Multivariate patterns of brain-cognition associations relating to vulnerability and clinical outcome in the at-risk mental states for psychosis.

BACKGROUND: Neuropsychological deficits are a core feature of established psychosis and have been previously linked to fronto-temporo-limbic brain alterations. Both neurocognitive and neuroanatomical abnormalities characterize clinical at-risk mental states (ARMS) for psychosis. However, structure-cognition relationships in the ARMS have not been directly explored using multivariate neuroimaging techniques. METHODS: Voxel-based morphometry and partial least squares were employed to study system-level covariance patterns between whole-brain morphological data and processing speed, working memory, verbal learning/IQ, and executive functions in 40 ARMS subjects and 30 healthy controls (HC). The detected structure-cognition covariance patterns were tested for significance and reliability using non-parametric permutation and bootstrap resampling. RESULTS: We identified ARMS-specific covariance patterns that described a generalized association of neurocognitive measures with predominantly prefronto-temporo-limbic and subcortical structures as well as the interconnecting white matter. In the conversion group, this generalized profile particularly involved working memory and verbal IQ and was positively correlated with limbic, insular and subcortical volumes as well as negatively related to prefrontal, temporal, parietal, and occipital cortices. Conversely, the neurocognitive profiles in the HC group were confined to working memory, learning and IQ, which were diffusely associated with cortical and subcortical brain regions. CONCLUSIONS: These findings suggest that the ARMS and prodromal phase of psychosis are characterized by a convergent mapping from multi-domain neurocognitive measures to a set of prefronto-temporo-limbic and subcortical structures. Furthermore, a neuroanatomical separation between positive and negative brain-cognition correlations may not only point to a biological process determining the clinical risk for disease transition, but also to possible compensatory or dysmaturational neural processes.

Is evaluation of humorous stimuli associated with frontal cortex morphology? A pilot study using facial micro-movement analysis and MRI.

Humour involves the ability to detect incongruous ideas violating social rules and norms. Accordingly, humour requires a complex array of cognitive skills for which intact frontal lobe functioning is critical. Here, we sought to examine the association of facial expression during an emotion inducing experiment with frontal cortex morphology in healthy subjects. Thirty-one healthy male subjects (mean age: 30.8±8.9 years; all right-handers) watching a humorous movie ("Mr. Bean") were investigated. Markers fixed at certain points of the face emitting high-frequency ultrasonic signals allowed direct measurement of facial movements with high spatial-temporal resolution. Magnetic resonance images of the frontal cortex were obtained with a 1.5-T Magnetom using a coronar T2- and protondensity-weighted Dual-Echo-Sequence and a 3D-magnetization-prepared rapid gradient echo (MPRAGE) sequence. Volumetric analysis was performed using BRAINS. Frontal cortex volume was partly associated with slower speed of "laughing" movements of the eyes ("genuine" or Duchenne smile). Specifically, grey matter volume was associated with longer emotional reaction time ipsilaterally, even when controlled for age and daily alcohol intake. These results lend support to the hypothesis that superior cognitive evaluation of humorous stimuli - mediated by larger prefrontal grey and white matter volume - leads to a measurable reduction of speed of emotional expressivity in normal adults.

Neuroanatomical correlates of executive dysfunction in the at-risk mental state for psychosis.

Deficits in executive functioning have been described as a core feature of schizophrenia and have been linked to patterns of fronto-temporo-limbic brain alterations. To date, such structure-cognition relationships have not been explored in a clinically defined at-risk mental state (ARMS) for psychosis using whole-brain neuroimaging techniques. Therefore, we used voxel-based morphometry in 40 ARMS and 30 matched healthy control (HC) individuals to investigate whether gray and white matter volumes (1) correlated with the performance in the Trail-Making Test B (TMT-B), an established measure of executive functioning, and (2) were volumetrically linked to the ventromedial prefrontal cortex (VMPFC), found to be associated with TMT-B in the ARMS during the first analysis step. We found the ARMS subjects to be specifically impaired in their TMT-B performance versus HC. Brain-cognition associations involving the insular cortices were observed in the HC, but not in the ARMS individuals. Conversely, TMT-B correlations in the VMPFC, the cerebellum, the fronto-callosal white matter were detected in the ARMS, but not the HC group. The VMPFC was linked to the temporo-limbic cortices in HC, whereas the connectivity pattern in the ARMS involved the left temporal and dorsolateral prefrontal cortex, the cerebellum, the right SMA and extended portions of the fronto-callosal white matter. These findings suggest that executive deficits are already present in the ARMS for psychosis and may be subserved by structurally altered networks of interconnected cortical and subcortical brain regions in line with the disconnectivity hypothesis of schizophrenia.

