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There is strong neuroimaging evidence that cortical alterations represent a core pathophysiological feature of major depressive disorder (MDD). Differential contributions of cortical features of neurodevelopmental origin, which may distinctly contribute to MDD vulnerability, disease-onset, or symptom expression, are unclear at present.We investigated distinct markers of cortical neurodevelopment, i.e. local cortical gyrification (LGI) and thickness (CT) in patients with MDD (n = 38) and healthy controls (HC, n = 22) using 3 T structural magnetic resonance imaging data and surface-based data analysis techniques. CT and LGI were computed using the Computational Anatomy Toolbox (CAT12). Analyses were performed for the entire cortical surface followed by a complementary regions-of-interest approach.MDD patients showed significantly greater LGI in frontal, cingulate, parietal, temporal, and occipital regions compared to HC (FDR-corrected at p 0.05 using threshold-free cluster enhancement). No significant differences of CT were found. In the MDD-group, correlations were found between duration of illness in years and number of depressive episodes and LGI of frontal, temporal, and parietal regions (p 0.05).Main limitations are the relatively modest sample size and a cross-sectional study design. We did not control for early environmental factors potentially influencing neurodevelopment, such as childhood trauma. We report associations uncorrected for multiple comparisons.The data suggest different local trajectories of cortical change in MDD. In addition, our data support the notion that aberrant cortical development may serve as a vulnerability marker of MDD, as well as a potential predictor of disease course.

In schizophrenia temporal cortical volume loss differs between patients presenting with persistent auditory verbal hallucinations (pAVH) in contrast to those without hallucinatory symptoms (nAVH). However, it is unknown whether this deficit reflects a neural signature of neurodevelopmental origin or if abnormal temporal cortical volume is reflective of factors which may be relevant at later stages of the disorder. Here, we tested the hypothesis that local gyrification index (LGI) in regions of the temporal cortex differs between patients with pAVH (n=10) and healthy controls (n=14), and that abnormal temporal LGI discriminates between pAVH and nAVH (n=10). Structural magnetic resonance imaging at 3T along with surface-based data analysis methods was used. Contrary to our expectations, patients with pAVH showed lower LGI in Broca´s region compared to both healthy persons and nAVH. Compared to nAVH, those individuals presenting with pAVH also showed lower LGI in right Broca's homologue and right superior middle frontal cortex, together with increased LGI in the precuneus and superior parietal cortex. Regions with abnormal LGI common to both patient samples were found in anterior cingulate and superior frontal areas. Inferior cortical regions exhibiting abnormal LGI in pAVH patients were associated with overall symptom load (BPRS), but not with measures of AVH symptom severity. The pattern of abnormal cortical folding in this sample suggests a neurodevelopmental signature in Broca's region, consistent with current AVH models emphasizing the pivotal role of language circuits and inner speech. Temporal cortical deficits may characterize patients with pAVH during later stages of the disorder.

There is growing evidence that the cerebellum plays a crucial role in the pathophysiology of schizophrenia symptoms. Despite increasing evidence for cerebellar involvement in affective, attentive, and cognitive functions including language processing and perception, investigations of cerebellar contributions to auditory verbal hallucinations (AVH) in schizophrenia are lacking. Using structural magnetic resonance imaging at 3T, we investigated the data of 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH (pAVH), whereas the remaining ten patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Employing cerebellum-optimized segmentation techniques, i.e., the Spatially Unbiased Infratentorial Template (SUIT) toolbox, we investigated cerebellar gray matter volume (GMV) differences among the pAVH, nAVH, and a healthy control group, the magnitude of their expression between these groups and the relationship between GMV and schizophrenia symptom load. Lower GMV in pAVH patients compared to controls was found in lobules VIIb and VIIIa. Additionally, lower GMV in pAVH compared to nAVH patients was found in lobule VIIIa. A negative relationship between VIIIa GMV and overall positive symptoms was detected. Correlations with AVH-specific psychometric scores were not significant. This study shows that there are structural changes in the cognitive regions of the cerebellum that are linked to a clinical phenotype presenting with persistent positive symptoms such as AVH. The results suggest that the cerebellum and its associated neural circuits do play a role in the emergence of positive symptoms in schizophrenia, but probably not exclusively in AVH symptom expression.

Abnormal cortical cerebral blood flow and gray matter volume have been frequently reported in patients with major depressive disorder (MDD). In contrast, although the role of the cerebellum in MDD pathophysiology has attracted considerable interest more recently, studies investigating both functional and structural aspects of cerebellar integrity are scarce.In this study, we used structural and functional magnetic resonance imaging (MRI) to investigate cerebellar volume and regional cerebellar blood flow (rCBF) at rest in clinically acute MDD patients (n = 22) and healthy controls (n = 18). We acquired high-resolution structural images at 3 T together with perfusion images obtained with continuous arterial spin labeling. Cerebellar structure and function were investigated using cerebellum-optimized analysis techniques.Markedly increased rCBF was found in bilateral cerebellar areas VIIa and VIIIb (p0.05 family-wise-error [FWE] corrected). Significant differences in cerebellar volume between patients and controls were not found (p0.05, FWE-corrected). Left cerebellar area VIIa perfusion was significantly associated with depressive symptoms, as measured by the Hamilton Depression Rating Scale.Potential limitations of this study include the modest sample size, the cross-sectional design, the lack of task-related imaging and the heterogeneity of drug treatment.The data suggest contributions of "affective" cerebellar regions to MDD pathophysiology and symptom expression. While cerebellar perfusion at rest is compromised in MDD, cerebellar volume seems to be less affected.

