Multi-center MRI prediction models: Predicting sex and illness course in first episode psychosis patients.

Structural Magnetic Resonance Imaging (MRI) studies have attempted to use brain measures obtained at the first-episode of psychosis to predict subsequent outcome, with inconsistent results. Thus, there is a real need to validate the utility of brain measures in the prediction of outcome using large datasets, from independent samples, obtained with different protocols and from different MRI scanners. This study had three main aims: 1) to investigate whether structural MRI data from multiple centers can be combined to create a machine-learning model able to predict a strong biological variable like sex; 2) to replicate our previous finding that an MRI scan obtained at first episode significantly predicts subsequent illness course in other independent datasets; and finally, 3) to test whether these datasets can be combined to generate multicenter models with better accuracy in the prediction of illness course. The multi-center sample included brain structural MRI scans from 256 males and 133 females patients with first episode psychosis, acquired in five centers: University Medical Center Utrecht (The Netherlands) (n=67); Institute of Psychiatry, Psychology and Neuroscience, London (United Kingdom) (n=97); University of São Paulo (Brazil) (n=64); University of Cantabria, Santander (Spain) (n=107); and University of Melbourne (Australia) (n=54). All images were acquired on 1.5-Tesla scanners and all centers provided information on illness course during a follow-up period ranging 3 to 7years. We only included in the analyses of outcome prediction patients for whom illness course was categorized as either "continuous" (n=94) or "remitting" (n=118). Using structural brain scans from all centers, sex was predicted with significant accuracy (89%; p<0.001). In the single- or multi-center models, illness course could not be predicted with significant accuracy. However, when reducing heterogeneity by restricting the analyses to male patients only, classification accuracy improved in some samples. This study provides proof of concept that combining multi-center MRI data to create a well performing classification model is possible. However, to create complex multi-center models that perform accurately, each center should contribute a sample either large or homogeneous enough to first allow accurate classification within the single-center.

A population-based morphometric MRI study in patients with first-episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects.

OBJECTIVES: Many morphometric magnetic resonance imaging (MRI) studies that have investigated the presence of gray matter (GM) volume abnormalities associated with the diagnosis of bipolar disorder (BD) have reported conflicting findings. None of these studies has compared patients with recent-onset psychotic BD with asymptomatic controls selected from exactly the same environment using epidemiological methods, or has directly contrasted BD patients against subjects with first-onset psychotic major depressive disorder (MDD). We examined structural brain differences between (i) BD (type I) subjects and MDD subjects with psychotic features in their first contact with the healthcare system in Brazil, and (ii) these two mood disorder groups relative to a sample of geographically matched asymptomatic controls. METHODS: A total of 26 BD subjects, 20 subjects with MDD, and 94 healthy controls were examined using either of two identical MRI scanners and acquisition protocols. Diagnoses were based on DSM-IV criteria and confirmed one year after brain scanning. Image processing was conducted using voxel-based morphometry. RESULTS: The BD group showed increased volume of the right dorsal anterior cingulate cortex relative to controls, while the MDD subjects exhibited bilateral foci GM deficits in the dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons). Direct comparison between BD and MDD patients showed a focus of GM reduction in the right-sided dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons) and a trend (p < 0.10, corrected) toward left-sided GM deficits in the dorsolateral prefrontal cortex of MDD patients. When analyses were repeated with scanner site as a confounding covariate the finding of increased right anterior cingulate volumes in BD patients relative to controls remained statistically significant (p=0.01, corrected for multiple comparisons). CONCLUSIONS: These findings reinforce the view that there are important pathophysiological distinctions between BD and MDD, and indicate that subtle dorsal anterior cingulate abnormalities may be relevant to the pathophysiology of BD.

Cognitive functioning in subjects with recent-onset psychosis from a low-middle-income environment: multiple-domain deficits and longitudinal evaluation.

Cognitive deficits are a key feature of recent-onset psychosis, but there is no consensus on whether such deficits are generalized or confined to specific domains. Besides, it is unclear whether cognitive deficits: a) are found in psychotic patients in samples from outside high-income countries; and b) whether they progress uniformly over time in schizophrenia and affective psychoses. We applied 12 tests organized into eight cognitive domains, comparing psychosis patients (n = 56, time from initial contact = 677.95+/-183.27 days) versus healthy controls (n=70) recruited from the same area of São Paulo, Brazil. Longitudinal comparisons (digit span and verbal fluency) were conducted between a previous assessment of the subjects carried out at their psychosis onset, and the current follow-up evaluation. Psychosis patients differed significantly from controls on five domains, most prominently on verbal memory. Cognitive deficits remained detectable in separate comparisons of the schizophrenia subgroup and, to a lesser extent, the affective psychosis subjects against controls. Longitudinal comparisons indicated significant improvement in schizophrenia, affective psychoses, and control subjects, with no significant group-by-time interactions. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non-affective nature, which persist over time.

