Schizophrenia is a severe mental disorder striking mainly young adults and leading to life-long disability in a substantial portion of the sufferers. On the other hand, substantial knowledge about its etiology and pathogenesis is still lacking. Therefore the European Science Foundation (ESF) sponsored a meeting of a panel of European experts on schizophrenia research to discuss the state of art and future perspectives of key topics in this area. The fields covered genetics, epidemiology, animal models, molecular neuropathology and imaging. This was a first step to establish a network of European groups dedicated to Schizophrenia research. The coming calls of the frame work program will be used to strengthen this network in order to achieve substantial progress in understanding and treating this devastating illness.

Psychiatric imaging, in particular functional imaging techniques such as functional magnetic resonance imaging (fMRI) are potentially powerful tools to explore the neurophysiological basis of the early stages of psychosis. Despite this impressive growth, neuroimaging has yet to become an established as diagnostic instrument this area, partly as a result of significant heterogeneity across the findings from research studies. The present review aims to: (i) assess the determinants of inconsistencies in the results from neuroimaging studies of the early stages of psychosis; and (ii) suggest approaches for future imaging research in this field that may reduce methodological differences between studies.

There is convincing evidence that schizophrenia is characterized by abnormalities in brain volume. At the Department of Psychiatry of the University Medical Centre Utrecht, Netherlands, we have been carrying out neuroimaging studies in schizophrenia since 1995. We focused our research on three main questions. First, are brain volume abnormalities static or progressive in nature? Secondly, can brain volume abnormalities in schizophrenia be explained (in part) by genetic influences? Finally, what environmental factors are associated with the brain volume abnormalities in schizophrenia?

Based on our findings we suggest that schizophrenia is a progressive brain disease. We showed different age-related trajectories of brain tissue loss suggesting that brain maturation that occurs in the third and fourth decade of life is abnormal in schizophrenia. Moreover, brain volume has been shown to be a useful phenotype for studying schizophrenia. Brain volume is highly heritable and twin and family studies show that unaffected relatives show abnormalities that are similar, but usually present to a lesser extent, to those found in the patients. However, also environmental factors play a role. Medication intake is indeed a confounding factor when interpreting brain volume (change) abnormalities, while independent of antipsychotic medication intake brain volume abnormalities appear influenced by the outcome of the illness.

In conclusion, schizophrenia can be considered as a progressive brain disease with brain volume abnormalities that are for a large part influenced by genetic factors. Whether the progressive volume change is also mediated by genes awaits the results of longitudinal twin analyses. One of the main challenges for the coming years, however, will be the search for gene-by-environment interactions on the progressive brain changes in schizophrenia.

Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that is increasingly being used for the non-invasive evaluation of brain white matter abnormalities. In this review, we discuss the basic principles of DTI, its roots and the contribution of European centres in its development, and we review the findings from DTI studies in schizophrenia. We searched EMBASE, PubMed, PsychInfo, and Medline from February 1998 to December 2006 using as keywords ‘schizophrenia’, ‘diffusion’, ‘tensor’, and ‘DTI’. Forty studies fulfilling the inclusion criteria of this review were included and systematically reviewed. White matter abnormalities in many diverse brain regions were identified in schizophrenia. Although the findings are not completely consistent, frontal and temporal white matter seems to be more commonly affected. Limitations and future directions of this method are discussed.

Repetitive transcranial magnetic stimulation (rTMS) applied over brain regions responsible for language processing is used to curtail potentially auditory hallucinations in schizophrenia patients and to investigate the functional organisation of language-related areas. Variability of effects is, however, marked across studies and between subjects. Furthermore, the mechanisms of action of rTMS are poorly understood.

Here, we reviewed different factors related to the structural and functional organisation of the brain that might influence rTMS-induced effects. Then, by analogy with aphasia studies, and the plastic-adaptive changes in both the left and right hemispheres following aphasia recovery, a hypothesis is proposed about rTMS mechanisms over language-related areas (e.g. Wernicke, Broca). We proposed that the local interference induced by rTMS in language-related areas might be analogous to aphasic stroke and might lead to a functional reorganisation in areas connected to the virtual lesion for language recovery.

Several lines of research suggest both dorsal and ventral prefrontal cortical dysfunction in bipolar disorder (BD). We used functional magnetic resonance imaging to compare patterns of brain activation in remitted BD patients and controls whilst performing tasks selected for their relative specificity in engaging either the dorsal (n-back sequential-letter working memory task) or ventral (gambling task) PFC. Seven BD patients were selected from participants of the Maudsley Bipolar Disorder Project on the basis of clinical remission, absence of cognitive deficits, and monotherapy with mood stabilisers. Subjects were individually matched by gender, age, and IQ to an equal number of healthy controls. In the n-back task, group differences were only present in response to increasing memory load. Patients did not show the predicted dynamic response in the dorsal PFC, but had increased activation in the parietal cortices. During the gambling task, controls showed significant activation in the ventral and dorsal PFC; this was attenuated in BD patients where increased activation was seen in lateral temporal and polar regions. Our findings suggest that there are trait abnormalities in dorsal and ventral PFC function in BD that may be more pronounced during tasks that rely on ventral–dorsal PFC interaction.

‘Munchausen's syndrome by proxy’ characteristically describes women alleged to have fabricated or induced illnesses in children under their care, purportedly to attract attention. Where conclusive evidence exists the condition's aetiology remains speculative, where such evidence is lacking diagnosis hinges upon denial of wrong-doing (conduct also compatible with innocence). How might investigators obtain objective evidence of guilt or innocence? Here, we examine the case of a woman convicted of poisoning a child. She served a prison sentence but continues to profess her innocence. Using a modified fMRI protocol (previously published in 2001) we scanned the subject while she affirmed her account of events and that of her accusers. We hypothesized that she would exhibit longer response times in association with greater activation of ventrolateral prefrontal and anterior cingulate cortices when endorsing those statements she believed to be false (i.e., when she ‘lied’). The subject was scanned 4 times at 3 Tesla. Results revealed significantly longer response times and relatively greater activation of ventrolateral prefrontal and anterior cingulate cortices when she endorsed her accusers' version of events. Hence, while we have not ‘proven’ that this subject is innocent, we demonstrate that her behavioural and functional anatomical parameters behave as if she were.

Severe mental illnesses such as schizophrenia and mood disorders have a major impact on public health. Disease prevalence and phenotypic expression are the products of environment and gene interactions. However, our incomplete understanding of their aetiology and pathophysiology thwarts primary prevention and early diagnosis and limits the effective application of currently available treatments as well as the development of novel therapeutic approaches. Neuroimaging can provide detailed in vivo information about the biological mechanisms underpinning the relationship between genetic variation and clinical phenotypes or response to treatment. However, the biological complexity of severe mental illness results from unknown or unpredictable interactions between multiple genetic and environmental factors, many of which have only been partially identified. We propose that the use of epidemiological principles to neuroimaging research is a necessary next step in psychiatric research. Because of the complexity of mental disorders and the multiple risk factors involved only the use of large epidemiologically defined samples will allow us to study the broader spectrum of psychopathology, including sub-threshold presentation and explore pathophysiological processes and the functional impact of genetic and non-genetic factors on the onset and persistence of psychopathology.