Department of Psychiatry and ORYGEN Research Centre, University of Melbourne, and Mental Health Research Institute, Parkville, Victoria
Department of Psychiatry, University of Melbourne, and Brain Research Institute,Victoria
ORYGEN Research Centre, PACE Clinic and Department of Psychiatry, University of Melbourne
Department of Psychiatry, University of Melbourne, and Mental Health Research Institute, Parkville, Victoria
ORYGEN Research Centre, PACE Clinic and Department of Psychiatry, University of Melbourne
Department of Psychiatry, University of Melbourne, and Mental Health Research Institute, Parkville, Victoria
ORYGEN Research Centre, PACE Clinic and Department of Psychiatry, University of Melbourne
Department of Psychiatry and Centre for Neuroscience, University of Melbourne, and Mental Health Research Institute, Parkville, Victoria, Australia
Correspondence: Dr Murat Yücel, Cognitive Neuropsychiatry Unit, c/o Mental Health Research Institute, 155 Oak Street (Locked Bag 11), Parkville, Victoria, Australia 3052. Tel: 3 9388 1633; fax: 3 9387 5061; e-mail: murat.yucel{at}wh.org.au
Declaration of interest P.D.M.'s group is receiving support from JanssenCilag for an intervention study in the ultra-high-risk group. Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To examine whether ACC morphological anomalies are present in a group at ultra-high risk of psychosis and whether such anomalies can be used to predict the subsequent development of a psychotic illness.
Method Magnetic resonance imaging of 75 healthy volunteers and 63 people at ultra-high risk of developing a psychotic disorder (all right-handed males) was used to examine ACC sulcal and gyral features.
Results Compared with the controls, significantly fewer people in the ultra-high risk group had a well-developed left paracingulate sulcus and significantly more had an interrupted left cingulate sulcus. There was no difference between those who did (n=21) and did not (n=42) subsequently develop a psychotic illness.
Conclusions Although ACC anomalies are present in young people considered to be at ultra-high risk of psychosis, they do not identify individuals who subsequently make the transition to psychosis.
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INTRODUCTION |
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METHOD |
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Participants were recruited to the study using methods detailed in previous publications (Velakoulis et al, 1999; Phillips et al, 2002; Pantelis et al, 2003). Briefly, healthy volunteers were recruited from ancillary hospital staff and the general population through advertisements. Attempts were made to recruit these individuals from socio-demographic backgrounds similar to those of the ultra-high-risk participants, and they were excluded if they had a personal or family history of psychotic illness. All members of the control group (n=75) had already participated in a larger normative study of the anterior cingulate cortex (Yücel et al, 2001), as well as a diagnostic comparison study (Yücel et al, 2002a). The ultra-high-risk group (n=63) was recruited from referrals to the Personal Assessment and Crisis Evaluation (PACE) clinic in Melbourne, Australia, between April 1995 and November 1999 (McGorry et al, 2001a,b; Yung et al, 2003). All participants were screened for comorbid medical and psychiatric conditions by clinical assessment, physical examination and neurological screen. Handedness was assessed using the Edinburgh Inventory (Oldfield, 1971). Exclusion criteria for all groups were: history of prior psychotic episode (treated or untreated); a history of significant head injury and/or loss of consciousness for more than 1 min; seizures; neurological disease such as epilepsy or cerebrovascular accident; impaired thyroid function; steroid use; preferred language not English; IQ<70; or DSMIV criteria of alcohol or substance misuse or dependence (American Psychiatric Association, 1994). Given the gender-related differences found in the normal anterior cingulate cortex (Paus et al, 1996; Yücel et al, 2001), the finding of ACC anomalies in male patients with established schizophrenia (Yücel et al, 2002a) and the general association of gender and handedness with brain anatomy (Petty, 1999), the sample was limited to right-handed males. Written informed consent was obtained from all participants, and local research and ethics committees approved the design and aims of the study.
