The Canadian Journal of Psychiatry, Vol 58, No 1, January 2013 W 1
Key Words: neuroimaging,
at-risk mental state
Received and accepted April
Neuroimaging Findings in the At-Risk Mental State:
A Review of Recent Literature
Stephen J Wood, PhD1; Renate L E P Reniers, PhD2; Kareen Heinze, MSc3
1 Professor of Adolescent Brain Development and Mental Health, School of Psychology, University of Birmingham, Edgbaston, England; Honorary Principal
Research Fellow, Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia.
Correspondence: School of Psychology, University of Birmingham, Edgbaston, UK B15 2TT; email@example.com.
2 Research Fellow, School of Psychology, University of Birmingham, Edgbaston, England.
3 Graduate Student, School of Psychology, University of Birmingham, Edgbaston, England.
The at-risk mental state (ARMS) has been the subject of much interest during the past 15
years. A great deal of effort has been expended to identify neuroimaging markers that can
inform our understanding of the risk state and to help predict who will transition to frank
psychotic illness. Recently, there has been an explosion of neuroimaging literature from
people with an ARMS, which has meant that reviews and meta-analyses lack currency.
Here we review papers published in the past 2 years, and contrast their findings with
previous reports. While it is clear that people in the ARMS do show brain alterations when
compared with healthy control subjects, there is an overall lack of consistency in which of
these alterations predict the development of psychosis. This problem arises because of
variations in methodology (in patient recruitment, region of interest, method of analysis,
and functional task employed), but there has also been too little effort put into replicating
previous research. Nonetheless, there are areas of promise, notably that activation of the
stress system and increased striatal dopamine synthesis seem to mark out patients in the
ARMS most at risk for later transition. Future studies should focus on these areas, and on
network-level analysis, incorporating graph theoretical approaches and intrinsic connectivity
W W W
2 W La Revue canadienne de psychiatrie, vol 58, no 1, janvier 2013
advent of clinical high-risk studies. These studies arose
from an interest in the prodromal phase of psychosis,1 and
resulted in the development of several schedules for the
identification of the ARMS.2,3 This risk state differs from
previously studied genetic risk for psychosis in that there
is no requirement that the person have a family history
of schizophrenia, and instead there must be some recent
change in psychological state, such as functional decline
or the development of attenuated psychotic symptoms.4
The advantage of this approach is that the transition rate
is much higher in a much shorter period (around 30% in
12 months5), allowing numerous biological investigations,
such as neuroimaging, to become feasible.
ARMS at-risk mental state
DTI diffusion tensor imaging
ERP event-related potential
FA fractional anisotropy
FEP first-episode psychosis
fMRI functional magnetic resonance imaging
MRS magnetic resonance spectroscopy
PET positron emission tomography
STG superior temporal gyrus
UHR ultra-high risk
• Neuroimaging studies in at-risk people show differences
from healthy people, but not outside the normal range.
• Clinical utility of neuroimaging in the prodrome is
dubious at present.
ur understanding of the development of psychotic
illnesses has been improved tremendously by the
Since the earliest publication of imaging data from an
ARMS population,6 there has been an explosion of work
in this area. Neuroimaging research, employing structural
and functional techniques, has played an important role
in identifying the neurobiological correlates of enhanced
risk for psychosis and determining the progressive changes
associated with transition.7 There have been several excellent
reviews and meta-analyses in recent years,7–11 but, because
of the rapid pace of publication, they already lack currency.
Here we discuss findings from neuroimaging studies of
people in the ARMS published during the past 2 years in
the light of previous findings and future opportunities.
One of the most surprising features of imaging research
in people with an ARMS is that the best replicated
neuroimaging findings in schizophrenia research, reduced
hippocampal and amygdala volumes and enlarged
lateral ventricles, have not been consistently found in
ARMS samples.7,12 Some studies have detected left
parahippocampal gyrus reductions,13,14 while others
suggest changes are more prominent on the right and in the
hippocampal corpus and tail.15 Some findings demonstrate
reduced hippocampal volume in ARMS,16 but others find
increases,17 emphasizing the inconsistency of the literature.