Volume reduction of the corpus callosum and its relationship with deficits in interhemispheric transfer of information in recent-onset psychosis.

The present study aimed to investigate the presence of corpus callosum (CC) volume deficits in a population-based recent-onset psychosis (ROP) sample, and whether CC volume relates to interhemispheric communication deficits. For this purpose, we used voxel-based morphometry comparisons of magnetic resonance imaging data between ROP (n =122) and healthy control (n = 94) subjects. Subgroups (38 ROP and 39 controls) were investigated for correlations between CC volumes and performance on the Crossed Finger Localization Test (CFLT). Significant CC volume reductions in ROP subjects versus controls emerged after excluding substance misuse and non-right-handedness. CC reductions retained significance in the schizophrenia subgroup but not in affective psychoses subjects. There were significant positive correlations between CC volumes and CFLT scores in ROP subjects, specifically in subtasks involving interhemispheric communication. From these results, we can conclude that CC volume reductions are present in association with ROP. The relationship between such deficits and CFLT performance suggests that interhemispheric communication impairments are directly linked to CC abnormalities in ROP.

Corpus callosum volumes in the 5 years following the first-episode of schizophrenia: Effects of antipsychotics, chronicity and maturation.

Background: White matter (WM) structural changes, particularly affecting the corpus callosum (CC), seem to be critically implicated in psychosis. Whether such abnormalities are progressive or static is still a matter of debate in schizophrenia research. Aberrant maturation processes might also influence the longitudinal trajectory of age-related CC changes in schizophrenia patients. We investigated whether patients with first-episode schizophrenia-related psychoses (FESZ) would present longitudinal CC and whole WM volume changes over the 5 years after disease onset. Method: Thirty-two FESZ patients and 34 controls recruited using a population-based design completed a 5-year assessment protocol, including structural MRI scanning at baseline and follow-up. The linear effects of disease duration, clinical outcome and antipsychotic (AP) use over time on WM and CC volumes were studied using both voxelwise and volume-based morphometry analyses. We also examined maturation/aging abnormalities through cross-sectional analyses of age-related trajectories of total WM and CC volume changes. Results: No interaction between diagnosis and time was observed, and clinical outcome did not influence CC volumes in patients. On the other hand, FESZ patients continuously exposed to AP medication showed volume increase over time in posterior CC. Curve-estimation analyses revealed a different aging pattern in FESZ patients versus controls: while patients displayed a linear decline of total WM and anterior CC volumes with age, a non-linear trajectory of total WM and relative preservation of CC volumes were observed in controls. Conclusions: Continuous AP exposure can influence CC morphology during the first years after schizophrenia onset. Schizophrenia is associated with an abnormal pattern of total WM and anterior CC aging during non-elderly adulthood, and this adds complexity to the discussion on the static or progressive nature of structural abnormalities in psychosis.

Cognitive deficits in first-episode psychosis: a population-based study in São Paulo, Brazil.

BACKGROUND: Studies conducted in high-income countries have reported significant cognitive deficits in first on set schizophrenia subjects relative to asymptotic controls, and it has been suggested that the severity of such deficits could be directly related to the duration of untreated psychosis (DUP). It is relevant to conduct similar studies in developing countries, given the supposedly better outcome for schizophrenia patients living in the latter environments. METHODS: We applied verbal fluency and digit span tests to an epidemiological-based series of patients with first-onset psychoses (n=179) recruited in the city of São Paulo, and compared the findings with those from non-psychotic control subjects randomly selected from the same geographical areas (n=383). RESULTS: Psychosis subjects showed lower scores on the three tests relative to controls, with greatest between-group differences for the backward digit span task (p<0.0001). There were no significant differences between subjects with affective and schizophreniform psychosis. Cognitive performance indices were negatively correlated with the severity of negative symptoms, but showed no relation to DUP. CONCLUSION: We found significant cognitive deficits in patients investigated early during the course of psychotic disorders in an environment that is distinct from those where the subjects investigated in previous studies have been drawn from. We found no support to the hypothesis of an association between greater cognitive deficits and a longer DUP.

Grey matter abnormalities in Brazilians with first-episode psychosis.