Criteria for the identification of the ultra-high-risk cohort have previously been outlined and their rationale described (Phillips et al, 1999; McGorry et al, 2001a; Yung et al, 2003). Briefly, individuals were categorised as being at ultra-high risk if they met operationally defined criteria for ultra-high risk of early transition to first-episode psychosis, defined as membership of at least one of three subsets. Identification of the first subset was based on state and trait risk factors, in which the individual has a first-degree relative with any history of a psychotic or bipolar illness, or has a schizotypal personality disorder as well as a reduction in the Global Assessment of Functioning (GAF; American Psychiatric Association, 1994) of more than 30 points from premorbid level maintained for at least 1 month. The second group was identified by the presence of attenuated psychotic symptoms, in which a subthreshold form of at least one of the following was experienced: ideas of reference, magical thinking, perceptual disturbances, paranoid ideation, and odd thinking and speech. Further, these symptoms had to have occurred at least several times per week and for at least 1 week. The third and final group was identified on the basis of brief limited intermittent psychotic symptoms (BLIPS) brief, self-limited bursts of acute psychotic symptoms occurring daily but with a duration of less than 1 week (and therefore meeting DSMIV diagnostic criteria for brief psychotic disorder). Symptoms must have resolved spontaneously. The composition of the ultra-high-risk cohort in terms of these subsets was: state and trait, 17.5% (n=11); attenuated psychotic symptoms, 39.7% (n=25); BLIPS, 12.7% (n=8); attenuated psychotic symptoms plus BLIPS, 9.5% (n=6); attenuated psychotic symptoms plus state and trait, 19% (n=12); BLIPS plus state and trait, 1.6% (n=1). In addition to these inclusion criteria, all those in the ultra-high-risk group were aged 1430 years. The 63 members of this group were drawn from a larger cohort of people at ultra-high risk who had participated in a series of studies within the PACE clinic; they were included in the current study if they agreed to an MRI scan and if they had been followed up for at least 12 months (maximum length of follow-up was 44 months) in terms of development or not of acute psychosis. About half (31) of the ultra-high-risk group initially agreed to participate in an intervention study prior to scanning, but treatment did not commence until after scanning was performed. Of these, 10 subsequently refused to participate and received supportive therapy alone (refusers), 12 received risperidone (mean daily dosage 13 mg) and cognitivebehavioural therapy (treatment group), and 9 received supportive therapy alone (control group).
In order to identify the onset of acute levels of first-episode psychosis in the ultra-high-risk group, operationalised criteria for onset of psychosis were defined (Yung et al, 1998). Frank psychotic symptoms must be experienced for longer than 1 week to fulfil these criteria, which are informed by the common threshold for prescribing anti-psychotic medication. Participants in the ultra-high-risk group were monitored regularly following the baseline scan to detect whether this threshold for onset of acute psychotic symptoms had been reached, and were subsequently divided into two groups depending on outcome at the most recent follow-up interview: those with psychotic symptoms (n=21) and those without (n=42). The predominant diagnosis in the psychosis subgroup was schizophrenia (n=10), but there were also diagnoses of schizoaffective disorder (n=2), affective psychosis (n=6) and other psychotic disorder (n=3). The majority of the non-psychosis subgroup had no diagnosis at follow-up (n=24), and the remainder were diagnosed with major depressive disorder (n=4), panic disorder (n=2), obsessivecompulsive disorder (n=2), social phobia (n=3), dysthymia (n=2), adjustment disorder (n=1) and substance-induced mood disorder (n=2). Two members of the non-psychosis subgroup did not receive a formal diagnostic interview at the 12-month follow-up.
Socio-demographic and related measures
Information on age and height was gathered at intake from participants in
all groups (Table 1). All those
in the ultra-high-risk group were assessed at baseline and over the follow-up
period with the Brief Psychiatric Rating Scale (BPRS;
Overall & Gorham, 1962) and the Scale for the Assessment of Negative Symptoms (SANS;
Andreasen, 1983). A Structured
Clinical Interview for DSMIV Axis I Disorders (SCIDI;
First et al, 1997) was
used to assess all members of the ultra-high-risk group at the 12-month
follow-up point.
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Scanning protocol
Participants were scanned using identical 1.5 T scanners at the Cabrini
Hospital, the Royal Melbourne Hospital or the Royal Children's Hospital,
Melbourne. The sequences obtained from the latter two hospitals were
identical. A three-dimensional volumetric spoiled gradient recalled echo in
the steady state sequence generated 124 contiguous, 1.5-mm coronal slices.
