whereas
the right is more diffusely organized (Semmes 1968).
Data from a variety of sources indicate that hemispheric
differences can be best understood in terms of specific
principles that are relevant to defined cognitive functions.
So the left hemisphere is superior at encoding visual categories, but the right is better at representing overall visual
patterns (Brown and Kosslyn 1993).
Gender and Asymmetries of the
Nervous System
That there are hormonal influences on the brain is not in
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Schizophrenia Bulletin, Vol. 25, No. 1, 1999
considerable debate. Although there does appear to be
good evidence of structural difference in male and female
brains, particularly in more asymmetrical structures, this
theory has not found universal acceptance. For instance
Janowsky (1989) has argued that we do not know enough
about the composition of neural networks to conclude that
these structures are actually different in males and
females.
One of the most contentious issues in neurobiology is
the reported association between sexual orientation and
brain structure. For instance, Allen and Gorski (1991,
1992) have reported that the size of the anterior commissure varies with sexual preference. A further interesting
report showed an alteration of functional cerebral asymmetry during the menstrual cycle (Heister et al. 1989).
Dopamine is lateralized, and it is also modulated by estrogens; this may indicate a relationship between structure,
neurochemistry, and hormones that could be relevant to
the differing clinical presentations of schizophrenia in
men and women. It may also be relevant that there are
structural and functional neuroendocrine asymmetries in
the brain (Wittling and Schweiger 1993), as well as an
interrelationship between cortical and autonomic asymmetries, both of which may have structural as well as
physiological bases (Gallhofer et al. 1993; ShannahoffKhalsa 1993; Velikonja et al. 1993). These observations
may be significant in view of the frequent observations of
disturbances in autonomic, endocrine, and immunological
function in schizophrenia.
the most consistent asymmetries have been identified in
regions of heteromodal association cortex involved in language. For instance, von Economo and Horn (1930)
showed that left-sided auditory association cortex, which
lies largely within the PT, is consistently larger on the left
side. A series of studies by Galaburda and his collaborators have confirmed and extended these findings
(Galaburda et al. 1978, 1987, 1990; Galaburda and
Sanides 1980; Galaburda 1993). These asymmetries are
not confined to histology. In area Tpt, which occupies a
major portion of the PT and of the adjacent superior temporal gyms, there is a consistent increase in the amount of
choline acetyltransferase on the left (Amaducci et al.
1981). Further left-preponderant asymmetries have been
identified in the inferior parietal lobule, another portion of
the heteromodal association cortex with prominent language functions (Eidelberg and Galaburda 1984).
As might be anticipated, there is also an asymmetry
of regions of the brain that enjoy close connections with
these language-specific regions. The posterior thalamus
appears to be relevant to language functions (Bell 1968;
Geschwind and Galaburda 1984; Ojemann 1991). It is
usually the pulvinar that is implicated, but adjacent nuclei
probably also participate in language. One of these—the
lateralis posterior nucleus of the thalamus—is larger on
the left, but only in individuals with a larger left PT
(Eidelberg and Galaburda 1982). This nucleus does project to the inferior parietal lobule (Geschwind and
Galaburda 1984). More recently a unique population of
large neurons has been identified in the left hemisphere.
These lie in layer III of the anterior language area
(Brodmann's area 45), providing further support for a
structural asymmetry in a region with marked functional
lateralization (Hayes and Lewis 1993).
It is striking that the most marked asymmetries are
found in the PT and planum parietale (Jancke et al. 1994)
and in parts of the dorsolateral prefrontal cortex. All of
these lie within one of the most phylogenetically recent
portions of the brain: a widely distributed but highly interconnected system—the heteromodal association cortical
regions of the cerebral cortex. These appear to provide
the neurological substrate for higher functions of language, thinking, and ideation.
An interaction between sex hormones and laterality
was first suggested by Geschwind and Galaburda (1984;
pp. 211-224). A later, refined version of this hypothesis
posits that lower amounts of testosterone in the fetal
female brain lead to less regression in the tempero-parietal region of the left hemisphere, with a consequently
larger callosal isthmus. This, in turn, results in less functional asymmetry (Witelson 1991).