BACKGROUND: In low- and middle-income countries people with schizophrenia are reported to experience better outcomes than those in high-income countries. AIMS: To examine structural brain differences in people with first-episode psychosis and controls in Brazil. METHOD: Magnetic resonance imaging using voxel-based morphometry was performed on 122 people with first-episode psychosis and 94 controls. RESULTS: There were significant decreases in grey matter in the left superior temporal and inferior prefrontal cortices, insula bilaterally and the right hippocampal region in first-episode psychosis (P<0.05, corrected for multiple comparisons). The subgroup of people with schizophrenia (n=62) exhibited a similar pattern of decrease in grey matter relative to controls. CONCLUSIONS: Structural abnormalities reported in psychosis in high-income countries are also present in first-episode psychosis in Brazil.

Glutamatergic and neural dysfunction in postpartum depression using magnetic resonance spectroscopy.

Although postpartum depression (PPD) is a prevalent subtype of major depressive disorder, neuroimaging studies on PPD are rare, particularly those identifying neurochemical abnormalities obtained by proton magnetic resonance spectroscopy (¹H-MRS). The dorsolateral prefrontal (DLPF) and the anterior cingulate gyrus (ACG) are part of the neural pathways involved in executive functions and emotional processing, and both structures have been implicated in the neurobiology of depressive disorders. This study aimed to evaluate brain metabolites abnormalities in women with PPD compared with healthy postpartum (HP) women. Thirty-six PPD (34 without antidepressants) and 25 HP women underwent a ¹H-MRS acquired on a 3-T MRI system, with the volume of interest positioned in ACG and DLPF. An ANCOVA was conducted with age, postpartum time, and contraceptive type as covariates. PPD group presented significantly lower Glutamate+Glutamine (Glx, -0.95mM) and N-acetylaspartate+N-acetylaspartylglutamate (NAA, -0.60mM) values in DLPF. There were no significant differences between groups in ACG, but we found a significant increase of Glutamate (Glu, 2.18mM) and Glx (1.84mM) in participants using progestogen-only contraceptives. These findings suggest glutamatergic dysfunction and neuronal damage in the DLPF of PPD patients, similarly to other subtypes of depressive disorders. Progestogens seem to interfere in the neurochemistry of ACG.

Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness.

BACKGROUND: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity. METHODS: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. RESULTS: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. CONCLUSION: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.

Neuroanatomical classification in a population-based sample of psychotic major depression and bipolar I disorder with 1 year of diagnostic stability.

The presence of psychotic features in the course of a depressive disorder is known to increase the risk for bipolarity, but the early identification of such cases remains challenging in clinical practice. In the present study, we evaluated the diagnostic performance of a neuroanatomical pattern classification method in the discrimination between psychotic major depressive disorder (MDD), bipolar I disorder (BD-I), and healthy controls (HC) using a homogenous sample of patients at an early course of their illness. Twenty-three cases of first-episode psychotic mania (BD-I) and 19 individuals with a first episode of psychotic MDD whose diagnosis remained stable during 1 year of followup underwent 1.5 T MRI at baseline. A previously validated multivariate classifier based on support vector machine (SVM) was employed and measures of diagnostic performance were obtained for the discrimination between each diagnostic group and subsamples of age- and gender-matched controls recruited in the same neighborhood of the patients. Based on T1-weighted images only, the SVM-classifier afforded poor discrimination in all 3 pairwise comparisons: BD-I versus HC; MDD versus HC; and BD-I versus MDD. Thus, at the population level and using structural MRI only, we failed to achieve good discrimination between BD-I, psychotic MDD, and HC in this proof of concept study.

Neuroanatomical pattern classification in a population-based sample of first-episode schizophrenia.

Recent neuroanatomical pattern classification studies have attempted to individually classify cases with psychotic disorders using morphometric MRI data in an automated fashion. However, this approach has not been tested in population-based samples, in which variable patterns of comorbidity and disease course are typically found. We aimed to evaluate the diagnostic accuracy (DA) of the above technique to discriminate between incident cases of first-episode schizophrenia identified in a circumscribed geographical region over a limited period of time, in comparison with next-door healthy controls. Sixty-two cases of first-episode schizophrenia or schizophreniform disorder and 62 age, gender and educationally-matched controls underwent 1.5 T MRI scanning at baseline, and were naturalistically followed-up over 1 year. T1-weighted images were used to train a high-dimensional multivariate classifier, and to generate both spatial maps of the discriminative morphological patterns between groups and ROC curves. The spatial map discriminating first-episode schizophrenia patients from healthy controls revealed a complex pattern of regional volumetric abnormalities in the former group, affecting fronto-temporal-occipital gray and white matter regions bilaterally, including the inferior fronto-occipital fasciculus, as well as the third and lateral ventricles. However, an overall modest DA (73.4%) was observed for the individual discrimination between first-episode schizophrenia patients and controls, and the classifier failed to predict 1-year prognosis (remitting versus non-remitting course) of first-episode schizophrenia (DA=58.3%). In conclusion, using a "real world" sample recruited with epidemiological methods, the application of a neuroanatomical pattern classifier afforded only modest DA to classify first-episode schizophrenia subjects and next-door healthy controls, and poor discriminative power to predict the 1-year prognosis of first-episode schizophrenia.

