MULTIMODAL IMAGING OF PRODROMAL PSYCHOSIS: A CRITICAL
Paolo Fusar-Poli, Philip McGuire, Stefan Borgwardt
Department of Psychosis Studies, Institute of Psychiatry, London UK.
Address for correspondence: Dr. Paolo Fusar-Poli, Department of Psychosis Studies,
Institute of Psychiatry, De Crespigny Park 16, SE58AF London UK.
Phone +44 (0)77 8666 6570 ; Fax +44 (0)20 7848 0976 ; e-mail: email@example.com
The onset of schizophrenia is usually preceded by a prodromal phase characterized by
functional decline and subtle prodromal symptoms, which include attenuated
psychotic phenomena, cognitive deterioration and a decline in socio-occupational
function. Preventive interventions during this phase are of great interest because of
the impressive clinical benefits. However, available psychopathological criteria
employed to define a high risk state for psychosis have low validity and specificity.
Consequently there is an urgent need of reliable neurocognitive markers linked to the
pathophysiological mechanisms that underlie schizophrenia. Neuroimaging
techniques have rapidly developed into a powerful tool in psychiatry as they provide
an unprecedented opportunity for the investigation of brain structure and function.
This review shows that neuroimaging studies of the prodromal phases of psychosis
have the potentials to identify core structural and functional markers of an impending
risk to psychosis and to clarify the dynamic changes underlying transition to
psychosis and to address significant correlations between brain structure or function
and prodromal psychopathology. Additionally, neurochemical methods can address
the key role played by neurotransmitters such as dopamine and glutamate during the
psychosis onset. To conclude, multimodal neuroimaging may ultimately clarify the
neurobiology of the prodromal phases by the integration of functional, structural and
KEYWORDS: Prodromal, neuroimaging, high risk, psychosis, schizophrenia,
HR - High Risk
ARMS - At Risk Mental State
COPS -Criteria for Prodromal Syndromes
FMRI - Functional Magnetic Resonance Imaging
SMRI- Structural Magnetic Resonance Imaging
PET- Positron Emission Tomography
MRS- Magnetic Resonance Spectroscopy
NMDAR- N-methyl-D-aspartate receptor
VBM- Voxel-based Morphometry
HR-T- High Risk subjects with a subsequent transition to psychosis
HR-NT- High Risk subjects without a subsequent transition to psychosis
The onset of schizophrenia is usually preceded by a prodromal phase characterized by
functional decline and subtle prodromal symptoms, which include attenuated
psychotic phenomena, cognitive deterioration[2, 3]and a decline in socio-occupational
function . Research into the early phases of psychosis promises to provide
important clues to the mechanisms underlying schizophrenia and other psychotic
disorders. Investigation of subjects at the beginning of illness allows researchers to
minimize confounders such as neurodegenerative progress of disease,
institutionalization and long-term treatment, particularly with antipsychotics. To
explore vulnerability to psychosis current literature employs two research paradigms.
The genetic high-risk approach usually involves studying the non-psychotic first
degree relatives of patients. The clinical high-risk strategy focuses on individuals who
are considered to be at an increased risk for psychotic disorders based primarily on the
presence of clinical features such as attenuated psychotic symptoms or schizotypal
traits, brief limited intermittent psychotic symptoms or a recent decline in functioning,
characteristics that significantly increase the risk for imminent onset of psychosis.
Although these strategies allow researchers to identify individuals at enhanced risk for
psychosis , these symptoms overlap with psychotic experiences in healthy
individuals who are not at risk and do not seek clinical help. It follows that
identification of neurocognitive markers linked to the pathophysiological mechanisms
that underlie schizophrenia, may significantly augment the validity and specificity of
clinical features preceding illness onset. This is of great interest in the light of the
impressive clinical benefits of preventive interventions in psychosis[6-8]. There are,
at least, three possible mechanisms for improving the course of the disease by
intervention before onset of psychosis. First, it might be possible to prevent psychosis
by intervening in a crucial phase of beginning symptoms. Second, it might be possible
to improve the course of the disease by improving the mental state in the prodromal
phase or by postponing the first psychotic episode. Finally, the first psychotic episode
might have a more favorable course after intervention in the prodromal phase,
because the patient is already enrolled in a mental health treatment program: a
psychosis will be discovered soon after onset, and the patient might be more willing
to accept treatment, thus shortening the duration of untreated psychosis.