Similarly, ventricular enlargement has been identified in
one study18 but not in another,19 and in the amygdale, people
in the ARMS present with normal baseline volumes (in
contrast with schizophrenia patients) regardless of whether
they subsequently develop a psychotic illness.15,20,21
Meta-analysis has shown that, compared with healthy
control subjects, people in the ARMS show reduced grey
matter volume in right STG, left precuneus, left medial and
right middle frontal gyrus, and bilateral (para)hippocampal
regions and bilateral anterior cingulate.11 More recent work
has extended this to examine what may predict transition to
psychosis. There is some support for specific volume loss
in insular,22,23 temporal,24 parietal,25 and superior frontal20,26
brain areas in people who develop psychosis, compared
with those who do not. Some regions that may be expected
to show reductions prior to transition (such as the STG
and caudate nuclei) do not do so.27,28 Only one paper has
analyzed converted participants in the ARMS based of their
specific psychotic diagnosis. This revealed reductions in
the postcentral gyrus for schizophrenia spectrum disorders
and superior frontal and cingulate reductions for affective
psychosis, but no differences in the amygdala.20 While
these are only preliminary findings, they do suggest that
specific outcome diagnoses have different neurobiological
presentations in the ARMS phase.
One area of particular interest is the pituitary gland, which
in earlier work was shown to be significantly enlarged
in people with an ARMS who went on to transition to
psychosis (and, importantly, the greater the enlargement,
the shorter the period to transition29). Recently this work
has been replicated in a study from the Basel group,30 which
therefore strongly implicates overactivation of the stress
response systems of the pituitary with the development of
One confounder for all these findings is medication.
Although ARMS patients are less likely to be treated with
neuroleptics than those with FEP, there is some level of
exposure (either through trials or differing treatment at
various centres). There is evidence that long-term neuroleptic
treatment of primates has a widespread effect on brain
volume.31,32 However, evidence from human studies is not
convincing, largely because of the difficulty in conducting
placebo-controlled trials of the impact of neuroleptics on
imaging measures. One meta-analysis has specifically
excluded studies involving people in a neuroleptic-exposed
ARMS,33 and still demonstrated grey matter reductions in
temporal, limbic, and prefrontal regions, suggesting that
these reductions are unlikely to be caused by medication.
The Canadian Journal of Psychiatry, Vol 58, No 1, January 2013 W 3
Neuroimaging Findings in the At-Risk Mental State: A Review of Recent Literature
Another source of difficulty for determining the reliability
of the reported differences are the rates of current substance
use in ARMS groups.34 While this has not been directly
investigated in ARMS cohorts, chronic heavy cannabis use
has been shown to result in smaller volumes of both the
hippocampus and the amygdala,35 and patients with FEP
who use cannabis show significantly more brain volume
loss over time than those who do not.36 Clearly, it will
be important to clarify the role that substance use has in
causing brain alterations in people with an ARMS.
Functional Magnetic Resonance Imaging
While there is significant variability in findings from
structural brain imaging, it has been suggested that fMRI
may show more promise, given that it incorporates both
cognitive performance and neurobiological measurement.7
Many of the brain regions identified in volumetric studies
have shown reduced activation in functional imaging
comparisons of healthy control subjects and people in the
ARMS, particularly in clusters covering the left inferior
frontal gyrus, bilateral medial and superior frontal gyri,
and left anterior cingulate.10 The past 2 years have seen
an explosion of fMRI publications, but integrating them
is not straightforward. Although some studies of working
memory performance have replicated reduced frontal
activation in UHR samples,37–39 most have found increased
activity, especially in medial and inferior frontal regions.40–44
Scattered functional increases and decreases have also
been found in parietal (precuneus, superior parietal,
supramarginal, and postcentral gyrus), occipital, and basal
ganglia areas in response to varied tasks.38,39,41–46
Given the focus on hippocampal volume mentioned above,
there has been recent work investigating the functional
response of the hippocampus during memory encoding and
recognition.37 This task incorporated a design that involved
the participants encoding a list of words, and subsequently
trying to recognize them from among semantically related
lure words and unrelated novel words. While no differences
in hippocampal activation were identified during encoding,
reductions in left parahippocampal, left middle frontal, and
bilateral medial frontal activation were seen in people in
an ARMS, compared with control subjects.37 Further, in the
recognition phase, there was a significant difference between
the ARMS and control groups in the way the hippocampus
responded during correct recognition, compared with false
alarms (incorrectly identifying a lure word as previously
presented). Control subjects showed increased hippocampal
activity during the former, but reduced activity during the
latter, whereas the ARMS group showed little difference
between the 2 conditions.