Crow (1993) has woven a number of different observations into an ingenious hypothesis linking the different
ages at onset of schizophrenia in males and females with,
among other things, the gender differences in asymmetry.
He has also correctly predicted that normal asymmetry
would be disturbed in schizophrenia. These concepts are
very important and will be discussed in greater detail
later.
Structural Asymmetries Below the Tentorium. It has
become quite well recognized that asymmetries are found
at several levels of the nervous system. The decussation
of the pyramids is asymmetrical in both fetal (Yakovlev
and Rakic 1966) and adult human brains (Kertesz and
Geschwind 1971). A further common asymmetry has
been described in the lower medulla: an aberrant circumolivary bundle that may be involved in the innervation of
some muscles of articulation (Smith 1904).
Asymmetries of the Cellular
Organization of the Brain
Many architectonic asymmetries have been identified in
the brain. While an examination of these lies outside our
immediate field of interest, it is important to be aware that
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Neurochemical Asymmetries.
R.G. Petty
We have already
the observation that unmedicated patients perform poorly
on tasks typically ascribed to the right hemisphere, such as
sorting shapes. However, treatment reverses the side of
the deficit (Tomer and Flor-Henry 1989). These observations are suggestive of an antipsychotic-induced inhibition
of function in the right hemisphere.
referred to the asymmetry of choline acetyltransferase
activity in the superior temporal gyrus (Amaducci et al.
1981). In addition, the left pulvinar contains more norepinephrine than the right (Oke et al. 1978). Postmortem
analysis of neurotransmitters is notoriously difficult.
Nevertheless, studies have indicated further left-right
asymmetries in the content of dopamine, glutamic acid
decarboxylase, and gamma aminobutyric acid in the basal
ganglia (Glick et al. 1982). Possible doubt about the
validity of these findings has been allayed by discoveries
of similar biochemical asymmetries in the rat (Carlson
and Glick 1989). These asymmetries, particularly an
increased content of dopamine in the left globus pallidus,
could have significant behavioral consequences. It has
been suggested that these asymmetries in rats may be
related to paw preference and hemionentation (Carlson
and Glick 1989). There are some data to suggest that
behavioral lateralization of neonatal rats is related to
asymmetries in cerebral dopamine (Afonso et al. 1993).
In a more indirect, but potentially important study, children with early treated phenylketonuria, which is associated with developmental dopamine depletion, were studied on tasks of visual attention. The boys showed clear
evidence of left-hemisphere dysfunction, but the girls did
not (Craft et al. 1992). If confirmed, this finding may well
have far-reaching consequences for our understanding of
the development of gender differences in functional, and
perhaps also in structural lateralization. It is now clear
that dopamine turnover in the right and left nigrostriatal
pathways is reciprocally regulated (Glowinowski et al.
1984). A further famous and potentially behaviorally significant experiment involved the administration of lysergic acid diethylamide (LSD-25) to patients before and
after temporal lobectomy. It was shown that ablation of
the right temporal lobe is associated with a disappearance
of the perceptual effects of the drug (Serafetinides 1965),
implying an asymmetry of 5-hydroxytryptamine type 1A
and 2 receptors—the main site of action of LSD.
Schizophrenia
The possibility of a relationship between disturbances in
cerebral asymmetry and psychosis was first raised almost
120 years ago (Crichton-Browne 1879). Other articles in
this issue of the Schizophrenia Bulletin deal with components of cerebral asymmetry. We shall not reiterate information in them, other than to point out that data derived
from several different types of studies have indicated
abnormalities in the left hemisphere. These studies
include neuropsychological testing (for a review see
Nasrallah 1986); attention (Posner et al. 1988); auditory
acuity (Mathew et al. 1993); brain electrical activity mapping (Morihisa et al. 1983); recordings of the P300 potential (Morstyn et al. 1983; Holinger et al. 1992; Faux et al.
1990, 1993); EEG (Morrison et al. 1991; Koukkou et al.