Brain imaging is a potentially powerful tool to improve the specificity and validity of
an early diagnosis and to sustain preventive intervention prior the onset of illness. In
this review, we will consider the role of neuroimaging techniques in the prodromal
phases of psychosis. Neuroimaging techniques have rapidly developed into a
powerful tool in psychiatry as they provide an unprecedented opportunity for the
investigation of brain structure and function. We will first outline the applications of
structural magnetic resonance imaging for the investigation of brain abnormalities
underlying the pre-psychotic phases and psychosis onset. Then we will discuss the
specific potentials of functional magnetic resonance techniques to address the
neurofunctional correlates of an enhanced risk to psychosis, identify neurobiological
markers of psychosis transition and evaluate the effects of antipsychotic on brain
function during prodromal psychosis. In a final section we will further discuss the role
of neurochemical imaging to study the role played by central neurotransmitters such
as dopamine and glutamate in prodromal psychosis. Finally we will illustrate recent
developments of neuroimaging methods which allow the integration of data across
Structural MRI in established psychosis
Neuroimaging studies clearly indicate that schizophrenia is associated with
neuroanatomical abnormalities, with the most replicated findings being ventricular
enlargement, higher prevalence of cavum septum pellucidum abnormalities and
reductions in frontal and medial temporal lobe grey matter volume[10, 11] . However
the extent to which these are related to a vulnerability to schizophrenia, as opposed to
the disorder per se, is less certain.
Grey matter volume abnormalities in prodromal psychosis: cross sectional studies
Studies in subjects at genetic risk for psychosis indicate qualitatively similar
abnormalities are evident in first-degree relatives and co-twins of patients with
schizophrenia[12-15]. However, it is not clear as yet at what stage of the disorder
these brain abnormalities occur. Similarly, relatively little is known about the nature
of the abnormalities in subjects at clinical risk for psychosis (i.e. with an “at-risk
mental state’, ARMS). In a cross-sectional study from Basel, MRI data from an high
risk (ARMS) sample (n=35) were compared with healthy controls and first-episode
patients. Compared with healthy controls, both first-episode patients and high-risk
subjects showed significantly less gray matter volume in the posterior part of the left
superior temporal gyrus and the adjacent part of the left insula, and in a second region
involving the posterior cingulate gyrus and precuneus [16, 17, 18](Figure 1).
However, the high risk group was heterogenous including both, patients who later
developed psychosis and those who did not. Within the high risk group, those subjects
who developed psychosis (HR-T; n=12) had less grey matter than subjects who did
not (HR-NT; n=23) in the right insula, inferior frontal and superior frontal gyrus [16,
17, 18]. These volumetric differences within the high risk group were associated with
the subsequent development of psychosis and could be related to a process which
underlies a progression from a high risk state towards a psychotic illness.
Grey matter changes during the transition to psychosis: longitudinal studies
The transition from prodromal phase into frank psychosis and the first two years of
the first-episode has been associated with frontal and temporal decreases in gray
matter. Using voxel-based approach, HR-T (subjects with ‘prodromal’ symptoms who
developed psychosis) showed a longitudinal reduction in gray matter volume in the
left parahippocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate
gyri. In this first longitudinal MRI study in ARMS, it was found that the HR-T
showed a longitudinal reduction in gray matter volume in the left parahippocampal,
fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri. In another
longitudinal study with largely the same subjects, greater brain contraction was
found in the right prefrontal region in HR-T compared with HR-NT(Figure 2). These
findings are consistent with prospective studies in patients with established
schizophrenia, which indicate that longitudinal reductions in regional gray matter
volume also occur in chronic patients [21-26].
To summarize the contrasting MRI findings in prodromal psychosis we have recently
conducted a voxel based meta-analysis including twenty studies of subjects at
enhanced clincal or genetic risk to psychosis. The overall sample consisted of 746
controls and 920 high risk subjects. We concluded that GM volume reductions in
temporo-parietal, bilateral prefrontal and limbic cortex are neuroanatomical correlates
of an enhanced vulnerability to psychosis (Figure 3), while transition to psychosis
was associated with reductions in superior temporal and inferior frontal areas.