BackgroundMajor depressive disorder (MDD) is characterized by alterations in brain function that are identifiable also during the brain's ‘resting state’. One functional network that is disrupted in this disorder is the default mode network (DMN), a set of large-scale connected brain regions that oscillate with low-frequency fluctuations and are more active during rest relative to a goal-directed task. Recent studies support the idea that the DMN is not a unitary system, but rather is composed of smaller and distinct functional subsystems that interact with each other. The functional relevance of these subsystems in depression, however, is unclear.MethodHere, we investigated the functional connectivity of distinct DMN subsystems and their interplay in depression using resting-state functional magnetic resonance imaging.ResultsWe show that patients with MDD exhibit increased within-network connectivity in posterior, ventral and core DMN subsystems along with reduced interplay from the anterior to the ventral DMN subsystems.ConclusionsThese data suggest that MDD is characterized by alterations of subsystems within the DMN as well as of their interactions. Our findings highlight a critical role of DMN circuitry in the pathophysiology of MDD, thus suggesting these subsystems as potential therapeutic targets.

Background: Structural magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). So far, structural changes have been found mainly in preHD approaching the estimated motor onset of the disease (i.e. less than 15 years from onset), whereas structural findings in preHD far from the estimated motor onset have been inconclusive. Objectives: The aims of this study were to investigate the sensitivity of different methodological approaches to structural data in far-from-onset preHD (mean estimated time to motor onset = 21.4 years) and to explore the relationship between brain structure, clinical variables and cognition. Methods: High-resolution MRI data at 3 T were obtained from 20 preHD individuals and 20 healthy participants and subsequently analyzed using voxel-based morphometry (VBM), cortical surface modeling and subcortical segmentation analysis techniques. Results: VBM analyses did not reveal significant between-group differences, whereas cortical surface modeling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls. Significant correlations were found between striatal structure, estimated time to motor onset and executive performance, whereas cortical changes were not significantly correlated with these parameters. Conclusion: These data suggest that a combined methodological approach to structural MRI data could increase the sensitivity for detecting subtle neurobiological changes in early preHD. As consistently shown across different methods, the association between striatal structure and clinical measures supports the notion that changes in striatal volume could represent a more robust marker of disease progression than cortical changes.

Abnormal cortical volume is well-documented in patients with major depressive disorder (MDD), but cerebellar findings have been heterogeneous. It is unclear whether abnormal cerebellar structure relates to disease state or medication. In this study, using structural MRI, we investigated cerebellar volume in clinically acute (with and without psychotropic treatment) and remitted MDD patients. High-resolution structural MRI data at 3T were obtained from acute medicated (n=29), acute unmedicated (n=14) and remitted patients (n=16). Data from 29 healthy controls were used for comparison purposes. Cerebellar volume was investigated using cerebellum-optimized voxel-based analysis methods. Patients with an acute MDD episode showed increased volume of left cerebellar area IX, and this was true for both medicated and unmedicated individuals (p

Major depressive disorder (MDD) and borderline personality disorder (BPD) show substantial overlap in both affective symptom expression and in regional brain volume reduction. To address the specificity of structural brain change for the respective diagnostic category, we investigated structural networks in MDD and BPD to identify shared and distinct patterns of abnormal brain volume associated with these phenotypically related disorders. Using magnetic resonance imaging at 3 T, we studied 22 females with MDD, 17 females with BPD and without comorbid posttraumatic stress disorder, and 22 age-matched female healthy controls. We used “source-based morphometry” (SBM) to investigate naturally grouping patterns of gray matter volume variation (i.e. “structural networks”) and the magnitude of their expression between groups. SBM identified three distinct structural networks which showed a significant group effect (p b 0.05, FDR-corrected). A bilateral frontostriatal network showed reduced volume in MDD compared to both controls and BPD patients. A medial temporal/medial frontal network was found to be significantly reduced in BPD compared to both controls and MDD patients. Decreased cingulate and lateral prefrontal volume was found in both MDD and BPD when compared to healthy individuals. In MDD significant relationships were found between depressive symptoms and a cingulate/lateral prefrontal structural pattern. In contrast, overall BPD symptoms and impulsivity scores were significantly associated with medial temporal/medial frontal network volume. The data suggest both distinct and common patterns of abnormal brain volume in MDD and BPD. Alterations of distinct structural networks differentially modulate clinical symptom expression in these disorders.