Use of neuroanatomical pattern regression to predict the structural brain dynamics of vulnerability and transition to psychosis.

BACKGROUND: The at-risk mental state for psychosis (ARMS) has been associated with abnormal structural brain dynamics underlying disease transition or non-transition. To date, it is unknown whether these dynamic brain changes can be predicted at the single-subject level prior to disease transition using MRI-based machine-learning techniques. METHODS: First, deformation-based morphometry and partial-least-squares (PLS) was used to investigate patterns of volumetric changes over time in 25 ARMS individuals versus 28 healthy controls (HC) (1) irrespective of the clinical outcome and (2) according to illness transition or non-transition. Then, the baseline MRI data were employed to predict the expression of these volumetric changes at the individual level using support-vector regression (SVR). RESULTS: PLS revealed a pattern of pronounced morphometric changes in ARMS versus HC that affected predominantly the right prefrontal, as well as the perisylvian, parietal and periventricular structures (p<0.011), and that was more pronounced in the converters versus the non-converters (p<0.010). The SVR analysis facilitated a reliable prediction of these longitudinal brain changes in individual out-of training cases (HC vs ARMS: r=0.83, p<0.001; HC vs converters vs non-converters: r=0.83, p<0.001) by relying on baseline patterns that involved ventricular enlargements, as well as prefrontal, perisylvian, limbic, parietal and subcortical volume reductions. CONCLUSIONS: Abnormal brain changes over time may underlie an elevated vulnerability for psychosis and may be most pronounced in subsequent converters to psychosis. Pattern regression techniques may facilitate an accurate prediction of these structural brain dynamics, potentially allowing for an early recognition of individuals at risk of developing psychosis-associated neuroanatomical changes over time.

Differences in hippocampal volume between major depression and schizophrenia: a comparative neuroimaging study.

Several studies have demonstrated that structural brain change is detectable in the hippocampus in both patients, with schizophrenia and major depression. Only few studies, however, compared both clinical disease entities directly and no larger study has tried to take different disease stages into account. The objectives of this study are to investigate whether hippocampal volumes are reduced in patients with schizophrenia and those with major depression with the same duration of illness compared to healthy controls and to assess further changes at different disease stages. A total of 319 inpatients and healthy controls were enrolled and investigated with magnetic resonance imaging (MRI). Hippocampal volumes were measured using the segmentation software BRAINS. Bilateral hippocampal volume reductions were detected in both schizophrenic and depressed patients compared to healthy control (HC) subjects. Although younger, schizophrenic (SZ) patients showed in their MRI scans significant bilaterally reduced hippocampal volumes compared to patients with major depression. Although the hippocampal reductions were similar at the onset of symptomatic manifestation of both diseases, there was a further significant reduction of the left hippocampus in the recurrently ill SZ subgroup. The data suggest rather dynamic structural brain alterations in schizophrenia compared to major depression. Here, the presented application of the comparative neuroscience approach, by the use of large neuroimaging MRI databases, seems highly valuable. In the field of psychiatry, with its still controversial operationalized descriptive diagnostic entities, the cross-nosological approach provides a helpful tool to better elucidate the still unknown brain pathologies and their underlying molecular mechanisms beyond a single nosological entity.

Neuroanatomical correlates of different vulnerability states for psychosis and their clinical outcomes.

BACKGROUND: Structural brain abnormalities have been described in individuals with an at-risk mental state for psychosis. However, the neuroanatomical underpinnings of the early and late at-risk mental state relative to clinical outcome remain unclear. AIMS: To investigate grey matter volume abnormalities in participants in a putatively early or late at-risk mental state relative to their prospective clinical outcome. METHOD: Voxel-based morphometry of magnetic resonance imaging data from 20 people with a putatively early at-risk mental state (ARMS-E group) and 26 people with a late at-risk mental state (ARMS-L group) as well as from 15 participants with at-risk mental states with subsequent disease transition (ARMS-T group) and 18 participants without subsequent disease transition (ARMS-NT group) were compared with 75 healthy volunteers. RESULTS: Compared with healthy controls, ARMS-L participants had grey matter volume losses in frontotemporolimbic structures. Participants in the ARMS-E group showed bilateral temporolimbic alterations and subtle prefrontal abnormalities. Participants in the ARMS-T group had prefrontal alterations relative to those in the ARMS-NT group and in the healthy controls that overlapped with the findings in the ARMS-L group. CONCLUSIONS: Brain alterations associated with the early at-risk mental state may relate to an elevated susceptibility to psychosis, whereas alterations underlying the late at-risk mental state may indicate a subsequent transition to psychosis.

