Reduced intrinsic visual cortical connectivity is associated with impaired perceptual closure in schizophrenia.

Sensory perceptual processing deficits, such as impaired visual object identification and perceptual closure, have been reported in schizophrenia. These perceptual impairments may be associated with neural deficits in visual association areas, including lateral occipital cortex and inferior temporal areas. However, it remains unknown if such deficits can be found in the intrinsic architecture of the visual system. In the current study, we measured perceptual closure performance and resting-state functional connectivity using functional magnetic resonance imaging (FMRI) in 16 schizophrenia patients and 16 matched healthy controls. We estimated intrinsic functional connectivity using self-organized grouping spatial ICA, which clusters component maps in the subject space according to spatial similarity. Patients performed worse than controls in the perceptual closure task. This impaired closure performance of patients was correlated with increased severity of psychotic symptoms. We also found that intrinsic connectivity of the visual processing system was diminished in patients compared to controls. Lower perceptual closure performance was correlated to lower visual cortical intrinsic connectivity overall. We suggest that schizophrenia is associated with impaired intrinsic connectivity of the visual system, and that it is a potential mechanism leading to impaired visual object perception. These findings contribute to increasing evidence for impairments of higher visual functions in schizophrenia.

Abnormal Connectional Fingerprint in Schizophrenia: A Novel Network Analysis of Diffusion Tensor Imaging Data.

The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal-frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder.

The When and Where of Working Memory Dysfunction in Early-Onset Schizophrenia-A Functional Magnetic Resonance Imaging Study.

Behavioral evidence indicates that working memory (WM) in schizophrenia is already impaired at the encoding stage. However, the neurophysiological basis of this primary deficit remains poorly understood. Using event-related fMRI, we assessed differences in brain activation and functional connectivity during the encoding, maintenance and retrieval stages of a visual WM task with 3 levels of memory load in 17 adolescents with early-onset schizophrenia (EOS) and 17 matched controls. The amount of information patients could store in WM was reduced at all memory load levels. During encoding, activation in left ventrolateral prefrontal cortex (VLPFC) and extrastriate visual cortex, which in controls positively correlated with the amount of stored information, was reduced in patients. Additionally, patients showed disturbed functional connectivity between prefrontal and visual areas. During retrieval, right inferior VLPFC hyperactivation was correlated with hypoactivation of left VLPFC in patients during encoding. Visual WM encoding is disturbed by a failure to adequately engage a visual-prefrontal network critical for the transfer of perceptual information into WM. Prefrontal hyperactivation appears to be a secondary consequence of this primary deficit. Isolating the component processes of WM can lead to more specific neurophysiological markers for translational efforts seeking to improve the treatment of cognitive dysfunction in schizophrenia.

Adolescent brain maturation and cortical folding: evidence for reductions in gyrification.

Evidence from anatomical and functional imaging studies have highlighted major modifications of cortical circuits during adolescence. These include reductions of gray matter (GM), increases in the myelination of cortico-cortical connections and changes in the architecture of large-scale cortical networks. It is currently unclear, however, how the ongoing developmental processes impact upon the folding of the cerebral cortex and how changes in gyrification relate to maturation of GM/WM-volume, thickness and surface area. In the current study, we acquired high-resolution (3 Tesla) magnetic resonance imaging (MRI) data from 79 healthy subjects (34 males and 45 females) between the ages of 12 and 23 years and performed whole brain analysis of cortical folding patterns with the gyrification index (GI). In addition to GI-values, we obtained estimates of cortical thickness, surface area, GM and white matter (WM) volume which permitted correlations with changes in gyrification. Our data show pronounced and widespread reductions in GI-values during adolescence in several cortical regions which include precentral, temporal and frontal areas. Decreases in gyrification overlap only partially with changes in the thickness, volume and surface of GM and were characterized overall by a linear developmental trajectory. Our data suggest that the observed reductions in GI-values represent an additional, important modification of the cerebral cortex during late brain maturation which may be related to cognitive development.