Neurofunctional correlates of an enhanced risk to psychosis
Available fMRI studies in high risk subjects indicate that some functional
neuroimaging abnormalities in schizophrenia are evident before the onset of the
disorder. These alterations are qualitatively similar to the changes seen in established
schizophrenia but less marked. For example, our group has recently addressed the
neurofunctional correlates of working memory in subjects at enhanced clinical risk for
psychosis by employing a traditional n-back task (Figure 4). Subjects at high risk
for psychosis showed reduced prefrontal and parietal activation relative to controls
during the menmonic paradigm (Figure 4). The fMRI data revealed a relatively
reduced blood oxygen level–dependent response in the dorsolateral and medial
prefrontal cortex of subject at high risk for psychosis. Abnormalities in prefrontal
activation during cognitive tasks have previously been described in the prodromal
phases of psychosis (for a meta-analysis see ) and have consistently been reported
in the early phases of schizophrenia. In another study we employed fMRI to
investigate cortical function during a false memory task. During the encoding
phase, subjects at risk for psychosis read lists of words aloud. Following a delay, they
were presented with target words, semantically related lure words and novel words
and required to indicate if each had been presented before. Behaviorally, the subjects
at clinical risk for psychosis made more false alarm responses for novel words than
controls and had a lower discrimination accuracy for target words. During encoding,
high risk subjects showed less activation than healthy controls in the left middle
frontal gyrus, the bilateral medial frontal gyri, and the left parahippocampal gyrus
(Figure 5). As indicated by the plot in figure 5, these neurofunctional differences
were associated with diminished recognition performance and may reflect the greatly
increased risk of psychosis associated with the prodromal phases of psychosis.
Overall, the fMRI studies addressing the neurofuncitonal correlates of vulnerability to
psychosis raise the possibility that neuroimaging could be used to detect
pathophysiological changes associated with the disorder before the onset of frank
illness. This is of particular clinical interest because only a proportion of people with
prodromal symptoms go on to develop schizophrenia (see below here), and
neuroimaging might facilitate the targeting of novel preventive treatments to this
Neurofunctional mapping of psychosis transition
Overall functional imaging studies indicate that the neurofunctional abnormalities
during cognitive tasks are qualitatively similar but less severe in high risk subjects
compared to first-episode patients. However, the onset and the time course such
alterations are mostly unknown. Indeed, it is critical to the understanding of the
pathogenesis of these brain changes to clarify their onset and the dynamic
neurobiological processes underlying the transition from a high-risk state to full-
blown psychosis. To address this point some fMRI studies have compared high-risk
subjects with (HR-T) and without (HR-NT) later transition to psychosis. We have
summarized fMRI longitudinal studies addressing psychosis transition in a recent
meta-analysis which confirmed abnormalities in the prefrontal cortex.
Specifically, decreased activation in anterior cingulate cortex and increased activation
in left parietal lobe were described in genetic HR-T relative to controls in a
prospective fMRI cross-sectional study. These neurofunctional abnormalities
could delineate a pathological process in the affected brain regions as well as a
compensatory process to volumetric region-specific reductions in gray or white
Brain connectivity in the pre-psychotic phases
An alternative approach to identifying functional abnormalities in particular brain
regions has been to look for abnormalities in the integration of function between brain
regions, such as the prefrontal and temporal cortex. In a recent study we have
investigated frontotemporal connectivity in subjects at enhanced clinical risk for
psychosis. Superior temporal lobe (STG) dysfunction is a robust finding in functional
neuroimaging studies of schizophrenia and is thought to be related to a disruption of
fronto-temporal functional connectivity but the stage of the disorder at which these
functional alterations occur is unclear. We addressed this issue by using Dynamic
Causal Modelling and fMRI to study subjects in the prodromal and first episode
phases of schizophrenia during a working memory task (n-back). We found that
the STG was differentially engaged across the three groups. There was deactivation of
this region during the task in controls, whereas subjects with a first episode of
psychosis showed activation and the response in subjects at high risk was
intermediately relative to the two other groups (Figure 6). There were
corresponding differences in the effective connectivity between the STG and the
middle frontal gyrus across the three groups, with a negative coupling between these
areas in controls, a positive coupling in the first episode group, and an intermediate
value in the high risk group (Figure 6). We concluded that a failure to deactivate the
superior temporal lobe during tasks that engage prefrontal cortex is evident at the
onset of schizophrenia and may reflect a disruption of fronto-temporal
connectivity. However, although there appear to be abnormalities in functional
connectivity in schizophrenia, a single pattern of dysconnectivity that characterises its
pathophysiology has yet to be identified.
