ReviewNeurofunctional correlates of vulnerability to psychosis: A systematic review and meta-analysis
Introduction
Early clinical intervention in schizophrenia has recently become a major objective of mental health services, while research on the early phase of the disorder may provide important clues to the mechanisms underlying schizophrenia. Thus, the identification of a syndrome or set of traits that reflect a predisposition to schizophrenia is fundamental from both a clinical and a research perspective (Tsuang et al., 2002). The presence of individuals who are at “high-risk” but not psychotic is consistent with evidence that schizophrenia results from the interaction of environmental with genetic and neurodevelopmental factors, with the latter associated with clinical, neurobiological and neuropsychological features before the onset of psychosis (Cannon, 2005; Tsuang et al., 2000). Two research paradigms that have been widely used to investigate vulnerability to psychosis are the genetic and clinical high-risk strategy. The genetic high-risk approach involves the non-psychotic, co-twins of patients or their non-psychotic relatives (Johnson et al., 2003; Van Erp et al., 2004; Whyte et al., 2006). Unaffected co-twin and relatives share a proportion of their ill relatives’ alleles. Thus, if a susceptibility allele is related to a putative intermediate phenotype, co-twins and relatives may express that phenotype at a frequency higher than the general population. Deficits that are specific to (or more severe) in the patient (as compared to the unaffected relatives/co-twin), are thought to reflect non-genetic influences and have been termed “disease-related”, while deficits that depend on the presence of a predisposing genotype are called “vulnerability-related” (James, 1971; Whalley et al., 2004). 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, brief limited intermittent psychotic symptoms (BLIPS) or a recent decline in functioning, characteristics that significantly increase the risk for imminent onset of psychosis (Yung et al., 1996). The term ‘‘At Risk Mental State’’ (ARMS) has been suggested of people with these features rather than the term “prodromal”, to delineate a syndrome associated with a high-but not inevitable risk of development of psychotic disorder in the near future (Yung et al., 1998). Studies of this group may identify abnormalities that occur in advance of the onset of frank psychosis.
Subjects at increased risk for psychosis because of genetic factors or because they have an ARMS can present attenuated positive (Johnstone et al., 2005; Yung et al., 2004) and negative (Lencz et al., 2004) psychotic symptoms and display cognitive deficits relative to healthy volunteers (Brewer et al., 2006; Johnstone et al., 2005). For both type of high-risk subject, their neuropsychological status is generally intermediate relative to controls and patients with schizophrenia (Hawkins et al., 2004). Specific neurocognitive deficits of working memory (Brewer et al., 2005; Lencz et al., 2006; Niendam et al., 2006), information processing and motor speed (Niendam et al., 2006), olfactory function (Brewer et al., 2006) appear to be potent trait markers for psychosis. However, ‘prodromal’ symptoms overlap with psychotic experiences in healthy individuals who are not at genetic risk and do not seek clinical help (Broome et al., 2004; Hanssen et al., 2005). Consequently, there is a critical need for identifying neurocognitive markers that are more closely linked to the pathophysiological mechanisms that underlie schizophrenia, and therein augment the validity and specificity of clinical features preceding illness onset.
Over the past years, brain imaging has rapidly developed as a powerful tool to explore the neurophysiological basis of the vulnerability to psychosis. Thus, previous reviews of structural magnetic resonance imaging (sMRI) studies have evidenced significant abnormalities in high-risk state (Pantelis et al., 2005), schizotypal disorder (Dickey et al., 2002), first episode psychosis (Pantelis et al., 2005; Vita et al., 2006) and have addressed multiple pathological processes at different stages of brain development in schizophrenia (Pantelis et al., 2005; Ward, 2000). Other reviews have summarised the magnetic resonance spectroscopy (MRS) findings in the schizophrenic spectrum (Steen et al., 2005) or functional neuroimaging findings (fMRI) in schizotypal disorder (Siever et al., 2002). The aim of this article is to systematically review fMRI studies of familial and ARMS high-risk subjects. We have included studies using functional MRI, PET, SPET and MRS, and where possible have sought to contrast the findings in those at risk with data form patients in the first episode of psychosis.
Section snippets
fMRI studies in high-risk subjects and first episode psychosis
We conducted a comprehensive MEDLINE (1992–2006), EMBASE (1992–2006), PsycINFO (1992–2006) search in the English-language literature. The search terms were: first episode psychosis, prodromal psychosis, high-risk psychosis, schizophrenia, fMRI. We hand-searched the references of all manuscripts for further relevant publications. To qualify for inclusion in the review studies must have: (1) been an original paper in a peer-reviewed journal; (2) included a group of subjects with first episode
Number of studies identified
Twenty-four studies met the inclusion criteria and were reviewed. The paper by Parellada et al. (1998) was excluded since it enrolled in a same group first episode psychosis and established schizophrenic subjects. Since the paper by Callicott et al. (2003) comprises a replication study with a separate sample, two different reviews were performed.
Inclusion criteria for high-risk and first episode subjects
The inclusion criteria for first episode psychosis were operationally defined as: (i) the first psychiatric hospitalisation for psychosis (Braus et
Behavioural performance
Many of the functional imaging studies comparing clinical samples and healthy subjects revealed activation differences alongside performance differences. It is thus difficult to determine whether the activation differences are a secondary effect of poor performance (Callicott et al., 2000; Frith 2005; Perlstein et al., 2001). Poor performance can reflect an engaged brain system that fails to perform, or a brain system that is disengaged due to other causes of bad performance or task design (
Limits
Limitations of this study are well acknowledged. First, although the observed neurofunctional differences were largely limited to frontal areas, it must be emphasised that most studies selected neurocognitive tasks which usually engage frontal areas or performed a region of interest approach (ROI) in the fMRI data analysis. Consequently, current findings cannot exclude significant effects on regions outside the set of the preselected ROIs, neither drawn any conclusion about the functional
Conclusions
A high-risk of psychosis is associated with a set of neurofunctional abnormalities that are qualitatively similar to those observed in patients with the disorder. As these findings are not attributable to effects of the illness or its treatment (Heydebrand et al., 2004; Riley et al., 2000), they may represent markers of increased vulnerability to psychotic disorders. Distinguishing the correlates of vulnerability to psychosis from those of schizophrenia “per se” is likely to inform our
Acknowledgements
This study was supported by grants from the Italian Ministry of Health and the European Union (six framework programme) for GENDEP project (contract LSHB-CT2003-503428) to Biological Psychiatric Unit, the IRCCS-FBF, Italy.
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