Imaging parameters for the Cabrini Hospital sequences (those for the Royal
Melbourne and Royal Children's Hospitals are given in parentheses) were: echo
time (TE) 9 ms (3.3 ms); repetition time (TR) 36 ms (14.3 ms); flip angle
35° (30°); matrix size 256x192 (256x256); field of view 20
cm615 cm (24 cmx24 cm) voxel dimensions 0.781 mmx0.781
mmx1.5 mm (0.938 mmx0.938 mmx1.5 mm). Head movement was
minimised by foam padding and by straps secured across the forehead and chin.
Each scanner was calibrated fortnightly using the same proprietary phantom to
ensure stability and accuracy of measurements. In a direct comparison of
whole-brain volumes obtained from these machines we have previously shown that
there is no significant group by scanner interaction
(Velakoulis et al,
1999). In any case, our measures of gross morphological features
(i.e. the presence or absence of major sulci) are unlikely to be influenced by
minor variations between scanners. Imaging data were coded to ensure
participant confidentiality and masked rating. Image analysis was performed
using MEDx version 3.0 (Sensor Systems, Stirling, VA, USA).
Classification of anterior cingulate morphology
Paracingulate morphology and cingulate continuity
A protocol was generated to classify aspects of anterior cingulate cortex
sulcal and gyral patterns including the presence and absence of the
paracingulate sulcus (Yücel et
al, 2001), as well as the continuity of the cingulate sulcus.
The cingulate sulcus was considered to be continuous unless there was a clear
interruption (defined as a gap of more than 10 mm) in its course, present for
at least three adjacent slices (Fig.
1). The paracingulate sulcus was defined as the sulcus located
dorsal to the cingulate sulcus with a course clearly parallel to the cingulate
sulcus. Based on the presence or absence of the paracingulate sulcus and its
anteroposterior length, three categories of morphology were derived: prominent
paracingulate sulcus, present paracingulate sulcus and absent paracingulate
sulcus.
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Raters were instructed to obtain a midsagittal section, align the
anteriorposterior commissural (ACPC) line horizontally and move
three or four slices laterally from the midline in order to classify the
anterior cingulate cortex morphologically. Assessing the cortex over several
sagittal slices in this way is important to avoid classifying superficial
dimples and to eliminate the effects of sampling error from both the right and
left sides of the medial frontal walls and from the fluid-filled space between
them. Both intrarater and interrater reliability for the classification of
paracingulate sulcus morphology had been previously established using 24
randomly chosen cases (48 hemispheres)
(Yücel et al,
2001): weighted values were 0.96 and 0.90, respectively.
Intrarater and interrater reliability for the classification of cingulate
sulcus continuity was established using 16 randomly chosen cases (32
hemispheres), with
values of 0.95 and 0.92, respectively. In all
cases, both raters were, at all times, blind to participant details.
Paracingulate asymmetry index
An asymmetry index was assigned to each individual based on the combination
of left and right paracingulate sulcus morphology, as described by Yücel
et al (2001). For
example, the paracingulate sulcus in the prominent
classification is more explicit (i.e. greater anteroposterior extent of the
sulcus) than that in the present pattern, which in turn is more
explicit than that in the absent pattern. Thus an asymmetry
index was assigned to each individual in terms of a leftward (left>right),
symmetric (left=right), or rightward (left<right) bias, indicating whether
an individual has a symmetrically or asymmetrically folded paracingulate
sulcus and in which direction. The asymmetry index is important because it
provides an alternative to the unpaired comparison that examines
patterns of ACC morphology across the population. That is, the individual's
one cerebral hemisphere acts as a control for the other. Also, the use of the
asymmetry index as a single dependent variable derived from the values for
each hemisphere avoids the difficulty of analysing repeated-measures variables
(i.e. left v. right) within this categorical analysis framework.
Statistical analyses
All data were analysed using the Statistical Package for the Social
Sciences, version 10.0 for Windows. Demographic data were compared using
one-way analyses of variance for psychopathology scores, age and height.