1993); positron emission tomography (Gur et al. 1987;
Berman and Weinberger 1990; Friston et al. 1992; Wilson
and Mathew 1993); single photon emission tomography
(SPECT) (Suzuki et al. 1993); and biochemistry
(Reynolds 1983; Kerwin et al. 1988). With so much evidence pointing toward the left hemisphere and/or an
imbalance between the two sides, it is not surprising that a
great deal of effort has been expended on the search for
structural asymmetries in schizophrenia. We must, however, mention that although there is much to suggest left
hemisphere dysfunction in schizophrenia, some evidence
suggests that dysfunction in the right hemisphere, with a
diminution of activity, is the key abnormality (Cutting
1990, 1992, 1994; Persaud and Cutting 1991). These
models, however, are not necessarily mutually exclusive.
The normal state of affairs is a functional balance between
and within each hemisphere: For virtually every task there
is a potential contribution from each hemisphere, although
some tasks tend to be preferentially mediated by one
hemisphere or the other.
It is valuable to consider the interrelationships of
structural and biochemical asymmetries. The latter appear
to be a real phenomenon, not simply a reflection of
increases or decreases in local tissue mass. However, the
precise interactions among structure, biochemistry, and
function remain obscure. There are, however, some data
to suggest that antipsychotic medications do have a lateralized effect. Acute treatment with haloperidol has lateralized effects on dopamine turnover in the rat brain (Jerussi
and Taylor 1982). Furthermore, treatment is associated
with a small but significant shift in electroencephalography
(EEG) voltage to the left (Serafetinides 1973) and with lateralized alterations in visual evoked responses
(Myslobodsky et al. 1983). This notion is buttressed by
What has become known as the "typical" pattern of
anatomical asymmetry—a predominance of the left parietooccipital regions—was described in the early years of this
century and was speculated to be related to the functional
specialization of the hemispheres (Smith 1907). The possibility that mental disturbances might be related to some
derangements of the normal pattern of asymmetry of the
brain had been raised by the detailed studies of Southard
(1915) and subsequently by Inglessis (1925). However, in
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Structural Asymmetries of the Human Brain
sphere. Over the years, a number of studies have examined the function of the corpus callosum in schizophrenia,
with interesting, but still inconclusive results (David
1987, 1993; Doty 1989; Raine et al. 1989).
The most consistent in vivo finding in schizophrenia
is enlargement of the lateral ventricles, although a recent
meta-analysis has revealed that the degree of this enlargement is much smaller than previously thought, and like
some other findings, the differences between normal controls and patients have tended to become smaller as more
studies have been performed (Van Horn and McManus
1992). The finding, however, remains robust, and in some
reports the enlargement has been found to be asymmetrical, the enlargement of the left being greater (Crow et al.
1988, 19896; Crow 1990a; DeLisi et al. 1991, 1992).
This preferential enlargement of the left lateral ventricle
has also been found in postmortem study (Brown et al.
1986; Crow et al. 1989a). This investigation also convincingly demonstrated that this asymmetrical enlargement was found only in patients with an antemortem diagnosis of schizophrenia, but not in roughly matched
patients with Alzheimer's disease, in whom the enlargement was the same on the two sides. This enlargement
either reflects atrophy, or an arrest of brain growth, with a
consequent failure of the brain to attain the adult proportions of brain to ventricular volumes. One of the key
inquiries in research examining the neurobiological basis
of schizophrenia is directed at establishing whether these
brain abnormalities are progressive. It is also now emerging that ventricular enlargement is most pronounced in the
temporal horns, again mainly on the left (Brown et al.
1986), and is associated with schizophrenia symptoms
(Degreef et al. 1992; Kawasaki et al. 1993). The presence
of enlarged ventricles has received such detailed examination because it may be a marker of a particular subtype of
schizophrenia. Certainly, enlargement of the lateral ventricles is associated with an earlier age at onset (DeLisi et
al. 1991, 1992). Enlargement of the third ventricle has
been associated with neuropsychological deficit
(Bomstein et al. 1992).