Behavioral and neuroimaging studies in patients with borderline personality disorder (BPD) have associated orbitofrontal cortex (OFC) dysfunction with distinct symptom clusters such as impulsivity. It is unclear, however, whether abnormal patterns of OFC activity are also present during resting-state conditions and whether OFC dysfunction is specifically associated with impulsivity in BPD. This study tested the hypothesis that BPD patients would exhibit changes of OFC baseline perfusion and explored the relationship between regional cerebral blood flow and distinct BPD symptom clusters, such as impulsivity, dissociation tension and depressive symptoms. Using continuous arterial spin labeling magnetic resonance imaging at 3 Tesla, we investigated 16 women with BPD according to DSM-IV criteria and 16 healthy female control participants during resting-state conditions. Between-group comparisons were conducted using an analysis of variance (p

Functional neuroimaging studies on cognitive dysfunction in schizophrenia have suggested regional brain activation changes in the dorsolateral prefrontal cortex and the medial temporal lobe. However, less is known about the functional coupling of these areas during cognitive performance. In this study, we used functional magnetic resonance imaging, a verbal working memory (WM) task and multivariate statistical techniques to investigate the functional coupling of temporally anticorrelated neural networks during cognitive processing in patients with schizophrenia (n=16) compared to healthy controls (n=16). Independent component analysis identified 18 independent components (ICs) among which two ICs were selected for further analyses. These ICs included temporally anticorrelated networks which were most highly associated with the delay period of the task in both healthy controls and patients with schizophrenia. Functional network abnormalities in patients with schizophrenia were detected within a "task-positive" lateral frontoparietal network, where increased functional connectivity was found in bilateral dorsolateral prefrontal regions. In addition, aberrant functional coupling of the hippocampal cortex in patients with schizophrenia was detected within a "task-negative" medial frontotemporal network. In patients with schizophrenia, functional connectivity indices in the left dorsolateral prefrontal cortex and the right hippocampal cortex were positively correlated with accuracy during the WM task, while the connectivity strength in the right dorsolateral prefrontal cortex was negatively correlated with measures of symptom severity. These data suggest that within two temporally anticorrelated network states, patients with schizophrenia exhibit increased and persistent dorsolateral prefrontal and hippocampal connectivity during WM performance.

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntington's disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event‐related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy‐related activation confounds. Voxel‐based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso‐ and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM‐related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

Background Dysfunctional reward processing, accompanied by a limited ability to tolerate reward delays, has been proposed as an important feature in attention-deficit/hyperactivity disorder (ADHD). Methods Using functional magnetic resonance imaging (fMRI), brain activation in adult patients with ADHD ( n = 14) and healthy control subjects ( n = 12) was examined during a series of choices between two monetary reward options that varied by delay to delivery. Results Compared with healthy control subjects, hyporesponsiveness of the ventral-striatal reward system was replicated in patients with ADHD and was evident for both immediate and delayed rewards. In contrast, delayed rewards evoked hyperactivation in dorsal caudate nucleus and amygdala of ADHD patients. In both structures, neural activity toward delayed rewards was significantly correlated with self-rated ADHD symptom severity. Conclusions The finding of ventral-striatal hyporesponsiveness during immediate and delayed reward processing in patients with ADHD further strengthens the concept of a diminished neural processing of rewards in ADHD. Hyperactivation during delayed reward processing, gradually increasing along the ventral-to-dorsal extension of the caudate nucleus, and especially the concomitant hyperactivation of the amygdala are in accordance with predictions of the delay aversion hypothesis.

While functional neuroimaging studies on attention and executive function in schizophrenia have reported several functionally aberrant cortical regions, less is known about the relationship of cognitive impairment and regional volume alterations. In order to investigate the relationship between cognitive impairment and structural alterations, we studied healthy control subjects and partially remitted, medicated inpatients with DSM-IV schizophrenia using voxel-based morphometry (VBM) and a standardised neuropsychological test battery. Schizophrenic patients showed reduced grey matter (GM) density in the bilateral temporal cortex, the left inferior parietal lobule, the cingulate gyrus and the left middle frontal gyrus. Reduced GM volume was additionally found in the left hippocampal gyrus and the right superior frontal cortex. Reduced white matter density was found in the posterior corpus callosum. Structure-cognition regression analyses revealed that decreased GM density of the left inferior parietal and the right middle temporal cortex was associated with worse performance during divided attention. Worse performance during the spatial span was associated with volumetric abnormalities of the hippocampal gyrus. These results indicate that regional abnormalities in brain structure may offer an account for some impaired cognitive domains in patients with schizophrenia, while other cognitive domains may remain relatively less affected by volumetric alterations.

Behavioral studies indicate deficits in phonological working memory (WM) and executive functioning in dyslexics. However, little is known about the underlying functional neuroanatomy. In the present study, neural correlates of WM in adolescents and young adults with dyslexia were investigated using event-related functional magnetic resonance imaging (fMRI) and a parametric verbal WM task which required the manipulation of verbal material. Dyslexics were not significantly slower than controls; however, they were less accurate with the highest WM demand. The functional analysis excluded incorrectly performed and omitted trials, thus controlling for potential activation confounds. Compared with control subjects, both increased and decreased activation of the prefrontal cortex were found in the dyslexic group. Dyslexics showed significantly more activation than controls with increasing WM demand in the left superior frontal gyrus (BA 8), as well as in the inferior frontal gyrus including Broca's area (BA 44) and its right homologue. Less activation was found in the middle frontal gyrus (BA 6) and in the superior parietal cortex (BA 7). A positive correlation between activation of prefrontal regions and verbal WM performance (as measured by digit span backwards) was found only in the dyslexic group. Accuracy deficits at the highest cognitive demand during the verbal WM task and the digit span backwards suggest that manipulation rather than maintenance is selectively impaired in dyslexics. The fMRI data provide further evidence for functional differences in cortical regions associated with language processing and executive function in subjects with dyslexia.