With such a large number of regions of signal change
observed in functional studies, it is surprising that only
a few studies have adopted a network approach in an
attempt to reveal patterns of interacting areas. The earliest
such study45 used dynamic causal modelling to examine
frontotemporal connectivity during a sentence completion
task. Despite no difference between ARMS and control
subjects in activation within a frontotemporal network,
there was increased activation in the ARMS within the
anterior cingulate. This increased activation seemed to be
related to frontotemporal connectivity, such that increased
anterior cingulate engagement in the ARMS was required
to maintain normal integration. A subsequent study47
exploring this further suggested that the anterior cingulate
was less involved in task-relevant network organization.
While this is an important study, given it is the first to use
graph theoretical approaches in people in the ARMS, it was
unusual in that the analysis grouped the ARMS subjects into
high and low symptoms cohorts based on a median split.
To our knowledge, this kind of comparison has not been
done for any other study, making comparison extremely
difficult. Nonetheless, graph theoretical approaches are
likely to be extremely useful in the future, as are studies of
intrinsic connectivity networks.48 Indeed, there is already
one exploratory study49 of intrinsic networks that found
abnormal resting-state network activity in a group of people
in the ARMS.
Very few functional imaging studies have analyzed data
based on later transition to psychosis, and those that have
are underpowered (for example, Sabb et al43). There have
been analyses of change in activation associated with
clinical improvement, and these suggest that there is a
compensatory increase in bold response in occipitoparietal,
inferior frontal, anterior cingulate, and parahippocampal
regions.26,40,46 However, these findings are from a single,
overlapping, UHR sample, and thus require replication.
Other Imaging Modalities
MRS is a technique that allows in vivo investigation of the
neurochemical integrity of people at risk for psychosis. The
only MRS meta-analysis conducted to date9 found robust
reductions in NAA levels in the thalamus of people in
the ARMS when compared with healthy control subjects,
indicating reduced neuronal integrity of this region. NAA
reductions in the temporal lobe were also found, but only
at trend level. While further studies have not attempted
to replicate the former alteration, there does seem to be
agreement that NAA reductions in the temporal lobe are
not a key feature of the ARMS phenotype. Two papers,
comprising a combined 96 patients in the ARMS, failed to
find any NAA alterations in temporal regions,16,50 although
the number of transitions was low. However, evidence
implicating glutamatergic dysfunction in the prodromal
phase has continued to be produced. Elevated glutamate
levels (and also NAA) have been reported in the dorsal
caudate,51 and reduced thalamic glutamate and NAA levels
are associated with abnormal frontal ERPs.52 Further, the
abnormal relation between temporal glutamate levels
and both left parahippocampal activation during memory
encoding53 and elevated dopamine synthesis and storage
in the striatum54 supports the idea of a whole brain system
disorder preceding the onset of frank psychosis.55 However,
this hypothesis is limited by the lack of comparisons based
4 W La Revue canadienne de psychiatrie, vol 58, no 1, janvier 2013
on transition to psychosis, and these findings are based on a
single (fairly small) sample.