Association between psychotic symptoms and cortical thickness reduction across the schizophrenia spectrum.

The current study provides a complete magnetic resonance imaging (MRI) analysis of thickness throughout the cerebral cortical mantle in patients with schizophrenia (SZ) and rigorously screened and matched unaffected relatives and controls and an assessment of its relation to psychopathology and subjective cognitive function. We analyzed 3D-anatomical MRI data sets, obtained at 3 T, from 3 different subject groups: 25 SZ patients, 29 first-degree relatives, and 37 healthy control subjects. We computed whole-brain cortical thickness using the Freesurfer software and assessed group differences. We also acquired clinical and psychometric data. The results showed markedly reduced cortical thickness in SZ patients compared with controls, most notably in the frontal and temporal lobes, in the superior parietal lobe and several limbic areas, with intermediate levels of cortical thickness in relatives. In both patients and relatives, we found an association between subjective cognitive dysfunction and reduced thickness of frontal cortex, and predisposition toward hallucinations and reduced thickness of the superior temporal gyrus. Our findings suggest that changes in specific cortical areas may predispose to specific symptoms, as exemplified by the association between temporal cortex thinning and hallucinations.

Association between white matter fiber integrity and subclinical psychotic symptoms in schizophrenia patients and unaffected relatives.

In this study, we investigate whether aberrant integrity of white matter (WM) fiber tracts represents a genetically determined biological marker of schizophrenia (SZ), and its relation with clinical symptoms. We collected brain DTI data from 28 SZ patients, 18 first-degree relatives and 22 matched controls and used voxel-based analysis with tract-based spatial statistics (TBSS) in order to compare fractional anisotropy (FA) between groups. Mean voxel-based FA values from the entire skeleton of each group were compared. We did a multiple regression analysis, followed by single post-hoc contrasts between groups. FA values were extracted from the statistically significant areas. The results showed significantly smaller FA values for SZ patients in comparison with controls in cortico-spinal tracts, in commissural fibers, in thalamic projections, in association fibers and in cingulum bundles. A significant increase of FA in SZ patients in comparison with healthy controls was only found in the arcuate fasciculus. Relatives had intermediate values between patients and controls which were deemed significant in the comparison to patients and controls in association fibers, arcuate fasciculus and cingulum bundles. Lower FA values in association fibers were significantly associated with predisposition toward hallucinations (in SZ patients and relatives), with higher PANSS scores of positive symptoms and with duration of illness (SZ patients). Our results suggest that clinical and subclinical presentations of psychotic symptoms are associated with aberrant integrity of multiple WM tracts. This association may represent an endophenotype of schizophrenia, since it is present in unaffected relatives as well. Such endophenotypes may serve as quantitative traits for future genetic studies and as candidate markers for early and preclinical identification of subjects at risk.

Interhemispheric hypoconnectivity in schizophrenia: fiber integrity and volume differences of the corpus callosum in patients and unaffected relatives.

Changes in hemispheric asymmetry and inter-hemispheric connectivity have been reported in schizophrenia. However, the genetic contribution to these alterations is still unclear. In the current study, we applied an automatic segmentation method to structural MRI and diffusion tensor imaging (DTI) data and examined volume and fiber integrity of the corpus callosum (CC), the main interhemispheric fiber tract, in 16 chronic schizophrenia (SZ) patients, matched first degree relatives and controls. SZ patients and relatives had smaller CC volumes than controls, particularly in the posterior genu, isthmus and splenium. Fractional anisotropy (FA), an indicator of fiber integrity, was reduced in patients and relatives in the whole CC, the inferior genu, the superior genu and the isthmus. Correspondingly, the mean diffusivity (MD) values of the whole CC and the isthmus were higher in patients and their unaffected relatives, indicating decreased compactness and increased intercellular space. Relatives had intermediate values in the volumetric and fiber integrity measurements between patients and controls. Lower CC volume and fiber integrity in SZ patients were associated with more severe auditory hallucinations. These results support the connectivity hypothesis of SZ (Friston, 1998) and particularly highlight the altered interhemispheric connectivity, which appears to be a genetic feature of SZ risk.