McNemar's test for symmetry was used to test whether the number of cases of
paracingulate sulcus asymmetry in one direction was counterbalanced by an
equal number of cases with an asymmetry in the other direction. A significant
value indicates an asymmetric pattern in the sample a greater
explicitness of cortical folding in one direction. More complex models
including interaction effects could not be examined within this analytic
framework. Therefore, the effect of diagnostic group on paracingulate sulcus
morphology was further examined using chi-squared analyses in which the
morphology on the left or right (with three ordered categories) or asymmetry
index (with three ordered categories; see above) was the dependent variable.
The effect of diagnostic group on cingulate sulcus continuity was also
examined using a 2x2 2 analysis with continuity
correction in which the continuity on the left or right (with two categories:
one segment or more than one segment) were the dependent variables. In all
analyses, age was used as an independent variable.
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RESULTS |
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Anterior cingulate cortex morphology
Although the cingulate sulcus was present in all hemispheres studied, the
presence or absence of the paracingulate sulcus was extremely variable within
and between hemispheres. Across hemispheres, 74% of the control group and 61%
of the ultra-high-risk group showed evidence of a paracingulate sulcus either
present or prominent.
Cingulate sulcus continuity
The proportions of participants with a continuous or interrupted cingulate
sulcus can be seen in Table 2.
There was a significant difference between the two groups for continuity in
the left hemisphere: the ultra-high-risk group was more likely than the
control group to have an interrupted cingulate sulcus on the left hemisphere.
There was no significant main effect of age on cingulate sulcus
continuity.
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Paracingulate morphology
The paracingulate sulcus classifications across each hemisphere of each
diagnostic group can be seen in Table
3. There was a significant difference between the groups for
paracingulate sulcus morphology in the left hemisphere: the ultra-high-risk
group was less likely than the control group to have a prominent paracingulate
sulcus on the left hemisphere. There was no significant main effect of age on
morphology.
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Paracingulate asymmetry
The McNemar test for symmetry was used to test whether the number of cases
of paracingulate sulcus asymmetry in one direction was counterbalanced by an
equal number of cases with an asymmetry in the other direction, separately for
each group. Results showed a significant asymmetry in the control group
(2(3)=21.16; P<0.001) but not in the ultra-high-risk group
(
2(3)=2.73; P<0.43), indicating a biased distribution of
paracingulate sulcus morphology in controls but not in those at ultra-high
risk. Asymmetry of the paracingulate sulcus was further examined using the
asymmetry index measure, which enables the use of
2 analyses
to make direct group comparisons. The proportions of leftward, symmetric and
rightward asymmetries were 51% (n=38), 31% (n=23) and 19%
(n=14) respectively for healthy controls, and 37% (n=23),
37% (n=23) and 27% (n=17) respectively in the
ultra-high-risk group. A direct comparison of the two groups on asymmetry
showed no significant difference (
2(2)= 2.97; P<0.23).
Finally, there was no significant main effect of age on paracingulate sulcus
asymmetry.
Psychosis v. non-psychosis ultra-high-risk groups
There was no significant difference between the psychosis and non-psychosis
subgroups of the ultra-high-risk group for either the left or right hemisphere
on measures of cingulate sulcus continuity, paracingulate sulcus morphology or
paracingulate sulcus asymmetry, including the McNemar test (all P
values greater than 0.1).
Effects of treatment
Thirty-one people in the ultra-high-risk group were receiving some form of
therapy after baseline (12 risperidone and 19 supportive therapy), which might
have affected their transition to psychosis
(McGorry et al,
2002). However, reanalysis of the data excluding those receiving
risperidone treatment (n=10 in the psychosis subgroup and
n=2 in the non-psychosis subgroup) did not alter the results. In any
case, this issue has no bearing on the findings of anterior cingulate cortex
anomalies in the ultra-high-risk group as a whole.