In addition to the asymmetries in the ventricular system, temporal lobe size itself is reduced in patients with
schizophrenia, again more on the left than the right
(Bogerts et al. 1990; Dauphinais et al. 1990). In two postmortem studies, the normal asymmetry of the lateral
(Sylvian) fissure (left longer and flatter than the right) was
found to be lost in schizophrenia (Crow et al. 1992; Falkai
et al. 1992). However, it remains uncertain whether the
reduction in temporal lobe volume is already present at
the time of the onset of the illness (DeLisi et al. 1991,
1992). There has also been debate about whether both
gray and white matter are decreased (Suddath et al. 1989;
Zipursky et al. 1992) or whether the reduced volume is
both cases, the findings were not conclusive and were
largely ignored during the years when psychological and
social theories supplanted biological observations.
Southard's articles now appear prescient. Not only
did he comment on ventricular enlargement (which he
termed "internal hydrocephalus"), but he stated quite
clearly that "the atrophies and aplasias when focal show a
tendency to occur in the left cerebral hemisphere"
(p. 662). Finally, he also pointed out the predilection for
the pathological lesion to affect the "association centers of
Flechsig" (Flechsig 1908, 1920), which we would identify
as the interlinked system of heteromodal association cortex, which has recently been strongly implicated in the
pathology of schizophrenia (Schlaepffer et al. 1994).
More recently, interest in comparing the two hemispheres
was rekindled by the observations and subsequent theorizing of differential behavioral effects of lesions in each
hemisphere, leading to a redistribution of the normal balance between the two hemispheres (Flor-Henry 1969,
1976, 1983). Flor-Henry reported that when psychosis
developed in association with an epileptic focus in the left
hemisphere, it tended to be schizophrenia-like, while a
focus in the right hemisphere is more likely to be associated with an affective psychosis. While initially these
observations were thought to be relevant only to epilepsy,
it was not long before a potential link to schizophrenia
itself was being considered.
An early investigation using air encephalography had
reported ventricular enlargement restricted to the left side
in 9 of 27 chronic psychotic patients (Hunter et al. 1968).
In two CT scan studies, it was reported that "density" of
the left hemisphere was reduced on the left side in
patients but not in controls (Golden et al. 1981; Largen et
al. 1983). This observation was subsequently replicated
in one study of chronic schizophrenia patients (Coffman
et al. 1984) and in another of monozygotic twins discordant for schizophrenia (Reveley et al. 1987).
Although the suggestion that asymmetry of the hemispheres may play some role in schizophrenia is normally
assumed to be a modern concept, the idea that disturbances within the corpus callosum resulting in aberrant
intrahemispheric communication might underlie psychotic
illnesses was first proposed by Wigan in 1841 (Clarke
1987). A development of the idea was proposed by
Jaynes (1977) in his well-known book, in which he proposed that many of the symptoms of schizophrenia could
be ascribed to a relative overactivity in the right hemisphere of the brain, such that the experience of auditory
haUucination actually represented the reception by the left
hemisphere of verbal activity by the right. Contemporary
observation of reversal of the normal asymmetry of the
planum temporale may provide some support for this thesis, if indeed this structure is active in the right hemi-
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R.G. Petty
localized to only some regions of the temporal lobe, such
as the superior temporal gyros (Barta et al. 1990; Shenton
et al. 1992); the PT (Hoff et al. 1992; Rossi et al. 1992;
Bilder et al. 1993; Petty et al. 1995); or the medial parts of
the temporal lobe, specifically the hippocampus and
amygdala (Delisi et al. 1986; Bogerts et al. 1990). The
left hippocampus is usually reduced in volume in patients
compared with controls (Breier et al. 1992). The left
parahippocampal region has been found to have a reduced
volume compared with matched controls (Young et al.
1991; Kawasaki et al. 1993). More recently, DeLisi et al.
(1994) examined the temporal lobes of a large group of
patients with schizophrenia and demonstrated a reduction
in the normal pattern of asymmetry in more anterior parts
of the temporal lobes and, in females only, a trend toward
less asymmetry posteriorly. They were unable to find
reductions in the volume of the anterior portions of the
left temporal lobe. However, as the authors themselves
acknowledge, there were technical limitations in this
study: 5 mm slices were used with 2 mm gaps—far larger
than those used in studies reporting positive findings.
As work on brain structure in schizophrenia has progressed, further efforts have been made to relate deviations of symmetry to specific clinical features. Hoff et al.