Background Executive deficits associated with frontal lobe dysfunction are prominent in depression. We applied a newly developed WM task to investigate the neural correlates of executive processes with functional magnetic resonance imaging (fMRI) at comparable performance levels analyzing correct trials only. Methods We studied 12 partially remitted, medicated inpatients meeting DSM-IV criteria for major depressive disorder and 17 healthy controls. We used a parametric version of a delayed match-to-sample WM task requiring manipulation of verbal material during a delay period in an event-related fMRI design. Results Depressed patients were generally slower and load-dependently less accurate than healthy controls. Patients showed significantly more activation of left dorsolateral prefrontal cortex with highest cognitive load. Additionally, they showed higher activation in ventromedial prefrontal cortex during the control condition. Limitations The fact that patients were taking different antidepressant drugs could limit the explanatory power of the present results. Conclusions Increased lateral prefrontal activation despite comparably successful performance – when only correct trials were analyzed – in patients with depression can be interpreted as evidence for compensatory recruitment of prefrontal cortical resources.

Evidence from animal models and neuropathological data has revealed cerebellar pathology in Huntington's disease (HD). The extent of cerebellar dysfunction in preclinical stages and in early manifest HD is unclear. In this study, using MRI we investigated cerebellar changes in preclinical (preHD) and early manifest HD individuals. High-resolution structural MRI data at 3 Tesla were obtained from two independent preHD samples (n = 20/25 participants), from two independent cohorts of healthy controls (n = 20/24 participants) and from patients with early manifest HD (n = 20 participants). Resting-state functional MRI data were acquired from 20 healthy controls and 20 HD patients. Cerebellar volume was investigated using cerebellum-optimized voxel-based analysis methods. Corticocerebellar connectivity at rest was investigated by means of seed-region correlations. In both preHD samples, between-group analyses revealed no change of cerebellar volume. In contrast, early manifest HD patients exhibited lower right cerebellar lobule VIIa volume (p < 0.05 cluster-corrected). Within the control group regions functionally coupled to right cerebellar lobule VII comprised bilateral cerebellar regions, right prefrontal and cingulate areas, whereas within manifest HD, functional coupling was found in paracentral, lingual and inferior frontal areas. Paracentral connectivity strength in patients was associated with disease burden and motor symptoms. These data suggest intact cerebellar volume in preHD. In contrast, early manifest HD patients exhibit atrophy of specific cerebellar subregions and abnormal corticocerebellar functional coupling. In early HD, the association between paracentral lobule function and clinical parameters suggests that corticocerebellar connectivity strength is related to the evolution of HD biology and the severity of HD motor signs.

Abnormal brain volume has been frequently demonstrated in major depressive disorder (MDD). It is unclear if these findings are specific for MDD since aberrant brain structure is also present in disorders with depressive comorbidity and affective dysregulation, such as borderline personality disorder (BPD). In this transdiagnostic study, we aimed to investigate if regional brain volume loss differentiates between MDD and BPD. Further, we tested for associations between brain volume and clinical variables within and between diagnostic groups.22 Females with a DSM-IV diagnosis of MDD, 17 females with a DSM-IV diagnosis of BPD and without comorbid posttraumatic stress disorder, and 22 age-matched female healthy controls (HC) were investigated using magnetic resonance imaging. High-resolution structural data were analyzed using voxel-based morphometry.A significant (p0.05, cluster-corrected) volume decrease of the anterior cingulate cortex (ACC) was found in MDD compared to HC, as opposed to volume decreases of the amygdala in BPD compared to both HC and MDD. Sensitivity and specificity of regional gray matter volume for a diagnosis of MDD were modest to fair. Amygdala volume was related to depressive symptoms across the entire patient sample.Potential limitations of this study include the modest sample size and the heterogeneous psychotropic drug treatment.ACC volume reduction is more pronounced in MDD with an intermediate degree of volume loss in BPD compared to HC. In contrast, amygdala volume loss is more pronounced in BPD compared to MDD, yet amygdala volume is associated with affective symptom expression in both disorders.

Posterior cortical volume changes and abnormal visuomotor performance are present in patients with Huntington's disease (HD). However, it is unclear whether posterior cortical volume loss contributes to abnormal neural activity, and whether activity changes predict cognitive dysfunction. Using magnetic resonance imaging (MRI), we investigated brain structure and visual network activity at rest in patients with early HD (n = 20) and healthy controls (n = 20). The symbol digit modalities test (SDMT) and subtests of the Visual Object and Space Perception Battery were completed offline. For functional MRI data, a group independent component analysis was used. Voxel-based morphometry was employed to assess regional brain atrophy, and ‘biological parametric mapping’ analyses were included to investigate the impact of atrophy on neural activity. Patients showed significantly worse visuomotor and visual object performance than controls. Structural analyses confirmed occipitotemporal atrophy. In patients and controls, two spatiotemporally distinct visual systems were identified. Patients showed decreased activity in the left fusiform cortex, and increased left cerebellar activity. These findings remained stable after correction for brain atrophy. Lower fusiform cortex activity was associated with lower SDMT performance and with higher disease burden scores. These associations were absent when cerebellar function was related to task performance and disease burden. The results of this study suggest that regionally specific functional abnormalities of the visual system can account for the worse visuomotor cognition in HD patients. However, occipital volume changes cannot sufficiently explain abnormal neural function in these patients. Postprint