fMRI and longitudinal outcomes in subjects at high risk for psychosis
Although people with prodromal signs of psychosis show neurofunctional alterations
underlying executive processes when they first present to clinical services, the
longitudinal course of these abnormalities, and how they relate to subsequent clinical
and functional outcome is relatively unclear. To address this point we employed
longitudinal fMRI during verbal fluency in a cohort of subjects at clinical risk for
psychosis and in healthy controls. We found that  the normalization of the
abnormal prefrontal response over time was directly related to the improvement in
severity of hallucination-like experiences. These studies provide evidence that in
prodromal psychosis brain changes concur with symptomatic improvement. In
addition they emphasize the importance of early interventions in the treatment of
schizophrenia, suggesting that the observed neurophysiological abnormalities are
something that could perhaps be modulated by active interventions before the
Dopamine and psychosis
The most enduring neurochemical theory of schizophrenia centres upon dysregulation
of dopaminergic neurotransmission. All currently licensed antipsychotic drugs block
dopamine receptors, indicating that manipulation of dopaminergic function is
fundamental to therapeutic response in psychosis. Striatal hyperdopaminergia has
been postulated to be fundamental to the generation of the psychotic symptoms that
characterize schizophrenia. In recent years, neurochemical imaging techniques such
as positron emission tomography (PET) have enabled the striatal dopaminergic
system to be characterized in vivo in patients with schizophrenia .
Dopamine dysregulation prior to the onset of psychosis
Whilst there is consistent evidence indicating a link between dopamine dysregulation
and established psychosis, all the studies were conducted in people who had already
developed psychosis. It is therefore possible that rather than causing psychosis, the
dopamine dysregulation is secondary- occurring as a consequence of some other
factor. To determine whether this is the case or not it is necessary to study people in
the phase just preceding the development of psychosis.
Dopamine function has recently studied in subjects with prodromal signs of
schizophrenia, all of whom had attenuated psychotic symptoms. Presynaptic striatal
dopamine synthesis capacity (Kostant influx, see Figure 7) was elevated in people
who were at high risk of schizophrenia but did not have the disorder, to a degree
approaching that in patients with established schizophrenia (Figure 7). Furthermore,
striatal dopamine levels were directly correlated with the severity of prodromal
symptoms in high risk subjects (Figure 7). The findings remained robust after
adjustment for putative factors that might influence the PET measurements.
These data suggest that increased subcortical dopamine activity is already present
before the full expression of schizophrenia, consistent with the putative role of
dopamine in the pathophysiology of psychosis. However, as not all high risk subjects
go on to develop psychosis, and dopamine dysfunction may also occur in the
relatives of patients with schizophrenia, elevated dopamine activity may also be a
correlate of an increased vulnerability to psychosis. Follow-up of high risk subjects is
therefore needed to determine whether elevated striatal dopamine activity leads to
psychosis or is a correlate of vulnerability.
Glutamate in established psychosis
The glutamate hypothesis of schizophrenia arose in the 1980s from converging
findings – firstly, that patients with schizophrenia had reduced CSF glutamate ,
and secondly that drugs such as phencyclidine (PCP) and ketamine, which induce
effects markedly similar to both positive and negative symptoms of schizophrenia, act
as high affinity antagonists for the N-methyl-D-aspartate receptor (NMDAR) [37, 38].
This evidence has been further supported by the recent finding that most of the
candidate genes for schizophrenia are associated with glutamatergic
neurotransmission at the NMDAR containing synapse . In addition to the growing
genetic support for a primary glutamatergic basis for the illness , two groups have
reported reduced NMDAR mRNA in left hippocampus in post-mortem brain [40, 41],
while an in vivo single photon emission tomography (SPET) study showed a relative
reduction in left hippocampal NMDAR binding in patients with schizophrenia .
Glutamatergic change and, by extension, excitotoxicity, appears to be a feature of the
early phase of psychosis. If glutamatergic changes drive transition to psychosis, it
might be expected that these changes may also be present in individuals prodromal for
Glutamate dysfunction in prodromal psychosis
Several groups have investigated brain glutamate abnormalities in individuals at high
risk of psychosis. Adolescents at high genetic risk of schizophrenia (having relatives
with schizophrenia) were reported to have increased glutamine/glutamate in medial
frontal cortex by Tibbo and colleagues , and work in our laboratory has found
increased glutamine in anterior cingulate, but reduced glutamate in left thalamus in
subjects at risk of psychosis . We also found that in ARMS subjects, lower
thalamic glutamate levels were associated with reduced gray matter volume in medial
temporal cortex and insula (Figure 8), and in a longitudinal study of patients with
first episode schizophrenia, Theberge found that reductions in thalamic glutamine
levels correlated with reductions in parietal and temporal grey matter . Reductions
in thalamic glutamate could lead to reduced thalamic GABAergic interneuron activity
and, by extension, disinhibition of thalamocortical glutamate projection neurons.