Increase of striatal dopamine transmission in first episode drug-naive schizophrenic patients as demonstrated by [(123)I]IBZM SPECT.

Acute psychotic exacerbation in schizophrenia is associated with a "striatal hyperdopaminergic state". The aim of this investigation was to test this hypothesis by assessing striatal dopamine D(2) receptor availability using single photon emission computed tomography (SPECT) and the specific D(2) radioligand [(123)I]IBZM in first episode, drug-naïve, schizophrenic patients and compare it with that in healthy control subjects. Additionally, D(2) radioligand binding was correlated with the extent of psychopathology assessed by specific rating scales including Positive and Negative Syndrome Scale (PANSS). Twenty-three acutely ill, treatment-naïve, inpatients suffering from a first acute psychosis were studied. Patients were assigned to a psychopathological syndrome-type according to PANSS positive and negative subscale results. The PANSS items delusions, conceptual disorganization, and hallucinatory behaviour were chosen to assess the extent of the acute psychotic syndrome. Patients showed a significantly lower specific [(123)I]IBZM binding compared with the control group. Positive and negative syndrome type patients differed significantly with respect to specific IBZM binding. There was a significant negative correlation between IBZM binding and the PANSS item 'hallucinatory behaviour' in patients with pronounced positive symptoms. The data obtained show a significant difference between acute psychotic patients, patients with predominant negative syndrome, and healthy controls, according to the concept of a "hyperdopaminergic state" in psychotic exacerbation.

Use of neuroanatomical pattern classification to identify subjects in at-risk mental states of psychosis and predict disease transition.

CONTEXT: Identification of individuals at high risk of developing psychosis has relied on prodromal symptomatology. Recently, machine learning algorithms have been successfully used for magnetic resonance imaging-based diagnostic classification of neuropsychiatric patient populations. OBJECTIVE: To determine whether multivariate neuroanatomical pattern classification facilitates identification of individuals in different at-risk mental states (ARMS) of psychosis and enables the prediction of disease transition at the individual level. DESIGN: Multivariate neuroanatomical pattern classification was performed on the structural magnetic resonance imaging data of individuals in early or late ARMS vs healthy controls (HCs). The predictive power of the method was then evaluated by categorizing the baseline imaging data of individuals with transition to psychosis vs those without transition vs HCs after 4 years of clinical follow-up. Classification generalizability was estimated by cross-validation and by categorizing an independent cohort of 45 new HCs. SETTING: Departments of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany. PARTICIPANTS: The first classification analysis included 20 early and 25 late at-risk individuals and 25 matched HCs. The second analysis consisted of 15 individuals with transition, 18 without transition, and 17 matched HCs. MAIN OUTCOME MEASURES: Specificity, sensitivity, and accuracy of classification. RESULTS: The 3-group, cross-validated classification accuracies of the first analysis were 86% (HCs vs the rest), 91% (early at-risk individuals vs the rest), and 86% (late at-risk individuals vs the rest). The accuracies in the second analysis were 90% (HCs vs the rest), 88% (individuals with transition vs the rest), and 86% (individuals without transition vs the rest). Independent HCs were correctly classified in 96% (first analysis) and 93% (second analysis) of cases. CONCLUSIONS: Different ARMSs and their clinical outcomes may be reliably identified on an individual basis by assessing patterns of whole-brain neuroanatomical abnormalities. These patterns may serve as valuable biomarkers for the clinician to guide early detection in the prodromal phase of psychosis.

Structural correlates of psychopathological symptom dimensions in schizophrenia: a voxel-based morphometric study.

