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Malaysian Journal of Medical Sciences
School of Medical Sciences, Universiti Sains Malaysia
ISSN: 1394-195X
Vol. 18, Num. 1, 2011, pp. 6-11
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Malaysian Journal of Medical Sciences, Vol. 18, No. 1, 2011, pp. 6-11
Review Article
Neuroimaging in the Field of Psychoses
Saxby Pridmore1, Georgina Bowe2
1Department of Psychiatry, University of Tasmania, Private Bag 27, Hobart,
Tasmania 7001, Australia
2Royal Hobart Hospital, GPO Box 1061, Hobart, Tasmania 7001, Australia
Correspondence: Professor Saxby Pridmore,
MB, BS, BMedSc (Tasmania), DPhysio (Melbourne), MD (Tasmania),
Department of Psychiatry,
University of Tasmania, Private Bag 27, Hobart,
Tasmania 7001,
Australia,
Tel: +0409 825 029,
Fax: +03 6226 4777,
Email: S.Pridmore@utas.edu.au
Submitted: 18 Sep 2010
Accepted: 20 Sep 2010
Code Number: mj11002
Abstract
This review looks at the recent findings in the neuroimaging of the psychoses,
with a view to clarifying the question of the unitary versus the two-disorder
theory of psychosis. Schizophrenia is associated with significantly more cortical
grey matter loss than bipolar disorder. The distribution of these losses is
different; schizophrenia is characteristically associated with loss of the
medial and middle frontal, the superior temporal gyri, and the dorsolateral
prefrontal cortex, while bipolar disorder has particular loss in the medial
frontal gyrus and the anterior cingulate cortex. Both disorders were associated
with extensive white matter deficits. In summary, neuroimaging indicates different
patterns of grey matter loss for schizophrenia and bipolar disorder. However,
neuroimaging of white matter reveals a good deal of overlap between these two
disorders. Thus, neuroimaging does not suggest a unitary psychosis or a two-psychosis
model, instead it suggests a two-dimensional psychosis field, on which disorders
are located according to two dimensions, the degree of grey matter loss and
the degree of white matter abnormality.
Keywords: bipolar disorder, magnetic resonance imaging, psychoses, schizophrenia,
tomography
Introduction
Schizophrenia and bipolar disorder are common, disabling disorders. They were
known as “functional” (by which was meant, no organic basis has
been demonstrated) as opposed to the “organic” disorders (such
as dementia, for which a structural basis can be demonstrated at autopsy).
However, the term “functional” says more about the technology of
the day than about a particular disorder, and in recent years, neuroimaging
has begun to illustrate the structural abnormalities of these disorders.
In 1893, Emil Kraepelin divided the extant single category of psychosis into
two (the modern equivalents being schizophrenia and bipolar disorder). His
concept has guided much of the psychiatric research and clinical work for the
last century. However, there have been repeated calls to return to the unitary
theory of psychosis (1). Recent neuroimaging may inform this debate.
Coaxial tomography became available in the 1970s, and was immediately used
to demonstrate increased cerebral ventricular size in people with schizophrenia
(2), but limited progress was achieved. Magnetic resonance imaging (MRI) then
revolutionized neuroimaging. This review will be limited to structural MRI,
with some mention of its use in diffusion tensor imaging (DTI; which depends
on water diffusing more rapidly in the direction aligned with the internal
structure of white matter).
In MRI, voxel-based morphometry (VBM) is a technique in which neuroanatomical
differences are detected by comparing voxels across the entire brain. This
method has some technical difficulties (3,4). Small abnormalities may go undetected,
and perhaps the best use of VBM is the identification of candidate regions
(5). In region-of-interest (ROI) MRI, candidate regions are examined in greater
detail.
Patient factors also introduce comparison difficulties. Diagnostic criteria
may vary, and different disease stages may have different pathological features.
Furthermore, some medications are known to alter grey matter volume.
A comprehensive assessment of the literature was conducted in PubMed using “neuroimaging,
schizophrenia” and “neuroimaging, bipolar disorder” as the
search terms. A selection of papers were examined and reported under these
headings: 1) schizophrenia, 2) bipolar disorder, and 3) comparisons of schizophrenia
and bipolar disorder.
Schizophrenia
In a meta-analysis of whole brain volumes in first-episode, medication-naïve
patients with schizophrenia, Steen et al. (6) found a 2.7% reduction in comparison
with healthy controls.