Functional neuroimaging studies have reported task-related brain activation changes in preclinical individuals carrying the Huntington's disease (HD) gene mutation (preHD). Little is known about "task-negative" activity, i.e., patterns of task-related deactivation in preHD, and about the stability of any deactivation changes over the course of the disease. Here, we explored task-related deactivation and functional connectivity of "task-negative" networks (TNNs) in preHD followed over a time period of 2 years. Thirteen far-from-onset preHD (mean time to estimated motor onset = 19.5 years) and thirteen healthy controls were investigated. We used functional magnetic resonance imaging (fMRI), a verbal working memory task, and uni- and multivariate analysis techniques for fMRI data. Behavior was similar in preHD and controls at baseline and did not change 2 years later. At both time points, deactivation was similar in preHD and controls. Within two spatio-temporally distinct TNNs, preHD had lower functional connectivity in the posterior cingulate cortex and higher functional connectivity in the left anterior prefrontal cortex compared to controls (p < 0.05, cluster-corrected). These findings remained stable at follow-up. Anterior prefrontal connectivity correlated with disease burden scores both at baseline and at follow-up. Over time, preHD exhibited higher connectivity in a dorsal cingulate region. Functional connectivity differences within this region were inversely associated with changes of motor function. These data provide first evidence for TNN connectivity changes in preHD followed over a period of 2 years. The relationship between dorsal cingulate connectivity and motor function suggests that "task-negative" activity may capture time-sensitive neural and functional processes in preHD.

Abnormal structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. This study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. “source-based morphometry” (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a reduction of medial and inferior frontal, insular and bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with “physical” AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal, insular and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.

The present study investigated the association between traits of the Five Factor Model of Personality (Neuroticism, Extraversion, Openness for Experiences, Agreeableness, and Conscientiousness) and neural correlates of error monitoring obtained from a combined Eriksen-Flanker-Go/NoGo task during event-related functional magnetic resonance imaging in 27 healthy subjects. Individual expressions of personality traits were measured using the NEO-PI-R questionnaire. Conscientiousness correlated positively with error signaling in the left inferior frontal gyrus and adjacent anterior insula (IFG/aI). A second strong positive correlation was observed in the anterior cingulate gyrus (ACC). Neuroticism was negatively correlated with error signaling in the inferior frontal cortex possibly reflecting the negative inter-correlation between both scales observed on the behavioral level. Under present statistical thresholds no significant results were obtained for remaining scales. Aligning the personality trait of Conscientiousness with task accomplishment striving behavior the correlation in the left IFG/aI possibly reflects an inter-individually different involvement whenever task-set related memory representations are violated by the occurrence of errors. The strong correlations in the ACC may indicate that more conscientious subjects were stronger affected by these violations of a given task-set expressed by individually different, negatively valenced signals conveyed by the ACC upon occurrence of an error. Present results illustrate that for predicting individual responses to errors underlying personality traits should be taken into account and also lend external validity to the personality trait approach suggesting that personality constructs do reflect more than mere descriptive taxonomies.

The default-mode network (DMN) refers to as a set of brain regions which are active when the brain does not engage in a cognitive task and which are deactivated with task-related cognitive effort. Altered function of the DMN has been associated with a decline of cognition in several neurodegenerative diseases and related at-risk conditions. In Huntington's disease, an autosomal dominant inherited neurodegenerative disorder, several studies so far have shown abnormal task-related brain activation patterns even in preclinical carriers of the Huntington's disease gene mutation (preHD). To date, however, the functional integrity of the DMN has not been addressed in this population. The aim of this study was to study the functional connectivity of the DMN in 18 preHD and 18 healthy controls who underwent functional magnetic resonance imaging during an attention task. A group independent component analysis identified spatiotemporally distinct patterns of two DMN subsystems. The spatial distribution of these components in preHD was similar to controls. However, preHD showed lower subsystem-specific connectivity in the anterior medial prefrontal cortex, the left inferior parietal and the posterior cingulate cortex (p0.05, cluster-corrected). Connectivity between the two DMN subsystems was increased in preHD compared to controls. In preHD individuals lower functional connectivity of the left inferior parietal cortex was associated with shorter reaction times in the attention task. This suggests that some functionally critical regions of the DMN may have to remain active to maintain or optimise cognitive performance in preHD.