(1992) found anomalous asymmetry of the Sylvian fissure, particularly in women. Interestingly, it was negatively associated with cognitive dysfunction. This is surprising, given the prevailing view that cognitive
dysfunction is more likely to be associated with aberrant
neurodevelopment (Buckley et al. 1993; Buckley and
O'Donovan 1994). In another study, increased volume of
the Sylvian fissure was found, but only in male schizophrenia patients (Ron et al. 1992). Finally, two studies
have found clear associations between alterations in the
normal asymmetry of the PT and thought disorder (Rossi
etal. 1994; Petty etal. 1995).
We are obviously still at an early stage of the investigation of structural asymmetries. While we have mentioned several studies in which clear asymmetries have
been identified, others have failed to make the same
observations. It is important to point out these negative
reports. For instance, Bartley et al. (1993) and Kulynych
et al. (1993) performed careful studies of 10 patients with
schizophrenia who had unaffected monozygotic twins and
10 with dizygotic twins; they were unable to detect differences in normal asymmetries in the schizophreniaaffected twins. Similarly, Kleinschmidt et al. (1994) were
unable to demonstrate a deviance of normal asymmetry in
first-episode schizophrenia patients. Other studies
directed toward different cortical and subcortical structures have failed to detect consistent asymmetries
(Casanova et al. 1990; Jernigan et al. 1991; Degreef et al.
1992; Levy et al. 1992). There are a number of reasons
for these different results. The most important reflect the
populations selected: Most have studied chronic male
patients, and, as we have seen, there are good reasons for
examining males and females separately. Furthermore
there continue to be different technologies in use. It also
has proven difficult to directly compare MRI analysis programs developed in different centers.
There are two major reasons for the concentration on
the temporal lobes in schizophrenia. One is the association between temporal lobe epilepsy and schizophrenialike psychoses. The second is the association between
schizophrenia and disorders of language (Andreasen
1979a, 1979ft), because the many regions of the brain
involved in the reception and production of language lie
in the superior portions of the temporal lobe.
Reduced asymmetries of the length of the PT have
been reported in individuals with developmental dyslexia
(Geschwind and Galaburda 1984; Larsen et al. 1990).
Several studies have shown clear disturbances of the normal asymmetry of the planum temporale in patients with
schizophrenia. Two were postmortem studies (Crow et al.
1992; Falkai et al. 1992), and five were in vivo (Hoff et al.
1992; Rossi et al. 1992; DeLisi et al. 1994; Kleinschmidt
et al. 1994; Petty et al. 1995). All but the DeLisi group
study showed reduction in the normal asymmetry of the
area, and the degree of reduction appears to be related to
the resolution of the methodology employed. Petty and
colleagues used perhaps the highest resolution SPGR
scans yet employed in studies of the region and found not
just a loss of normal asymmetry but a complete reversal,
in a small study of 14 patients. However, the power of
this study was amplified by the use of extremely rigorous
matching of controls to patients.
In 1979, Luchins et al. reported reversal of the normal asymmetries of the occipital and frontal lobes in
some patients with schizophrenia; that is, the patients had
wider right occipital lobes than left, and their left frontal
lobes were smaller than the right. Subsequently, Naeser et
al. (1981) and Tsai et al. (1983) reported reversals of
asymmetry in the occipital but not the frontal lobe, and
Luchins et al. (1981) replicated their earlier finding of
reversal of occipital lobe asymmetry. However, the situation became much less clear as a number of negative
reports began to appear (Andreasen et al. 1982; Jemigan
et al. 1982; Nyback et al. 1982; Weinberger et al. 1982;
Luchins and Meltzer 1983). In a critical review, Luchins
(1982) himself concluded that the only significant and
consistent finding was larger right frontal and left occipital brain regions in normal as well as affected individuals.
An analysis of all the studies published up until 1983
demonstrated the familiar observation that in biological
measurement the size of the effect tends to diminish as a
function of the level of experimental control.
128
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
Structural Asymmetries of the Human Brain
psychosis), Howard et al. (1994) found temporal lobe volume to be greater on the right in elderly controls (2.6%),
in schizophrenia patients (5.9%), and in patients with
delusional disorder (8.4%). This asymmetry was significant in both the schizophrenia and delusional disorder
patients, but not in the controls. These results appear to
be the reverse of the situation reported in young people
with schizophrenia. The explanation is not readily apparent, particularly because there are so few normative data
pertaining to brain volume measurements in the elderly.