In VBM studies of schizophrenia, reduced grey matter has been described in
the frontal, temporal, and thalamic regions. Similar changes have been reported
in first-episode and chronic schizophrenia, but the differences are more
marked in the latter (7).
In a longitudinal ROI study (8) people with chronic schizophrenia and healthy
controls were examined at two points, 4 years apart. The course of the illness
was charted using the Brief Psychiatric Rating Scale (BPRS) and periods of
hospitalization. People with chronic schizophrenia demonstrated significantly
accelerated lateral ventricular expansion and frontal cortical grey matter
loss. Rates of loss were greater in patients with higher BPRS scores and longer
periods of hospitalization.
Much interest has been directed toward early brain changes. This approach
may perhaps avoid complications introduced by medication and the chronic disease
process. An understanding of early brain changes may also assist in early diagnosis,
and eventually, in prevention. To this end, people at risk of schizophrenia
(either by a change in the premorbid mental state, or possible genetic disposition)
have been identified and serially investigated.
Pantelis et al. (9) examined young people at increased risk for schizophrenia.
In this cross-sectional study, subjects who developed psychosis compared with
those who did not, showed less grey matter in the right lateral temporal, medial
temporal, and inferior frontal neocortex and in the cingulate cortex bilaterally.
Subjects who developed psychosis were re-scanned 1 year later, at which point,
there was a loss of grey matter in the left fusiform, parahippocampal, orbitofrontal,
and cerebellar cortices. Therefore, some grey matter abnormalities predated
the onset of psychosis, and others came later. A similar study (10) found reduced
grey matter in posterior and anterior cingulate areas, lateral and medial temporal
lobes, and lateral frontal cortex in young patients prior to the development
of psychosis in comparison with at-risk individuals who did no develop psychosis
and healthy controls.
A recent VBM study (11) compared a group of patients with formal thought disorder
with healthy controls. Thought disorder was gauged using the Scale for the
Assessment of Thought, Language, and Communication. The severity of thought
disorder was negatively correlated with the grey matter volume of the left
temporal pole, left superior temporal gyrus, the right cuneus/lingual gyrus,
and the right middle orbital gyrus. These findings support an analysis of 15
VBM studies (12) which indicated the left medial temporal lobe the left superior
temporal gyrus as key regions of anatomical difference between people with
schizophrenia and healthy subjects.
A DTI study of people with schizophrenia (13) revealed significant white matter
disruption compared to healthy controls in the uncinate fasciculus, arcuate
fasciculus, cingulum, and corpus callosum.
Bipolar Disorder
Bipolar disorder may feature psychosis, which makes comparison with schizophrenia
interesting. The whole brain volume in bipolar disorder appears to be preserved
(14). However, moderate ventricular enlargement has been frequently demonstrated
(15), suggesting some tissue loss.
VBM studies in bipolar disorder have yielded variable findings. Some studies
have failed to find grey matter differences in patients relative to healthy
controls, suggesting that these changes in bipolar disorder are less pronounced
than those found in schizophrenia (16). ROI studies in bipolar disorder have
described ventricular enlargement and white matter hyper-intensities as the
most robust changes, with grey matter differences generally being small (17).
VBM studies of early stage bipolar disorder have been few and contradictory.
Janssen et al. (18) found reductions specific to the medial prefrontal cortex.
ROI studies of early stage bipolar disorder have also been few and inconsistent.
Koo et al. (19) found reduced left subgenual cingulate cortex; however, Fornito
et al. (20) reported increased right subgenual cingulate cortex in male patients.
Koo et al. (19) performed a longitudinal study of bipolar disorder, conducting
scans at the first episode of psychosis, and again about 3 years later. A reduction
was demonstrated in the volume of the anterior cingulate cortex. Moorhead et
al. (21) studied people with chronic bipolar disorder for over a 4-year period
and found progressive grey matter reduction in the fusiform, hippocampal, and
cerebellar cortex, but not in the anterior cingulate cortex.
Savits et al. (22) compared two groups of patients with bipolar disorder (medicated
and unmedicated) with healthy controls. The unmedicated patients had significantly
smaller amygdalae and the medicated patients had larger amygdalae (trending
towards significance) compared with the healthy controls. The disease process
was believed to account for the reduced size of the amygdalae in the unmedicated
group, and the medication was believed to account for the increased size of
the amygdale in the medicated group.
Heng et al. (23) reviewed 18 DTI studies of the white matter of people with
bipolar disorder. They concluded a loss of white matter connectivity (involving
prefrontal and frontal regions), projection, associative and commissural fibres
was a feature of bipolar disorder.