Structural neuroimaging has substantially advanced the neurobiological research of schizophrenia by describing a range of focal brain alterations as possible neuroanatomical underpinnings of the disease. Despite this progress, a considerable heterogeneity of structural findings persists that may reflect the phenomenological diversity of schizophrenia. It is unclear whether the range of possible clinical disease manifestations relates to a core structural brain deficit or to distinct structural correlates. Therefore, gray matter density (GMD) differences between 175 schizophrenic patients (SZ) and 177 matched healthy control subjects (HC) were examined in a three-step approach using cross-sectional and conjunctional voxel-based morphometry (VBM): (1) analysis of structural alterations irrespective of symptomatology; (2) subdivision of the patient sample according to a three-dimensional factor model of the PANSS and investigation of structural differences between these subsamples and healthy controls; (3) analysis of a common pattern of structural alterations present in all patient subsamples compared to healthy controls. Significant GMD reductions in patients compared to controls were identified within the prefrontal, limbic, paralimbic, temporal and thalamic regions. The disorganized symptom dimension was associated with bilateral alterations in temporal, insular and medial prefrontal cortices. Positive symptoms were associated with left-pronounced alterations in perisylvian regions and extended thalamic GMD losses. Negative symptoms were linked to the most extended alterations within orbitofrontal, medial prefrontal, lateral prefrontal and temporal cortices as well as limbic and subcortical structures. Thus, structural heterogeneity in schizophrenia may relate to specific patterns of GMD reductions that possibly share a common prefrontal-perisylvian pattern of structural brain alterations.

In-vivo topography of structural alterations of the anterior cingulate in patients with schizophrenia: new findings and comparison with the literature.

The anterior cingulate cortex (ACC) is part of the rostral limbic system and is involved in cognitive and affective processes that have been reported to be disturbed in schizophrenia. Despite the evidence for ACC abnormalities in schizophrenia indicated by functional imaging studies, structural magnetic resonance imaging (MRI) studies of this region of interest (ROI) have been relatively few and the results inconsistent. The aim of the present study was to examine the hypothesis that different subregions of the ACC are differentially affected by the disease process of schizophrenia, a circumstance that might contribute to contradictory results of earlier structural ACC studies. We investigated ACC volumes in 50 male and right-handed patients with schizophrenia according to ICD-10 and DSM-IV. The patients were individually matched for age, sex, handedness and education with 50 control subjects. ACC was subdivided into four parts: precallosal, subgenual, precommissural and postcommissural regions. Measurements were performed with a 1.5 T magnetom vision apparatus. Regions of interest were defined on consecutive coronal MRI-slices. The software program BRAINS was used for volumetry and segmentation into gray and white matter. We detected that ACC gray matter volume of the right precallosal region and right total ACC was significantly reduced in schizophrenic patients compared with control subjects. In addition, left ACC gray matter was selectively reduced in the subgenual region. These results confirmed our hypothesis that different ACC regions are differentially affected by structural alterations in schizophrenia, a circumstance that might explain in part the discrepant findings of former structural imaging studies of the ACC.

Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression.

CONTEXT: Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity, which is believed to be altered in patients with major depression. OBJECTIVE: To examine the effect of the BDNF Val66Met polymorphism on hippocampal and amygdala volumes in patients with major depression and in healthy control subjects. DESIGN: Cross-sectional comparison between patients and controls. SETTING: Inpatients with major depression from the Department of Psychiatry and Psychotherapy and healthy controls from the community were recruited. PARTICIPANTS: The study population of 120 subjects included 60 patients with major depression and 60 healthy controls. MAIN OUTCOME MEASURES: Using a combined strategy, hippocampal and amygdala volumes were estimated on high-resolution magnetic resonance images, and genotyping was performed for the BDNF Val66Met polymorphism. RESULTS: Patients had significantly smaller hippocampal volumes compared with controls (P = .02). Significantly smaller hippocampal volumes were observed for patients and for controls carrying the Met-BDNF allele compared with subjects homozygous for the Val-BDNF allele (P = .006). With respect to amygdala volumes, no significant differences between patients and controls and no significant main effects for the BDNF Val66Met polymorphism were observed. CONCLUSIONS: These genotype-related alterations suggest that Met-BDNF allele carriers might be at risk to develop smaller hippocampal volumes and may be susceptible to major depression. This study supports findings from animal studies that the hippocampus is involved in brain development and plasticity.

Hippocampal volume reduction and history of aggressive behaviour in patients with borderline personality disorder.