Integrating temporal and spatial scales: human structural network motifs across age and region of interest size.

Human brain networks can be characterized at different temporal or spatial scales given by the age of the subject or the spatial resolution of the neuroimaging method. Integration of data across scales can only be successful if the combined networks show a similar architecture. One way to compare networks is to look at spatial features, based on fiber length, and topological features of individual nodes where outlier nodes form single node motifs whose frequency yields a fingerprint of the network. Here, we observe how characteristic single node motifs change over age (12-23 years) and network size (414, 813, and 1615 nodes) for diffusion tensor imaging structural connectivity in healthy human subjects. First, we find the number and diversity of motifs in a network to be strongly correlated. Second, comparing different scales, the number and diversity of motifs varied across the temporal (subject age) and spatial (network resolution) scale: certain motifs might only occur at one spatial scale or for a certain age range. Third, regions of interest which show one motif at a lower resolution may show a range of motifs at a higher resolution which may or may not include the original motif at the lower resolution. Therefore, both the type and localization of motifs differ for different spatial resolutions. Our results also indicate that spatial resolution has a higher effect on topological measures whereas spatial measures, based on fiber lengths, remain more comparable between resolutions. Therefore, spatial resolution is crucial when comparing characteristic node fingerprints given by topological and spatial network features. As node motifs are based on topological and spatial properties of brain connectivity networks, these conclusions are also relevant to other studies using connectome analysis.

Imaging derived cortical thickness reduction in high-functioning autism: key regions and temporal slope.

Cortical thickness (CT) changes possibly contribute to the complex symptomatology of autism. The aberrant developmental trajectories underlying such differences in certain brain regions and their continuation in adulthood are a matter of intense debate. We studied 28 adults with high-functioning autism (HFA) and 28 control subjects matched for age, gender, IQ and handedness. A surface-based whole brain analysis utilizing FreeSurfer was employed to detect CT differences between the two diagnostic groups and to investigate the time course of age-related changes. Direct comparison with control subjects revealed thinner cortex in HFA in the posterior superior temporal sulcus (pSTS) of the left hemisphere. Considering the time course of CT development we found clusters around the pSTS and cuneus in the left and the paracentral lobule in the right hemisphere to be thinner in HFA with comparable age-related slopes in patients and controls. Conversely, we found clusters around the supramarginal gyrus and inferior parietal lobule (IPL) in the left and the precentral and postcentral gyrus in the right hemisphere to be thinner in HFA, but with different age-related slopes in patients and controls. In the latter regions CT showed a steady decrease in controls but no analogous thinning in HFA. CT analyses contribute in characterizing neuroanatomical correlates of HFA. Reduced CT is present in brain regions involved in social cognition. Furthermore, our results demonstrate that aberrant brain development leading to such differences is proceeding throughout adulthood. Discrepancies in prior morphometric studies may be induced by the complex time course of cortical changes.

Reduced laterality as a trait marker of schizophrenia--evidence from structural and functional neuroimaging.

Laterality is a characteristic principle of the organization of the brain systems for language, and reduced hemispheric asymmetry has been considered a risk factor for schizophrenia. Here we sought support for the risk factor hypothesis by investigating whether reduced asymmetry of temporal lobe structure and function is also present in unaffected relatives. Sixteen schizophrenia patients, 16 age-matched first-degree relatives, and 15 healthy controls underwent high-resolution three-dimensional anatomical imaging and functional magnetic resonance imaging during auditory stimulation. Both the overall auditory cortex and planum temporale volumes and the lateralization to the left hemisphere were markedly reduced in patients. The decrease of lateralization correlated with increased severity of symptoms. In addition, both the overall functional activation in response to auditory stimulation and its asymmetry were reduced in the patients. Relatives had intermediate values between patients and controls on both structural and functional measures. This study provides added support for the idea that reduced hemispheric asymmetry is a biological risk factor for schizophrenia.