Cannabis use, cognition and brain structure in first-episode psychosis.

Cannabis use is highly prevalent worldwide and it is associated with psychosis, but its effects on brain structure and cognition are still controversial. The aim of this paper is to investigate cognitive functioning and brain structure in patients with their first episode of psychosis who used Cannabis. We examined gray matter and lateral ventricle volumes in 28 patients with first-episode psychosis and a history of Cannabis use, 78 patients without a history of Cannabis use and 80 healthy controls who had not used Cannabis. Cognition was assessed using forward and backwards digit span tests, from the Wechsler Memory Scale-Third Edition (WMS-III) and the Controlled Oral Word Association Test (COWAT). Patients with a history of Cannabis use had less brain abnormalities, characterized by gray matter and lateral ventricle volume preservation, as well as less attentional and executive impairments compared to patients without a history of Cannabis use. Cannabis-using patients who develop psychosis have less neurodevelopmental impairment and better cognitive reserve than other psychotic patients; perhaps reflecting different etiological processes.

BDNF gene polymorphism, cognition and symptom severity in a Brazilian population-based sample of first-episode psychosis subjects.

OBJECTIVE: To investigate the influence of brain-derived neurotrophic factor (BDNF) gene variations on cognitive performance and clinical symptomatology in first-episode psychosis (FEP). METHODS: We performed BDNF val66met variant genotyping, cognitive testing (verbal fluency and digit spans) and assessments of symptom severity (as assessed with the PANSS) in a population-based sample of FEP patients (77 with schizophreniform psychosis and 53 with affective psychoses) and 191 neighboring healthy controls. RESULTS: There was no difference in the proportion of Met allele carriers between FEP patients and controls, and no significant influence of BDNF genotype on cognitive test scores in either of the psychosis groups. A decreased severity of negative symptoms was found in FEP subjects that carried a Met allele, and this finding reached significance for the subgroup with affective psychoses (p < 0.01, ANOVA). CONCLUSIONS: These results suggest that, in FEP, the BDNF gene Val66Met polymorphism does not exert a pervasive influence on cognitive functioning but may modulate the severity of negative symptoms.

Brain activity patterns during phonological verbal fluency performance with varying levels of difficulty: a functional magnetic resonance imaging study in Portuguese-speaking healthy individuals.

A large number of functional neuroimaging studies have investigated the brain circuitry which is engaged during performance of phonological verbal fluency tasks, and the vast majority of these have been carried out in English. Although there is evidence that this paradigm varies depending on the language spoken, it is unclear if this difference is associated with differences in brain activation patterns. Also, there is neuroimaging evidence that the patterns of regional cerebral activation during verbal fluency tasks may vary with the level of task demanded. In particular, the engagement of the anterior cingulate cortex seems to be relative to cognitive demand. We compared functional magnetic resonance imaging data in healthy Portuguese-speaking subjects during overt production of words beginning with letters classified as easy or hard for word production in Portuguese. Compared to the baseline condition, the two verbal fluency tasks (with either easy or hard letters) engaged a network including the left inferior and middle frontal cortices, anterior cingulate cortex, putamen, thalamus and cerebellum (p < .001). The direct comparison between the two verbal fluency conditions showed greater cerebellar activation in the easy condition relative to the hard condition. In the anterior cingulate cortex, there was a direct correlation between activity changes and verbal fluency performance during the hard condition only. Despite grammatical differences, the changes in patterns of brain activity during verbal fluency performance observed in our study are in accordance with findings of previous neuroimaging studies of verbal fluency carried out in English and other languages, with recruitment of a set of distributed cerebral areas during word production.

Age-related gray matter volume changes in the brain during non-elderly adulthood.