Disturbances of aggression and impulse control are important symptoms of borderline personality disorder (BPD). The hippocampus is part of the limbic system, which is involved in the control of these types of behaviour. The aim of our study was to investigate potential structural changes of the hippocampal formation in BPD and to evaluate if these are related to aggressive and impulsive behaviour. Twenty-five female and right-handed BPD patients (DSM-IV) and 25 healthy control subjects matched according to sex, age, handedness and educational status were examined. Magnetic resonance imaging (MRI) was performed using a 1.5-T Magnetom Vision system. The software program "BRAINS" was employed for segmentation and volumetry of the hippocampal formation. German versions of instruments were used to evaluate impulsive and aggressive behaviour. Hippocampal grey matter volume was significantly decreased in BPD patients: the reduction was more pronounced in patients with multiple hospitalizations. Hippocampal volume of the left hemisphere was inversely correlated with lifetime history of aggressive behaviour. However, no significant relationship was found between hippocampal volume and impulsive behaviour. Our study confirms previous results indicating a volume reduction of the hippocampal formation in BPD patients. Furthermore, this structural change might facilitate aggressive behaviour. Subsequent studies are required to clarify whether the reduction of hippocampal volume is a trait and risk factor for increased aggression.

Amygdala volume and depressive symptoms in patients with borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is characterized by a high prevalence of comorbid psychiatric disorders, including major depression (MD). The aim of this study was to examine whether a co-occurrence of MD is associated with structural changes in the amygdala of BPD patients. METHODS: Twenty-five right-handed, female patients with BPD and 25 matched healthy control subjects were examined. Diagnoses of BPD and MD were made according to DSM IV. Depressive symptomatology was determined with the Hamilton Depression Scale (HAMD). Magnetic resonance imaging scans were performed with 1.5 T Magnetom Vision (Siemens, Erlangen, Germany). The software program "BRAINS" was applied for brain volumetry and segmentation. The amygdala was delineated as "region of interest." RESULTS: Comparison of amygdala volumes between the whole group of BPD patients and control subjects revealed no significant difference. Amygdala volumes in both hemispheres were significantly larger in BPD patients with MD compared with those without MD. There was a significant correlation in BPD patients between left amygdala volume and depressive symptoms as measured by HAMD. CONCLUSIONS: Correlation of amygdala volume with depression in BPD patients might indicate a causal relationship. Future studies should clarify whether amygdala enlargement is a risk factor for MD in BPD patients or a consequence of the affective disorder.

D2 receptor occupancy during high- and low-dose therapy with the atypical antipsychotic amisulpride: a 123I-iodobenzamide SPECT study.

UNLABELLED: Amisulpride appears to be an effective agent for treating positive or negative symptoms of schizophrenia, depending on dose. The aim of this study was to assess striatal dopamine D(2) receptor availability by means of (123)I-iodobenzamide (IBZM) SPECT in patients treated with high and low doses of this atypical antipsychotic drug. METHODS: Twenty-nine patients (19 men and 10 women, age range, 19-68 y) with schizophrenia treated with high doses (15 patients; 400-1,200 mg/d; mean dose, 666.7 +/- 219.3 mg/d) or low doses (14 patients; 50-300 mg/d; mean dose, 228.6 +/- 93.5 mg/d) of amisulpride were examined. For assessment of plasma amisulpride concentration, blood samples were taken. Brain SPECT was performed 2 h after intravenous injection of 185 MBq of (123)I-IBZM. For semiquantitative evaluation, transverse slices corrected for attenuation (Chang's first-order method) were used to calculate specific binding in the striatum, with the frontal cortex used as background. RESULTS: In all patients treated with amisulpride, specific binding of (123)I-IBZM to D(2) receptors was significantly lower (P < 0.001) than in healthy controls (0.95). Both groups treated with amisulpride differed significantly in specific binding of (123)I-IBZM to dopamine D(2) receptors (0.20 vs. 0.31, P < 0.05). D(2) receptor blockade correlated well with the administered dose of amisulpride and with amisulpride plasma concentration. CONCLUSION: Our findings suggest that amisulpride treatment leads to a significant occupancy of postsynaptic dopamine D(2) receptors. The blockade of D(2) receptors tends to be significantly lower in patients receiving low-dose amisulpride therapy than in patients receiving high-dose therapy.