It may be, as the Howard group speculates, that normal
aging is associated with a gradual loss of the asymmetry
of brain volumes seen in younger adult life. Persistence
of this asymmetry could then be a risk factor for the eventual development of schizophrenia or delusional symptoms. Considerable data collected in a variety of studies
indicate that there is normally a balance between the
activity of the two hemispheres, and convincing arguments have been advanced to suggest that schizophrenia
symptoms may be linked to a predominance of right
hemispheric activity (Cutting 1990) or left hemispheric
underactivity (Gur 1979). The Howard group previously
found an asymmetrical dilatation of the lateral ventricles,
with significantly greater dilatation on the left, in patients
with both delusional disorder and late-onset schizophrenia, compared with controls (Howard et al. 1994). This
presumably reflects either arrested development of the left
temporal lobe or, alternatively, increased loss of tissue on
this side of the brain. Whichever explanation proves to be
correct, this finding is consistent with that reported by
Crow et al. (1988, 1990a, 1990*).
During the 1980s, Timothy Crow developed an ingenious hypothesis Unking the neurological lesions of schizophrenia to the development of cerebral asymmetry, and
he and his collaborators embarked on a number of investigations to test this hypothesis. At its simplest, the hypothesis proposes that schizophrenia is a disorder of the
genetic mechanisms that control the development of cerebral asymmetry. The prediction from this theory is that
the greatest disturbances will be seen in regions that normally show the highest degrees of asymmetry, such as the
planum temporale. This prediction has subsequently been
borne out. Furthermore, as additional studies have been
performed, more data have supported the contention that
the normal torque to which we referred earlier is diminished or absent in schizophrenia (Falkai et al. 1992). This
loss of torque can be detected in groups with an early
onset (Crow et al. 1989b) and in individuals experiencing
a first episode (Bilder et al. 1993, 1994). An alternative
explanation for the association between left-hemisphere
lesions and schizophrenia relates to the differential maturation of the right and left hemispheres, which renders the
left hemisphere more vulnerable to potential insults in the
second trimester of pregnancy. Thus it would follow that
structural asymmetries are an artifact of the timing of the
insult (Bracha 1991).
CT and MRI studies have shown remarkable agreement with results obtained from postmortem studies.
Most authors, as we have seen, have reported that the PT
is larger on the left and that the Sylvian fissure extends
farther back on the left and rises more steeply on the right
However, the volume of the temporal lobe is on average
larger on the right (LeMay 1986). In a group of 25
healthy individuals, Jack et al. (1988) found temporal lobe
volumes to be an average of 15.7 percent greater on the
right side. However, a considerable range in the values
was reported with no attempt to examine the potential
effects of gender or handedness. Studies that have
reported temporal lobe volumes in patients with schizophrenia have found that this right-greater-than-left asymmetry is maintained, although the degree is reduced.
Thus, Suddath et al. (1989) found right temporal lobe volumes 15.5 percent greater than the left in controls, but
only 12.5 percent greater in patients. In a further study
the increased volume of the right was 13.6 percent in controls and 8.6 percent in patients (Harvey et al. 1993).
The precise delineation of the frontal lobes presents a
number of technical difficulties that have hindered
progress in this area. However, as we discussed earlier, at
postmortem the total volume of the right frontal lobe is
about 13 percent larger than the left (Weinberger et al.
1982). The direction and approximate magnitude of this
asymmetry have been confirmed using CT in normal individuals (LeMay and Kido 1978; Chui arid Darnasio 1980).
In MRI studies, there does not seem to be a significant
difference in the relative sizes of right and left prefrontal
regions when controls and schizophrenia patients are
compared: Both show right side enlargement (Suddath et
al. 1989). However, the situation appears to be different
in the elderly. The volume of the right frontal lobe
exceeds the left by 1.7 percent in controls, by 0.3 percent
in patients with late-onset schizophrenia, but by 8.5 percent in patients with delusional disorder (Howard et al.