Neural synchrony and the development of cortical networks.

Recent data indicate that the synchronisation of oscillatory activity is relevant for the development of cortical circuits as demonstrated by the involvement of neural synchrony in synaptic plasticity and changes in the frequency and synchronisation of neural oscillations during development. Analyses of resting-state and task-related neural synchrony indicate that gamma-oscillations emerge during early childhood and precise temporal coordination through neural synchrony continues to mature until early adulthood. The late maturation of neural synchrony is compatible with changes in the myelination of cortico-cortical connections and with late development of GABAergic neurotransmission. These findings highlight the role of neural synchrony for normal brain development as well as its potential importance for understanding neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia.

Resting-state functional network correlates of psychotic symptoms in schizophrenia.

Schizophrenia has been associated with aberrant intrinsic functional organization of the brain but the relationship of such deficits to psychopathology is unclear. In this study, we investigated associations between resting-state networks and individual psychopathology in sixteen patients with paranoid schizophrenia and sixteen matched healthy control participants. We estimated whole-brain functional connectivity of multiple networks using a combination of spatial independent component analysis and multiple regression analysis. Five networks (default-mode, left and right fronto-parietal, left fronto-temporal and auditory networks) were selected for analysis based on their involvement in neuropsychological models of psychosis. Between-group comparisons and correlations to psychopathology ratings were performed on both spatial (connectivity distributions) and temporal features (power-spectral densities of temporal frequencies below 0.06 Hz). Schizophrenia patients showed aberrant functional connectivity in the default-mode network, which correlated with severity of hallucinations and delusions, and decreased hemispheric separation of fronto-parietal activity, which correlated with disorganization symptoms. Furthermore, the severity of positive symptoms correlated with functional connectivity of fronto-temporal and auditory networks. Finally, default-mode and auditory networks showed increased spectral power of low frequency oscillations, which correlated with positive symptom severity. These results are in line with findings from studies that investigated the neural correlates of positive symptoms and suggest that psychopathology is associated with aberrant intrinsic organization of functional brain networks in schizophrenia.

A fast B1-mapping method for the correction and normalization of magnetization transfer ratio maps at 3 T.

In neuroimaging, there is increasing interest in magnetization transfer (MT) techniques which yield information about bound water protons. One of the main applications is the investigation of the myelin integrity in the central nervous system (CNS). However, several problems may arise, in particular at high magnetic field strengths: B1 inhomogeneities may yield deviations of the MT saturation angle and thus non-uniformities of the measured MT ratio (MTR). This effect can be corrected for but requires in general additional time consuming B1 mapping. Furthermore, increased values of the specific absorption rate (SAR) may require a reduction of the saturation angle for individual subjects, impairing comparability of results. In this work, a B1 mapping method based on magnetization-prepared FLASH with slice selective preparation and excitation pulses and correction for relaxation effects is presented, yielding B1 maps with whole brain coverage, an in-plane resolution of 4 mm, a slice thickness of 3 mm, and a clinically acceptable duration of 46 s. The method is tested both in vitro and in vivo and applied in a subsequent in vivo study to show that MTR values in human brain tissue depend approximately linearly on the preparation angle, with a slope similar to values reported for 1.5 T. Calibration data and B1 maps are applied to B1 inhomogeneity corrections of MTR maps. Subsequently, it is shown that B1-corrected MTR maps acquired at reduced preparation angles due to individual SAR restrictions can be normalized, allowing for a direct comparison with maps acquired at the full angle.

Anatomical brain connectivity and positive symptoms of schizophrenia: a diffusion tensor imaging study.