Studies of white matter have been hugely assisted by the
development of DTI. One measure commonly derived from
this technique is FA, which is thought to reflect the diameter,
density, and orientation of axons, and provides information
about the integrity of white matter more generally. Two
studies in people in the ARMS have now been published,
from an overlapping cohort in the Netherlands.56,57 There
was generally reduced FA in superior frontal regions in
the patients with an ARMS who progressed to psychosis,
when compared with health control subjects, and lower
FA in the right putamen and left STG, when compared
with nontransitioned patients.56 Confusingly, FA was
significantly higher in the later-transitioned patients,
compared with the nontransitioned ones in the medial
temporal lobe. A subsequent investigation aimed at
comparing statistics from white matter tracts did not reveal
any significant differences.57 While this suggests that white
matter connectivity is disrupted in striatal and temporal
regions before the onset of psychosis, the differences are
mild, compared with those seen in later illness, suggesting
that white matter pathology arises subsequent to the
development of the disorder.
Another alternative neuroimaging technique that has
only recently been applied to an ARMS population is T2
relaxometry. This method offers a highly sensitive but
nonspecific indicator of neuronal pathology, with relaxation
times dependent on protons in macromolecules, iron
concentration, mobile fatty acids, and bound and free water
molecules.58,59 In a study of the hippocampal relaxation
times of 66 people in the ARMS (7 of whom transitioned
to psychosis),16 we showed significantly elevated T2 in the
left hippocampal head in the later-psychotic group, and this
elevation positively correlated with total positive symptoms
in the ARMS group as a whole. As with the DTI study by
Peters et al,57 this may indicate subtle changes in the medial
temporal lobe prior to transition to psychosis that cannot
be picked up by standard volumetric or spectroscopic
One particularly exciting finding in studies of people in
the ARMS comes from investigations of striatal dopamine
synthesis using PET. Elevated striatal synthesis of dopamine
is a feature of psychotic disorders, and has also been reported
in the ARMS.60 Recently, this work has been significantly
extended to examine the relation of this increased dopamine
synthesis with later transition to psychosis. In a sample of
24 people in the ARMS, 9 subjects developed a psychotic
disorder during a 3-year period and had significantly
elevated striatal dopamine synthesis at baseline assessment,
compared with healthy control subjects.61 Importantly, they
also differed significantly from the nontransition group,
implying that even though both ARMS groups presented
with positive symptoms, it was only in the later-psychotic
group that these were related to striatal dopamine. Further,
in a subgroup who could be followed-up for repeat PET
assessment (8 psychotic, 12 nonpsychotic), there was a
progressive increase in striatal dopamine synthesis in those
who transitioned.62 These findings provide some support
for treating people in the ARMS with antipsychotics, given
that these have been shown to prevent or delay transition in
randomized controlled trials.63,64
Challenges for the Future
Although studies of people at increased genetic risk are
not the focus of this review, it is worth mentioning that
findings in relatives of patients affected with psychosis, co-
twins of patients, and people with an ARMS share broadly
comparable neurocognitive abnormalities.65 However,
neuroimaging findings show significant differences
between the groups. When compared with people at
genetic high risk, clinical high-risk people show grey
matter reductions in bilateral anterior cingulate and grey
matter increases in left hippocampus, right STG, and left
insula.11 These findings suggest heterogeneity across high-
risk groups and emphasize the importance of transparent
criteria for inclusion in groups selected for research into
the neurobiology of transition to psychosis. The single
published multisite imaging study13 was a post hoc
collaboration that did not optimize recruitment or image
acquisition, highlighting the need for multisite studies with
shared protocols and closely matched methodology.
Most neuroimaging studies of people in the ARMS have
been cross-sectional and demonstrate that structural changes
found in patients with schizophrenia can be identified
before onset.66 Although there is good evidence for
progression of these volumetric abnormalities as psychosis
develops,67 most of this comes from a single sample and
needs replication. Longitudinal studies following large
groups of people in the ARMS are taking shape (notably
the Predictors and Mechanisms of Conversion to Psychosis
collaborative study [commonly referred to as NAPLS-2])
and show promise in revealing the time course and extent
of abnormalities associated with specific stages of illness.67
Multimodal techniques encompassing structural and
functional neuroimaging, adopting both graph theoretical
approaches and intrinsic connectivity networks,48 are most
suited for this purpose.
The Canadian Psychiatric Association proudly supports the
In Review series by providing an honorarium to the authors.
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