1994). It may be of interest that Swayze et al. (1992),
while still finding the right temporal lobe to be larger than
the left in schizophrenia patients, found small reduction
compared with controls but also found that right and left
temporal lobes were of equal volume in females with
Although some MRI studies have not shown a significant asymmetry of temporal lobe volume in schizophrenia patients or controls (Shenton et al. 1992), a reversal of
the normal pattern of asymmetry (i.e., left larger than
right) has been reported in some patients with schizophrenia (Luchins and Meltzer 1983; Tsai et al. 1983). In a
large study of patients with late paraphrenia (late-onset
129
R.G. Petty
Schizophrenia Bulletin, Vol. 25, No. 1, 1999
bipolar disorder, once again demonstrating the importance
of gender as an independent variable.
The comparison of early- and late-onset schizophrenia may present a useful avenue for further exploration, as
more sophisticated attempts are made to relate symptoms
to the neurobiological substrates of these illnesses.
However, such a comparison is not without its problems.
With increasing age there appears to be a progressive
increase in interindividual differences in brain appearance
(Jacoby et al. 1980). Therefore, the demonstration of
minor structural abnormalities in the brains of older psychiatric patients becomes difficult, when compared with
age-matched elderly controls. Thus, some of the subtle
MRI findings reported in early-onset schizophrenia
patients may be difficult to detect in the elderly, and the
consistent findings in the temporal lobes, particularly in
elderly patients with delusional disorder, are therefore
likely to be robust
One of the more interesting approaches to the study
of the organic substrate in schizophrenia is the attempt to
associate structural and functional abnormalities. There
have been several recent attempts to do this. In a study of
31 schizophrenia patients and 33 volunteer controls, auditory P300 event-related potential and smooth pursuit eye
movement abnormalities were associated with structural
brain changes measured using MRI. In the schizophrenia
group, P300 latency correlated negatively with the area of
the right and left cingulate cortex and positively with the
difference in size of the right and left amygdala. The
results were more marked in the more severely affected
individuals. In those schizophrenia patients whose P300
latency was greater than two standard deviations above
the control mean, the area of the left cingulate cortex was
significantly smaller than in controls, and the absolute
right-left difference in the area of the amygdala was significantly increased. Eye-tracking dysfunction in schizophrenia was not related to changes in the amygdala or cingulate cortex, but it was significantly correlated with
enlargement of the lateral ventricles. There was no specific association with enlargement of one side or the other.
Schizophrenia subjects with poor eye-tracking had significantly larger lateral ventricles than controls. Eye-tracking
dysfunction, but not P300 abnormality, was correlated
with the severity of both positive and negative symptoms
of schizophrenia (Blackwood et al. 1991). McCarley et
al. (1991, 1993) have identified a clear association
between reductions of the volume of the left posterior
temporal gyrus and abnormalities of the auditory P300
potential. Because this is the same region of the brain
associated with thought disorder (Shenton et al. 1992;
Rossi et al. 1994; Petty et al. 1995), the obvious implication is that this lateralized neurophysiological measure is
providing information about the substrate of disturbances
in communication. What these data appear to be telling us
is that more severe deviations of normal cerebral asymmetry are associated with more marked disturbances in
one particular measure of neurological dysfunction in
schizophrenia- This may be of importance in view of the
data suggesting an association of handedness with tardive
dyskinesia (McCreadie et al. 1982; Barr et al. 1989;
Joseph 1990), even though handedness is, as we have discussed, a poor indicator of structural asymmetry.
We have referred to possible dynamic changes in
functional laterality during the menstrual cycle. In one
interesting study, sadly not replicated, a dichotic listening
task showed a close relationship between disturbance of
laterality and psychotic symptoms: When the patient was
most ill, laterality was most disturbed, and recovery was
associated with a return to near normal laterality (Wexler
and Heninger 1979). It is tempting to speculate that the
better prognosis of females with schizophrenia is associated with the female brain being more plastic in contrast to
the greater structural asymmetries found in males, which
have the effect of forcing a functional lateralization.
In our view, structural and functional asymmetries,
and particularly their integration with clinical measures,
still have much to teach us about schizophrenia.
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PA.
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