Structural brain changes in schizophrenia are well documented in the neuroimaging literature. The classical morphometric analyses of magnetic resonance imaging (MRI) data have recently been supplemented by diffusion tensor imaging (DTI), which mainly assesses changes in white matter (WM). DTI increasingly provides evidence for abnormal anatomical connectivity in schizophrenia, most often using fractional anisotropy (FA) as an indicator of the integrity of WM tracts. To better understand the clinical significance of such anatomical changes, we studied FA values in a whole-brain analysis comparing paranoid schizophrenic patients with a history of auditory hallucinations and matched healthy controls. The relationship of WM changes to psychopathology was assessed by correlating FA values with PANSS scores (positive symptoms and severity of auditory hallucinations) and with illness duration. Schizophrenic patients showed FA reductions indicating WM integrity disturbance in the prefrontal regions, external capsule, pyramidal tract, occipitofrontal fasciculus, superior and inferior longitudinal fasciculi, and corpus callosum. The arcuate fasciculus was the only tract which showed increased FA values in patients. Increased FA values in this region correlated with increased severity of auditory hallucinations and length of illness. Our results suggest that local changes in anatomical integrity of WM tracts in schizophrenia may be related to patients' clinical presentation.

Mental imagery vividness as a trait marker across the schizophrenia spectrum.

We investigated the vividness of mental imagery and its possible relationship with the predisposition towards hallucinations in 52 schizophrenia (SZ) patients, 44 of their first-degree relatives (R) and two healthy control groups (high-schizotypy [CHS; n=24]; low-schizotypy [CLS; n=24]). We investigated phenomenological and cognitive trait markers of schizophrenia, including cognitive correlates of hallucinations and vividness of mental imagery, and the influence of individual psychopathology. Overall, scores on the mental imagery questionnaire (QMI [Sheehan, P.W., 1967. Reliability of a short test of imagery. Perceptual and Motor Skills 25, 744.]) suggested higher mental imagery vividness in first-degree relatives, high-schizotypy controls and patients, than in low-schizotypy controls. However, vividness of mental imagery was independent of predisposition towards hallucinations and cognitive test performance scores. These results suggest that vividness of mental imagery may be a trait marker across the schizophrenia spectrum. In addition we propose that imagery proneness is relatively independent of the individual psychopathology.

Summary of the 1st Schizophrenia International Research Society Conference oral sessions, Venice, Italy, June 21-25, 2008: the rapporteur reports.

The Schizophrenia International Research Society held its first scientific conference in Venice, Italy, June 21 to 25th, 2008. A wide range of controversial topics were presented in overlapping and plenary oral sessions. These included new genetic studies, controversies about early detection of schizophrenia and the prodrome, treatment issues, clinical characteristics, cognition, neuropathology and neurophysiology, other etiological considerations, substance abuse co-morbidity, and animal models for investigating disease etiology and for use as targets in drug studies. Young investigators in the field were awarded travel grants to participate in the congress and one of their roles was to summarize the oral sessions and subsequent discussions. The reports that follow are the culmination of this work produced by 30 young investigators who attended the congress. It is hoped that these summaries will be useful synopses of what actually occurred at the congress for those who did not attend each session or were unable to be present. The abstracts of all presentations, as submitted by the authors a few months prior, were previously published as supplement 2 to volume 102/1-3, June 2008.

Minds at rest? Social cognition as the default mode of cognizing and its putative relationship to the "default system" of the brain.

The "default system" of the brain has been described as a set of regions which are 'activated' during rest and 'deactivated' during cognitively effortful tasks. To investigate the reliability of task-related deactivations, we performed a meta-analysis across 12 fMRI studies. Our results replicate previous findings by implicating medial frontal and parietal brain regions as part of the "default system". However, the cognitive correlates of these deactivations remain unclear. In light of the importance of social cognitive abilities for human beings and their propensity to engage in such activities, we relate our results to findings from neuroimaging studies of social cognition. This demonstrates a remarkable overlap between the brain regions typically involved in social cognitive processes and the "default system". We, henceforth, suggest that the physiological 'baseline' of the brain is intimately linked to a psychological 'baseline': human beings have a predisposition for social cognition as the default mode of cognizing which is implemented in the robust pattern of intrinsic brain activity known as the "default system".