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DISCUSSION |
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Overall, these findings are consistent with previous research on cingulate sulcus continuity both in healthy individuals (Paus et al, 1996) and in people with schizophrenia (Leonard et al, 1999; further information available from the author upon request), and also with work on paracingulate sulcus morphology in the disease state (Yücel et al, 2002a). These findings are not attributable to the differences in age between the two participating groups, since there was no relationship between age and anterior cingulate cortex morphological patterns. In addition, the fact that we studied gross sulcal and gyral patterning means that our results are unaffected by the participants' use of medication, alcohol or other drugs. This study provides evidence of a lateralised disturbance of brain morphology in men identified as being at ultra-high risk of developing a psychotic illness, in line with the notion of Crow that disturbances of cerebral asymmetry are intimately associated with the disease process of psychosis (Crow et al, 1989). However, our findings indicate that although anterior cingulate cortex anomalies are present prior to illness onset, they do not identify individuals who will subsequently develop psychosis. This suggests that such anomalies are non-specific in their association with psychopathological problems in young people (i.e. sub-threshold psychosis, affective and anxiety features), in contrast to volumetric measures (Pantelis et al, 2003).
The paracingulate sulcus is a tertiary sulcus and is therefore less likely to be under the control of genetic factors, as suggested by recent twin studies of sulci and gyri (Bartley et al, 1997; Lohmann et al, 1999). Further, given that the patterns of sulci and gyri are essentially fixed early in life, anomalies of the paracingulate sulcus might be markers of subtle neurodevelopmental deviance caused by environmental or epigenetic factors and associated with an increased risk of psychopathological disorders. For example, it is known that the anterior cingulate cortex develops in close proximity to areas that are often affected by complications during the prenatal period such as haemorrhage and infarction (Pape et al, 1979; Slagle et al, 1989). Although such severe intra-uterine injuries are unlikely to be a common aetiopathological mechanism for either psychopathological disorder or psychosis, they have been associated with significant delays in development of the cingulate region, including increased interruptions in cingulate sulcus continuity (Slagle et al, 1989). Therefore, more subtle delays and/or alterations in the neurodevelopment of this region might be sufficient to cause the reduced prominence of the paracingulate sulcus and the increased interruption of the cingulate sulcus found in this study.
Functional consequences of anterior cingulate cortex anomalies
Although morphological anomalies of the anterior cingulate cortex are more
common in young people with psychopathological symptoms than in healthy
individuals, they are not more common in those who later demonstrate a
psychotic disorder. This implies that they are risk factors for mental state
changes rather than for any specific diagnosis. How this occurs is still
unclear, since the consequences of morphological changes in the anterior
cingulate cortex have yet to be elucidated. In a functional imaging study, we
found that this left-sided anomaly in the paracingulate sulcus of patients
with schizophrenia was reflected in a failure to activate the left
paracingulate during Stroop task performance
(Yücel et al,
2002b). In addition, both our own and other studies have
shown that verbal fluency performance is better in healthy individuals with a
normal leftward asymmetry of the paracingulate sulcus (further
information available from the author upon request). Taken together, these
findings suggest that morphological changes in this region can have
significant effects on behaviour.
Given that altered morphological asymmetry in the anterior cingulate cortex is not predictive of psychosis, it is possible that there is a multi-level (i.e. macro and micro) disturbance of anterior cingulate cortex integrity in patients who do make this transition. This could be related to the reported and heritable reductions in perfusion (Blackwood et al, 1999) and N-acetyl aspartate:choline ratios (Keshavan et al, 1997) in the anterior cingulate cortex of asymptomatic but high-risk relatives of patients with schizophrenia, and/or to the effects of environmental influences (such as drug use or stress) on the functional integrity of this region.
There is also evidence to suggest that the anterior cingulate cortex refines its connectivity and functional circuitry throughout life (e.g. its glucose metabolism increases with age; Van Bogaert et al, 1998), implying that ongoing developmental factors might also be relevant. It has been recently demonstrated that Stroop-task-related activity of the anterior cingulate cortex increases linearly from age 7 years to 22 years (Adleman et al, 2002), and that this is specific to the left anterior cingulate cortex the region identified as showing reduced folding in both schizophrenia (Yücel et al, 2002a) and ultra-high-risk states, and which is also hypoactive in people with schizophrenia during performance of the same task (Yücel et al, 2002b). Together, these findings lead us to speculate that the age-related improvements in anterior cingulate cortex connectivity and functional circuitry are also disrupted in people affected by schizophrenia, and perhaps to a lesser extent in those at ultra-high risk of psychotic disorder.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication August 9, 2002. Revision received November 22, 2002. Accepted for publication January 27, 2003.
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