Previous functional neuroimaging studies have shown brain activation abnormalities in clinically presymptomatic carriers of the Huntington's disease (preHD) gene mutation when performing complex cognitive tasks. However, little is known about the neural correlates of attentional processes in preHD. In this study, we used functional magnetic resonance imaging to investigate basic aspects of attentional processing in preHD individuals (n = 18) compared to healthy participants (n = 18) during an alertness task. Uni‐ and multivariate statistical techniques were used to assess task‐related regional brain activation and functional network connectivity. Compared to healthy controls, preHD individuals near to the estimated onset of clinical signs showed lower activation of right frontostriatal regions during phasic alertness (P < 0.001, uncorrected). Decreased striatal activation in this preHD subgroup was also evident when compared with those preHD individuals far from the estimated onset of HD signs. Lower putaminal activity was associated with longer reaction times and with proximity to onset. In addition, preHD participants near to onset had lower functional connectivity of motor regions when compared with controls and preHD individuals far from onset. Our data suggest that while alertness‐related performance remains normal, the underlying frontostriatal activity and motor cortex connectivity decline only when approaching the onset of unequivocal signs of HD. However, these attentional network changes might not be the sole explanation for the differences in cognitive task performance previously observed in preHD. Hum Brain Mapp 33:2161–2173, 2012. © 2011 Wiley Periodicals, Inc.

Magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). The aim of this study was to investigate the sensitivity of resting-state perfusion MRI in preHD and to identify neural changes, which could serve as biomarkers for future clinical trials. Differences in regional cerebral blood flow (rCBF) in 18 preHD and 18 controls were assessed with a novel MRI method based on perfusion images obtained with continuous arterial spin labeling. High-resolution structural data were collected to test for changes of brain volume. Compared with controls, preHD individuals showed decreased rCBF in medial and lateral prefrontal regions and increased rCBF in the precuneus. PreHD near to symptom onset additionally showed decreased rCBF in the putamen and increased rCBF in the hippocampus. Network analyses revealed an abnormal lateral prefrontal pattern in preHD far and near to motor onset. These data suggest early changes of frontostriatal baseline perfusion in preHD independent of substantial reductions of gray matter volume. This study also shows the feasibility of detecting neural changes in preHD with a robust MRI technique that would be suitable for longitudinal multisite application.

Background: Functional neuroimaging studies on schizophrenia have suggested abnormal task-related functional connectivity in patients with schizophrenia who have auditory verbal hallucinations (AVHs). However, little is known about intrinsic functional connectivity in these patients. Methods: Between January 2009 and February 2010, we studied patients with schizophrenia who had persistent and treatment-refractory AVHs in comparison with healthy controls. Using functional magnetic resonance imaging, we studied the functional connectivity of multiple resting state networks (RSNs) and their relation to symptom severity. We analyzed the data using a spatial group independent component analysis, and we used random-effects t tests to compare spatial components between groups. Results: There were 10 patients and 14 controls enrolled in this study. In total, 16 RSNs were identified, from which we selected 4 networks of interest for further analyses. Within a speech-related network, patients showed increased connectivity in bilateral temporal regions and decreased connectivity in the cingulate cortex. Within 2 additional RSNs associated with attention and executive control, respectively, patients exhibited abnormal connectivity in the precuneus and right lateral prefrontal areas. We found correlations between measures of AVH severity and functional connectivity of the left anterior cingulate, left superior temporal gyrus and right lateral prefrontal cortex. Limitations: The relatively small sample size, the patients’ use of antipsychotic medication and the lack of a clinical control group have to be considered as potential limitations. Conclusion: Our findings indicate that disrupted intrinsic connectivity of a speech-related network could underlie persistent AVHs in patients with schizophrenia. In addition, the occurrence of hallucinatory symptoms seems to modulate RSNs associated with attention and executive control.

Neuropsychological and functional neuroimaging studies have revealed early changes of cognition and brain function in individuals with the Huntington's disease (HD) gene mutation who are presymptomatic for the motor symptoms of the disease (preHD). However, little is known about whether changes of neural function progress over time. In this study, we used neuropsychological tests of attention, working memory and executive function, functional magnetic resonance imaging and voxel-based analyses of high-resolution structural data to explore the temporal dynamics of potential cognitive, functional and structural biomarkers in far from onset preHD (n = 13, mean time to the estimated motor symptom onset = 19.5 years) and healthy controls (n = 13) followed over a 2-year period. Behavioral measures were similar in preHD individuals and controls at baseline and remained normal 2 years later. At both time points, the left dorsolateral prefrontal cortex was less active in preHD than in controls during working memory performance. The left dorsolateral prefrontal cortex did not exhibit further loss of activity over time. Regions showing less gray matter volume in preHD at baseline did not show further volume loss over time. These data indicate that the activity in brain regions contributing to working memory processing differs consistently in HD expansion mutation carriers while cognitive performance remains normal. However, the present data do not support the notion of a progressive decline of left prefrontal cortex activity in far from onset preHD followed over a 2-year period.