Comparisons of Schizophrenia and Bipolar Disorder
Some recent studies have directly compared images of patients with schizophrenia
and bipolar disorder, in particular, where there have been psychotic features.
Kasai et al. (24), in a ROI study, compared the grey matter volume of the
left superior temporal gyrus of a group of people with first-episode schizophrenia,
a group of people with first-episode affective psychosis, and a group of healthy
controls, at two points in time, 1.5 years apart. They found progressive loss
of the left superior temporal gyrus in schizophrenia in contrast to patients
with affective psychosis and controls.
Coryell et al. (25) studied patients with major depressive disorder with psychotic
features, patients with schizophrenia, and healthy controls, at two points,
4 years apart. The people with major depressive disorder with psychotic features
had significantly smaller grey matter volumes on the left side of the posterior
subgenual prefrontal cortex. The volumes of this region for patients with schizophrenia
were also smaller than for the healthy controls. Four years later, the relative
size relationship was unchanged; however, for the depression group, the size
of this region had increased. This suggested (to the authors) that for this
disorder, this anatomical deficit is reversible, and that medication may have
played a role.
McDonald et al. (26) used VBM to compare the grey and white matter volumes
throughout the brain of groups of individuals with schizophrenia, bipolar disorder
with psychotic features, and healthy controls. The group with schizophrenia
had generalized grey matter loss (predominantly involving frontotemporal neocortex,
medial temporal lobe, insula, thalamus, and cerebellum). The group with bipolar
disorder did not have regions of significant grey matter loss. The authors
observed that the majority of the bipolar patients were on lithium, which may
have increased the volume of the grey matter of this group, and hence reduced
any differences in grey matter volume, which might otherwise have existed.
The pathological groups had anatomically overlapping white matter abnormalities
in regions occupied by major longitudinal and interhemispheric tracts (including
the superior longitudinal fasciculus, inferior longitudinal fasciculus, and
orbitofrontal fasciculus, as well and the anterior and posterior parts of the
corpus callosum).
Nakamura et al. (27) conducted a ROI study of the neocortical grey matter
of groups at first hospitalization for schizophrenia, first hospitalization
for affective disorder with psychosis, and no mental disorder. Patients were
scanned at intake and 1.5 years later. At first hospitalization, both the schizophrenia
and affective disorder groups demonstrated significantly less neocortical grey
matter than the healthy control groups; however, there was no significant volume
difference between the pathological groups. Longitudinally, however, the schizophrenia
group showed a neocortical grey matter reduction (-1.7%; mainly in the frontal
and temporal regions) and the affective disorder group showed a neocortical
grey matter increase (+3.6%), which the authors suggested may reflect the neurotrophic
effects of mood stabilizers.
Koo et al. (19) studied initial and progressive grey matter volume of cingulate
gyrus subregions in patients with first episode schizophrenia, patients with
first episode affective psychosis, and healthy controls. Subjects were scanned
twice, 1.5 years apart. Patients with affective psychosis, at initial assessment,
showed significant loss of the subgenual cingulate, which was progressive.
Patients with schizophrenia, on the other hand, had more widespread cingulate
deficits, which were less progressive. This suggested (to the authors) that
these disorders had different initial grey matter deficits and progression
over time. In addition, this group looked at the morphology of the paracingulate
sulcus. Cerebral folding occurs during the 2nd and 3rd trimester and is stable
thereafter, and consequently, the paracingulate can be used as a marker of
neurodevelopment. The authors found less fissuration of the paracingulate sulcus
in people with schizophrenia than healthy controls, suggesting neurodevelopmental
factors contribute to this disorder.
Janssen et al. (18) conducted an MRI study of early onset first-episode psychosis.
For inclusion, onset was prior to 18 years of age and the psychosis had persisted
for less than 6 months. Three diagnostic groups were identified: schizophrenia,
bipolar disorder, and other psychiatric conditions. Schizophrenia was associated
with grey matter volume loss in the left medial (superior) and left middle
frontal gyrus. Bipolar disorder, however, was associated with grey matter volume
loss of the left medial frontal gyrus only. The psychotic individuals who at
follow-up did not have a diagnosis of either schizophrenia or bipolar disorder
displayed different patterns. The authors noted that the schizophrenia and
bipolar psychosis both appeared associated with medial frontal gyrus, suggesting
some shared pathophysiology.