The corpus callosum in schizophrenia-volume and connectivity changes affect specific regions.

The corpus callosum (CC) is of great interest for pathophysiological models of schizophrenia. Volume and structural integrity of the CC have been examined by volumetric and diffusion tensor imaging (DTI) studies, but results were not consistent across methods or studies. A possible explanation may be varying methodologies and accuracy of measurements based on a single slice or small regions of interest. In addition, none of the studies examined volume and diffusion values in the same group of patients, and thus the relationship between these anatomical measures is not clear. We used an automatic algorithm to segment seven midline slices of the CC from DTI images. We compared volume and the DTI measures fractional anisotropy (FA) and mean diffusivity (MD) in the CC and its subdivisions in the schizophrenia patients and matched controls. Patients had decreased volume, decreased FA and increased MD of the whole CC. The important novel finding is, however, that not all regions were equally affected by anatomical changes. The results emphasize the importance of using different methods in evaluation of white matter (WM) in schizophrenia to avoid false negative findings. In addition, the measures were highly correlated with each other, implying a common pathological process influencing FA, MD and volume of the CC. Although we cannot rule out other mechanisms affecting volume, FA and MD, converging evidence from cytoarchitectonic and genetic studies suggests that WM changes observed in schizophrenia may involve disintegration of healthy, functional axons and strengthening of aberrant connections resulting in increased severity of clinical symptoms.

Visual hallucinations in schizophrenia investigated with functional magnetic resonance imaging.

We investigated a 27-year old patient with paranoid schizophrenia. Brain activity related to visual hallucinations was found in higher visual areas corresponding to the content of the hallucinations (faces, bodies, scenes) and the hippocampus. We assume that the hippocampal activity is related to the retrieval of visual images from memory and that sensory cortex activity is related to the vividness of the perceptual experience.

Contribution of impaired early-stage visual processing to working memory dysfunction in adolescents with schizophrenia: a study with event-related potentials and functional magnetic resonance imaging.

CONTEXT: Working memory (WM) deficits in patients with schizophrenia have mainly been associated with prefrontal dysfunction. However, the contribution of perceptual deficits and abnormalities in sensory areas has not been explored. The present study closes this important gap in our understanding of WM dysfunction in schizophrenia by monitoring neural activity during WM encoding and retrieval with event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). OBJECTIVE: To investigate the neurophysiological changes that contribute to WM impairment in early-onset schizophrenia at perceptual and cognitive stages using the ERP components P1, P3a, P370, and P570 and fMRI data from extrastriate visual areas. DESIGN: We conducted the study between June 1, 2003, and December 20, 2006. Electroencephalographic and fMRI data were acquired separately during a visual delayed discrimination task. Participants encoded up to 3 abstract shapes that were presented sequentially for 600 milliseconds each and decided after a 12-second delay whether a probe matched 1 of the sample stimuli. SETTING: Between-group study at an inpatient psychiatric hospital and outpatient psychiatric facilities. PARTICIPANTS: Seventeen adolescents with early-onset schizophrenia according to DSM-IV criteria and 17 matched controls participated in the study. MAIN OUTCOME MEASURES: Amplitude of the ERP components P1, P3a, P370, and P570 and the fMRI signal from extrastriate visual areas. RESULTS: The P1 amplitude was reduced in patients during encoding and retrieval. The P1 amplitude increased with WM load during encoding only in controls. In this group, a stronger P1 amplitude increase predicted better WM performance. The P1 reduction was mirrored by reduced activation of visual areas in patients in fMRI. The P370 amplitude during encoding and retrieval was also reduced in patients. CONCLUSIONS: The P1 amplitude reduction indicates an early visual deficit in adolescents with schizophrenia. Our findings suggest that P1 is of particular relevance for successful WM encoding. Early visual deficits contribute to impaired WM in schizophrenia in addition to deficits in later memory-related processes.