Several functional neuroimaging studies have reported regionally abnormal activation of the frontal cortex in individuals with borderline personality disorder (BPD) during cognitive and affective task performance. However, little is known about neural function in individuals with BPD during the resting state. Using functional magnetic resonance imaging (fMRI), this study investigated the functional connectivity of prefrontal and limbic networks in patients with BPD.Between January 2009 and March 2010, we investigated patients with BPD according to DSM-IV criteria and healthy controls by means of resting-state fMRI. The data were analyzed using a spatial group independent component analysis, and random effects t tests were used to compare spatial components between groups (p0.005, uncorrected).There were 17 women with BPD and 17 female healthy controls enrolled in this study. Within a network comprising cortical midline regions ("default mode network"), patients with BPD showed an increase in functional connectivity in the left frontopolar cortex (FPC) and the left insula, whereas decreased connectivity was found in the left cuneus. Within a network comprising predominantly right lateral prefrontal and bilateral parietal regions, patients with BPD showed decreased connectivity of the left inferior parietal lobule and the right middle temporal cortex compared with healthy controls. Two networks comprising lateral prefrontal and cingulate regions did not exhibit significant between-group differences. We found correlations between functional connectivity of the FPC and measures of impulsivity as well as between connectivity of the insula/cuneus and dissociation tension.Co-occurrent axis I disorders and medication use in this sample of patients with BPD have to be considered as potential limitations.These data suggest that abnormal functional connectivity of temporally coherent resting-state networks may underlie certain symptom clusters in patients with BPD.

Using a parametric version of a modified item-recognition paradigm with three different load levels and by means of event-related functional magnetic resonance imaging, this study tested the hypothesis that cerebral activation associated with intratrial proactive interference (PI) during working memory retrieval is influenced by increased context processing. We found activation of left BA 45 during interference trials across all levels of cognitive processing, and left lateralized activation of the dorsolateral prefrontal cortex (DLPFC, BA 9/46) and the frontopolar cortex (FPC, BA 10) with increasing contextual load. Compared with high susceptibility to PI, low susceptibility was associated with activation of the left DLPFC. These results suggest that an intratrial PI effect can be modulated by increasing context processing of a transiently relevant stimulus set. Moreover, PI resolution associated with increasing context load involves multiple prefrontal regions including the ventro- and dorsolateral prefrontal cortex as well as frontopolar brain areas. Furthermore, low susceptibility to PI might be influenced by increased executive control exerted by the DLPFC.

Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional neuroanatomy underlying cognitive dysfunction in dyslexia. In this study, functional magnetic resonance imaging and multivariate analytic techniques were used to investigate patterns of functional connectivity during a verbal WM task in individuals with dyslexia (n = 12) and control subjects (n = 13). Dyslexics were not significantly slower than controls; however, they were less accurate with increasing WM demand. Independent component analysis identified 18 independent components (ICs) among which two ICs were selected for further analyses. These ICs included functional networks which were positively correlated with the delay period of the activation task in both healthy controls and dyslexics. Connectivity abnormalities in dyslexics were detected within both networks of interest: within a “phonological” left-lateralized prefrontal network, increased functional connectivity was found in left prefrontal and inferior parietal regions. Within an “executive” bilateral frontoparietal network, dyslexics showed a decreased connectivity pattern comprising bilateral dorsolateral prefrontal and posterior parietal regions, while increased connectivity was found in the left angular gyrus, the left hippocampal cortex and the right thalamus. The functional connectivity strength in the latter regions was associated with WM task accuracy and with the numbers of errors during a spelling test. These data suggest functional connectivity abnormalities in two spatiotemporally dissociable brain networks underlying WM dysfunction in individuals with dyslexia.

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

In this fMRI study, we investigated theory of mind (ToM) in patients with paranoid schizophrenia. We hypothesized that the network supporting the representation of intentions is dysfunctional in patients with schizophrenia dependent on the type of intention involved. We used a paradigm including a control condition (physical causation) and three intention conditions (private intention, prospective social intention and communicative intentions) differing in the degree of social interaction. In all four experimental conditions patients performed worse than controls regarding accuracy and reaction time. They showed significantly less activation in three regions typically activated in ToM tasks, i.e. paracingulate cortex and bilateral temporo-parietal junctions. However, this dysfunction was dependent on the type of intention represented, i.e. was present only for social but not for non-social intentions. Moreover, part of the reduced activation was related to the fact that there was no signal drop in these regions for the physical causality condition as usually found in controls. This may be due to the tendency of schizophrenic patients to attribute intentionality to physical objects. Our findings have implications for the study and understanding of ToM in schizophrenia but also in other disorders like autism.

BackgroundIn patients with major depressive disorder (MDD), functional neuroimaging studies have reported an increased activation of the dorsolateral prefrontal cortex (DLPFC) during executive performance and working memory (WM) processing, and also an increased activation of the anterior cingulate cortex (ACC) during baseline conditions. However, the functional coupling of these cortical networks during WM processing is less clear.MethodIn this study, we used a verbal WM paradigm, event-related functional magnetic resonance imaging (fMRI) and multivariate statistical techniques to explore patterns of functional coupling of temporally dissociable dorsolateral prefrontal and cingulate networks. By means of independent component analyses (ICAs), two components of interest were identified that showed either a positive or a negative temporal correlation with the delay period of the cognitive activation task in both healthy controls and MDD patients.ResultsIn a prefronto-parietal network, a decreased functional connectivity pattern was identified in depressed patients comprising inferior parietal, superior prefrontal and frontopolar regions. Within this cortical network, MDD patients additionally revealed a pattern of increased functional connectivity in the left DLPFC and the cerebellum compared to healthy controls. In a second, temporally anti-correlated network, healthy controls exhibited higher connectivity in the ACC, the ventrolateral and the superior prefrontal cortex compared to MDD patients.ConclusionsThese results complement and expand previous functional neuroimaging findings by demonstrating a dysconnectivity of dissociable prefrontal and cingulate regions in MDD patients. A disturbance of these dynamic networks is characterized by a simultaneously increased connectivity of the DLPFC during task-induced activation and increased connectivity of the ACC during task-induced deactivation.

Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre-symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre-HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre-HD individuals. Methods: Sixteen healthy controls and sixteen pre-HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load-dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions. Results: In pre-HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre-HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre-HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre-HD individuals are modulated by cognitive demand.

In clinically presymptomatic individuals with the Huntington's disease (HD) gene mutation, functional neuroimaging data have suggested a dysfunction of multiple cortical and subcortical regions including the prefrontal and parietal cortex, as well as the striatum. Although it has been hypothesized that these activation differences most likely reflect aberrant corticostriatal circuits, the functional coupling of neural networks associated with cognitive performance has not been investigated so far. In this study, we used functional magnetic resonance imaging (fMRI) and multivariate analytic techniques to investigate memory-related patterns of functional connectivity in healthy controls (n=16) and pre-HD individuals (n=16). Independent component analyses (ICA) revealed distinct bilateral frontostriatal and frontoparietal networks that were activated during a verbal working memory paradigm in both healthy controls and pre-HD subjects. Compared with healthy controls, pre-HD individuals exhibited lower functional connectivity in left lateral prefrontal and parietal regions as well as in the bilateral putamen. Functional connectivity indices in the left putamen were negatively correlated with the CAG repeat size and the UHDRS behavioral score, and positively correlated with the predicted years to manifest symptom onset. The connectivity of the right putamen was negatively correlated with the UHDRS motor score. In pre-HD individuals, these results suggest an early frontostriatal and frontoparietal deficit of dissociable functional networks associated with executive processing.

Background Functional neuroimaging studies on both cognitive processing and psychopathology in patients with major depression have reported several functionally aberrant brain areas within limbic-cortical circuits. However, less is known about the relationship between psychopathology, cognitive deficits and regional volume alterations in this patient population. Methods By means of voxel-based morphometry (VBM) and a standardized neuropsychological test battery, we examined 15 patients meeting DSM-IV criteria for major depression disorder and 14 healthy controls in order to investigate the relationship between affective symptoms, cognitive deficits and structural abnormalities. Results Patients with depression showed reduced gray matter concentration (GMC) in the left inferior temporal cortex (BA 20), the right orbitofrontal (BA 11) and the dorsolateral prefrontal cortex (BA 46). Reduced gray matter volume (GMV) was found in the left hippocampal gyrus, the cingulate gyrus (BA 24/32) and the thalamus. Structure-cognition correlation analyses revealed that decreased GMC of the right medial and inferior frontal gyrus was associated with both depressive psychopathology and worse executive performance as measured by the Wisconsin Card Sorting Test (WCST). Furthermore, depressive psychopathology and worse performance during the WCST were associated with decreased GMV of the hippocampus. Decreased GMV of the cingulate cortex was associated with worse executive performance. Limitations Moderate illness severity, medication effects, and the relatively small patient sample size should be taken into consideration when reviewing the implications of these results. Conclusions The volumetric results indicate that regional abnormalities in gray matter volume and concentration may be associated with both psychopathological changes and cognitive deficits in depression.

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including the lateral prefrontal cortex, superior temporal areas and the striatum. However, less is known about the relationship of WM-dysfunction, cerebral activation, task-accuracy and diagnostic specificity. Using a novel WM-task and event-related functional magnetic resonance imaging (fMRI), we studied healthy control subjects ( n = 17) and partially remitted, medicated inpatients meeting DSM-IV criteria for schizophrenia ( n = 19) and major depressive disorder ( n = 12). Due to the event-related technique, we excluded incorrectly performed trials, thus controlling for accuracy-related activation confounds. Compared with controls, patients with schizophrenia showed less activation in frontoparietal and subcortical regions at high cognitive load levels. Compared with patients with depression, schizophrenic patients showed less prefrontal activation in left inferior frontal cortex and right cerebellum. In patients with schizophrenia, a lack of deactivation of the superior temporal cortex was found compared to both healthy controls and patients with depression. Thus, we could not confirm previous findings of impaired lateral prefrontal activation during WM performance in schizophrenic patients after the exclusion of incorrectly performed or omitted trials in our functional analysis. However, superior temporal cortex dysfunction in patients with schizophrenia may be regarded as schizophrenia-specific finding in terms of psychiatric diagnosis specificity.

We report the case of a previously healthy 47-year-old woman suffering an acute embolic stroke in the left middle cerebral artery distribution. A filiform structure along the line of the aortic valve was first identified by transesophageal echocardiography, leading to the diagnosis of a valvular strand. These masses are thought to represent giant Lambl’s excrescences, although differential diagnoses include several benign cardiac tumors, e.g. papillary fibroelastoma. Valvular strands have previously been associated with embolic events including stroke, although exact pathogenetic mechanisms and further patient management have not yet been fully established. This case report additionally provides a short overview of the currently existing literature. As a conclusion, standard recommendations for patient management and treatment cannot be derived from currently available evidence.