White matter hyper-intensities had been considered to be a characteristic
feature of mood disorder (17). However, Zanetti et al. (28), in a large and
well conducted study using MRI, found that white matter hyper-intensities were
equally represented in psychotic bipolar disorder and schizophrenia spectrum
disorders. Doubt about the specificity of white matter hyper-intensities in
bipolar disorder has been recently expressed by Gunde et al. (29). Interestingly,
McIntosh et al. (30) demonstrated DTI abnormalities in the uncinate fasciculus
in both schizophrenia and bipolar disorder, but Walterfang et al. (31) found
MRI differences between the corpus callosum of the first-episode affective
psychosis and schizophrenia spectrum patients.
El-Sayed et al. (32) studied young people with early onset schizophrenia spectrum
disorders, young psychotic people with mood disorders, and young healthy controls.
They found significantly lower total brain volume in those with schizophrenic
spectrum disorders compared with the other two groups. They found the schizophrenia
spectrum disorder patients had significantly reduced grey matter volume, particularly
in the frontal and parietal lobes, but found no difference in white matter
volumes.
Discussion
This paper does not mention every study in the field of neuroimaging in psychosis.
However, a good representative sample is presented, with particular attention
applied to the most recent studies.
In 1893, Emil Kraepelin divided the psychoses into two categories, schizophrenia
and bipolar disorder. However, some still question whether they are two distinct
disorders, or a single disorder which is expressed differently (the unitary
theory of psychosis). This paper asks whether neuroimaging can contribute to
this discussion.
Neuroimaging of schizophrenia finds a significant reduction in whole brain
volume (2,6). Grey matter loss has been consistently described in the anterior
and lateral prefrontal regions and the medial, lateral surfaces, and the superior
gyrus of the temporal lobe (8,10,33). A DTI study in schizophrenia (13) showed
significant white matter disruption throughout the brain compared with healthy
controls.
Neuroimaging of bipolar disorder finds the whole brain volume to be relatively
preserved (14), although there are reports of increased size of the lateral
ventricles (15), which can be attributed to white matter loss. In general,
grey matter loss has been described as relatively slight (16), and most
marked in the medial prefrontal cortex (18) and particularly the anterior cingulate
cortex (19). A review of DTI studies (23) in bipolar disorder found extensive
white matter deficits.
Direct comparison studies of schizophrenia and bipolar disorder are of particular
interest in addressing the question.
El-Sayed et al. (32) found significantly lower total brain volume in people
with schizophrenia spectrum disorders compared with people with mood disorders
with psychotic features.
McDonald et al. (26) found that schizophrenia was associated with greater
grey matter loss (predominantly involving frontotemporal neocortex, medial
temporal lobe, insula, thalamus, and cerebellum) compared with bipolar disorder
with psychotic features. Similar finding was made by El-Sayed et al. (32).
Others (27) conducted a longitudinal study and found that the grey matter in
schizophrenia continued to reduce (mainly in the frontal and temporal regions),
while in bipolar disorder, neocortical grey matter increased (which they attributed
to mood stabilizer effect). Janssen et al. (18) found schizophrenia was associated
with grey matter volume loss in the left medial (superior) and left middle
frontal gyrus, while bipolar disorder was associated with grey matter volume
loss of the left medial frontal gyrus only.
Kasai et al. (24) found progressive left superior temporal gyrus loss in schizophrenia
in contrast to patients with affective psychosis. Coryell et al. (25) found
significantly greater loss of subgenual prefrontal cortex in major depressive
disorder with psychotic features, compared to schizophrenia. Koo et al. (19)
made similar findings and concluded that patients with these disorders had
different initial grey matter deficits and progression over time.
McDonald et al. (26) found that patients with schizophrenia and bipolar disorder
with psychotic features had similar white matter abnormalities in all regions.
McIntosh et al. (30) demonstrated DTI abnormalities in the uncinate fasciculus
in people with both schizophrenia and bipolar disorder.
In summary, the evidence suggests that schizophrenia, compared with bipolar
disorder, is associated with more extensive grey matter loss, and white matter
deficits appear to be a feature of both conditions.
Conclusion
Neuroimaging indicates different patterns of grey matter loss for schizophrenia
and bipolar disorder. However, neuroimaging of white matter reveals a good
deal of overlap in these two disorders. Thus, neuroimaging does not suggest
a unitary psychosis or a two-psychosis model, instead it suggests a two dimensional
psychosis field, on which disorders are located according to two dimensions,
the degree of grey matter loss and the degree of white matter abnormality.
Authors’ Contributions
Conception and design, critical revision of the article, final approval of
the article: SP
Analysis and interpretation of the data, drafting of the article: SP, GB
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