Thus, the reductions in temporal cortex grey matter volume could arise secondary to
excess glutamate release. Alternatively, reductions in temporal cortex volume could
be primary and lead to secondary reductions in thalamic glutamate levels through
reductions in glutamatergic efferents from temporal cortex. Future studies examining
the longitudinal change in grey matter and glutamate levels in individuals with
prodromal psychosis are required to clarify these points.
Integration of neuroimaging findings across modalities
Recent advancements in imaging techniques allow researchers to combine different
imaging modalities. Multimodal neuroimaging during the prodromal phases of
psychosis is nowadays possible and has the potential to delineate the causal
relationship between key pathophysiological processes in the evolution of psychosis.
We have described above here a Magnetic Resonance Spectroscopy – Voxel based
morphometry (MRS-VBM) study addressing the relationship between gray matter and
thalamic glutamate in prodromal psychosis. Other examples are given by fMRI-PET
(Positron Emission Tomography)[29, 46] and fMRI-MRSand fMRI-
VBMstudies of subjects at enhanced risk for psychosis. The former studies aimed
at investigating the relationship between dopamine function and cortical activation in
people experiencing prodromal symptoms of psychosis. Abnormal cortical function
during cognitive tasks and elevated striatal dopaminergic transmission  are two of
the most robust pathophysiological features of schizophrenia. Both alterations in
prefrontal activation during working memory/executive processes and elevated
subcortical dopamine  are also evident in individuals with an enhanced risk for
psychosis. However, the exact relationship between them in the development of the
disorder remains to be established. To address this issue we studied medication-naive
subjects with prodromal signs for psychosis, measuring prefrontal activation during a
verbal fluency task with functional magnetic resonance imaging (fMRI) and
measuring dopamine synthesis capacity in the striatum with fluorine18–labeled
fluorodopa PET. We found that altered prefrontal activation in subjects at
enhanced risk for psychosis was related to elevated striatal dopamine function (Figure
9). In a following PET-fMRI study during working memory we uncovered a
positive correlation between frontal activation and fluorodopa uptake in the
associative striatum in controls but a negative correlation in the high risk group
(Figure 10). The key findings from these studies taken altogether is that in
individuals at very high risk of schizophrenia, altered prefrontal activation during a
task of executive/working memory function was directly related to striatal
hyperdopaminergia. This provided evidence of a link between dopamine dysfunction
and the perturbed prefrontal function, which may underlie the deficits in cognitive
processing evident in people with prodromal symptoms of psychosis and predate the
first episode of frank psychosis.
In another multimodal study using a combination of functional MRI and proton
magnetic resonance spectroscopy, we showed that in people with prodromal signs of
psychosis, medial temporal activation during a memory task is decoupled from local
glutamate levels (Figure 11). Both medial temporal cortical dysfunction and
perturbed glutamatergic neurotransmission were regarded as fundamental
pathophysiological features of psychosis but their relationship in humans was not
Neuroimaging studies of the prodromal phases of psychosis have the potentials to
identify core structural and functional markers of an impending risk to psychosis, to
clarify the dynamic changes underlying transition from a high risk state to full
psychotic episodes and to address significant correlations between brain structure or
function and prodromal psychopathology. On the other hand, neurochemical
investigations of the pre-psychotic phases can address the key role played by
neurotransmitters such as dopamine and glutamate during the psychosis onset. The
combination of neuroimaging across modalities may ultimately clarify the
neurobiology of the prodromal phases by the integration of functional, structural and
neurochemical findings. Despite a wide range of methodological differences between
studies, neuroimaging studies of the subjects who later develop psychosis may in
future lead to neuroanatomical and neurofunctional markers. These markers could be
used to enable the prediction of disease transition at an individual level. Additionally,
in order to prevent and normalize the observed neuroimaging abnormalities,
pharmacological and non-pharmacological interventions, such as psychosocial
intervention, family support, cognitive behavioral therapy (CBT) may be used in
future. Although the clinical relevance of brain abnormalities in this group is not fully
established, neuroimaging studies in prodromal subjects could provide the targets for
early intervention with that could potentially prevent a chronic trajectory of the
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