Previous magnetic resonance imaging (MRI) studies described consistent age-related gray matter (GM) reductions in the fronto-parietal neocortex, insula and cerebellum in elderly subjects, but not as frequently in limbic/paralimbic structures. However, it is unclear whether such features are already present during earlier stages of adulthood, and if age-related GM changes may follow non-linear patterns at such age range. This voxel-based morphometry study investigated the relationship between GM volumes and age specifically during non-elderly life (18-50 years) in 89 healthy individuals (48 males and 41 females). Voxelwise analyses showed significant (p<0.05, corrected) negative correlations in the right prefrontal cortex and left cerebellum, and positive correlations (indicating lack of GM loss) in the medial temporal region, cingulate gyrus, insula and temporal neocortex. Analyses using ROI masks showed that age-related dorsolateral prefrontal volume decrements followed non-linear patterns, and were less prominent in females compared to males at this age range. These findings further support for the notion of a heterogeneous and asynchronous pattern of age-related brain morphometric changes, with region-specific non-linear features.

Lateral ventricle differences between first-episode schizophrenia and first-episode psychotic bipolar disorder: A population-based morphometric MRI study.

OBJECTIVES: The extent to which psychotic disorders fall into distinct diagnostic categories or can be regarded as lying on a single continuum is controversial. We compared lateral ventricle volumes between a large sample of patients with first-episode schizophrenia or bipolar disorder and a healthy control group from the same neighbourhood. METHODS: Population-based MRI study with 88 first-episode psychosis (FEP) patients, grouped into those with schizophrenia/schizophreniform disorder (N=62), bipolar disorder (N=26) and 94 controls. RESULTS: Right and left lateral ventricular and right temporal horn volumes were larger in FEP subjects than controls. Within the FEP sample, post-hoc tests revealed larger left lateral ventricles and larger right and left temporal horns in schizophrenia subjects relative to controls, while there was no difference between patients with bipolar disorder and controls. None of the findings was attributable to effects of antipsychotics. CONCLUSIONS: This large-sample population-based MRI study showed that neuroanatomical abnormalities in subjects with schizophrenia relative to controls from the same neighbourhood are evident at the first episode of illness, but are not detectable in bipolar disorder patients. These data are consistent with a model of psychosis in which early brain insults of neurodevelopmental origin are more relevant to schizophrenia than to bipolar disorder.

Cognitive performance is related to cortical grey matter volumes in early stages of schizophrenia: a population-based study of first-episode psychosis.

BACKGROUND: Neuropsychological deficits have been reported in association with first-episode psychosis (FEP). Reductions in grey matter (GM) volumes have been documented in FEP subjects compared to healthy controls. However, the possible inter-relationship between the findings of those two lines of research has been scarcely investigated. OBJECTIVE: To investigate the relationship between neuropsychological deficits and GM volume abnormalities in a population-based sample of FEP patients compared to healthy controls from the same geographical area. METHODS: FEP patients (n=88) and control subjects (n=86) were evaluated by neuropsychological assessment (Controlled Oral Word Association Test, forward and backward digit span tests) and magnetic resonance imaging using voxel-based morphometry. RESULTS: Single-group analyses showed that prefrontal and temporo-parietal GM volumes correlated significantly (p<0.05, corrected) with cognitive performance in FEP patients. A similar pattern of direct correlations between neocortical GM volumes and cognitive impairment was seen in the schizophrenia subgroup (n=48). In the control group, cognitive performance was directly correlated with GM volume in the right dorsal anterior cingulate cortex and inversely correlated with parahippocampal gyral volumes bilaterally. Interaction analyses with "group status" as a predictor variable showed significantly greater positive correlation within the left inferior prefrontal cortex (BA46) in the FEP group relative to controls, and significantly greater negative correlation within the left parahippocampal gyrus in the control group relative to FEP patients. CONCLUSION: Our results indicate that cognitive deficits are directly related to brain volume abnormalities in frontal and temporo-parietal cortices in FEP subjects, most specifically in inferior portions of the dorsolateral prefrontal cortex.

White-matter hyperintensities in first-episode psychosis.

BACKGROUND: White-matter hyperintensities have been associated with both schizophrenia and mood disorders, particularly bipolar disorder, but results are inconsistent across studies. AIMS: To examine whether white-matter hyperintensities are a vulnerability marker for psychosis or are specifically associated with bipolar disorder. METHOD: T(2)-weighted magnetic resonance imaging data were acquired in 129 individuals with first-episode psychosis (either affective or non-affective psychoses) and 102 controls who were randomly selected from the same geographical areas. Visual white-matter hyperintensity ratings were used for group and subgroup comparisons. RESULTS: There were no statistically significant between-group differences in white-matter hyperintensity frequency or severity scores. No significant correlations were found between white-matter hyperintensity scores and duration of illness, duration of untreated psychosis, or severity of psychotic, manic or depressive symptoms. CONCLUSIONS: White-matter hyperintensities are not associated with vulnerability to psychosis in general, or specifically with affective psychoses. Further, first-episode psychosis investigations using more quantitative methods are warranted to confirm these findings.