High levels of neuroticism are associated with decreased cortical folding of the dorsolateral prefrontal cortex.

The personality trait neuroticism has been identified as a vulnerability factor for common psychiatric diseases and defining potential neuroanatomical markers for early recognition and prevention strategies is mandatory. Because both personality traits and cortical folding patterns are early imprinted and timely stable there is reason to hypothesize an association between neuroticism and cortical folding. Thus, to identify a putative linkage, we tested whether the degree of neuroticism is associated with local cortical folding in a sample of 109 healthy individuals using a surface-based MRI approach. Based on previous findings we additionally tested for a potential association with cortical thickness. We found a highly significant negative correlation between the degree of neuroticism and local cortical folding of the left dorsolateral prefrontal cortex (DLPFC), i.e., high levels of neuroticism were associated with low cortical folding of the left DLPFC. No association was found with cortical thickness. The present study is the first to describe a linkage between the extent of local cortical folding and the individual degree of neuroticism in healthy subjects. Because neuroticism is a vulnerability factor for common psychiatric diseases such as depression our finding indicates that alterations of DLPFC might constitute a neurobiological marker elevating risk for psychiatric burden.

The neural basis of the abnormal self-referential processing and its impact on cognitive control in depressed patients.

Persistent pondering over negative self-related thoughts is a central feature of depressive psychopathology. In this study, we sought to investigate the neural correlates of abnormal negative self-referential processing (SRP) in patients with Major Depressive Disorder and its impact on subsequent cognitive control-related neuronal activation. We hypothesized aberrant activation dynamics during the period of negative and neutral SRP in the rostral anterior cingulate cortex (rACC) and in the amygdala in patients with major depressive disorder. Additionally, we assumed abnormal activation in the fronto-cingulate network during Stroop task execution. 19 depressed patients and 20 healthy controls participated in the study. Using an event-related functional magnetic resonance imaging (fMRI) design, negative, positive and neutral self-referential statements were displayed for 6.5 s and followed by incongruent or congruent Stroop conditions. The data were analyzed with SPM8. In contrast to controls, patients exhibited no significant valence-dependent rACC activation differences during SRP. A novel finding was the significant activation of the amygdala and the reward-processing network during presentation of neutral self-referential stimuli relative to baseline and to affective stimuli in patients. The fMRI analysis of the Stroop task revealed a reduced BOLD activation in the right fronto-parietal network of patients in the incongruent condition after negative SRP only. Thus, the inflexible activation in the rACC may correspond to the inability of depressed patients to shift their attention away from negative self-related stimuli. The accompanying negative affect and task-irrelevant emotional processing may compete for neuronal resources with cognitive control processes and lead thereby to deficient cognitive performance associated with decreased fronto-parietal activation.

Association between white matter fiber structure and reward-related reactivity of the ventral striatum.

Individual responsiveness to rewards or rewarding stimuli may affect various domains of normal as well as pathological behavior. The ventral striatum/nucleus accumbens (NAcc) constitutes a key brain structure in the regulation of reward-appetitive behavior. It remains unclear, however, to which extent individual reward-related BOLD response in the NAcc is dependent on individual characteristics of connecting white matter fiber tracts. Using tract-based spatial statistics (TBSS) and statistical parametric mapping (SPM) this combined DTI - fMRI study investigated this question by correlating NAcc BOLD signal upon receipt of a monetary reward with different white matter characteristics (FA, axial diffusivity, radial diffusivity). The results show that increased integrity of white matter as assessed by FA in the cingulate and corpus callosum, the inferior fronto-occipital fasciculus, the anterior thalamic radiation and the anterior limb of the internal capsule was positively correlated with reward-related activation in the NAcc. There were no negative correlations as well as no significant results regarding axial and radial diffusivity. These findings indicate that microstructural properties of fiber tracts connecting, amongst others, the cortex with the striatum may influence intensity of reward-related responsiveness of the ventral striatum by constraining or increasing efficiency in information transfer within relevant circuitries involved in processing of reward.

Functional connectivity and grey matter volume of the striatum in schizophrenia.

BACKGROUND: Alterations in the dopaminergic reward system, predominantly the striatum, constitute core characteristics of schizophrenia. AIMS: Functional connectivity of the dorsal striatum during reward-related trial-and-error learning was investigated in 17 people with schizophrenia and 18 healthy volunteers and related to striatal grey matter volume and psychopathology. METHOD: We used voxel-based morphometry and psychophysiological interaction to examine striatal volume and connectivity. RESULTS: A reduced functional connectivity between left striatum and temporo-occipital areas, precuneus and insula could be detected in the schizophrenia group. The positive correlation between grey matter volume and functional connectivity of the left striatum yielded significant results in a very similar network. Connectivity of the left striatum was negatively correlated with negative symptoms. CONCLUSIONS: Present results suggest a disruption in striatal functional connectivity that is closely linked to grey matter morphometry of the striatum. Decreased connectivity between the striatum and psychopathologically relevant networks may explain the emergence of negative symptoms.

Multimodal functional and structural imaging investigations in psychosis research.

Substantial pathophysiological questions about the relationship of brain pathologies in psychosis can only be answered by multimodal neuroimaging approaches combining different imaging modalities such as structural MRI (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET) and magnetic-resonance spectroscopy. In particular, the multimodal imaging approach has the potential to shed light on the neuronal mechanisms underlying the major brain structural and functional pathophysiological features of schizophrenia and high-risk states such as prefronto-temporal gray matter reduction, altered higher-order cognitive processing, or disturbed dopaminergic and glutamatergic neurotransmission. In recent years, valuable new findings have been revealed in these fields by multimodal imaging studies mostly reflecting a direct and aligned correlation of brain pathologies in psychosis. However, the amount of multimodal studies is still limited, and further efforts have to be made to consolidate previous findings and to extend the scope to other pathophysiological parameters contributing to the pathogenesis of psychosis. Here, investigating the genetic foundations of brain pathology relationships is a major challenge for future multimodal imaging applications in psychosis research.

Structural brain alterations in patients with major depressive disorder and high risk for suicide: evidence for a distinct neurobiological entity?

Major depressive disorder (MDD) is associated with a considerably increased risk for suicide. There is evidence to suggest that a predisposition to suicidal behavior may exist which is independent of the disorder itself. Furthermore, suicide attempters with mood disorders have an up to sixfold higher rate of suicidal behavior in first-degree relatives than non-suicidal patients. Genetic and nongenetic factors may play a role in the familial transmission of suicidal behavior. One of these factors may be neurobiological alterations, the knowledge about which is still limited. The main goal was therefore to study morphometric brain abnormalities in the hypothesized fronto-limbic network in depressed patients with high risk for suicide in contrast to non-high risk depressed patients. 15 patients with MDD and with own suicidal behavior and/or with suicidal behavior in first-degree relatives defined as a high risk group, 15 depressed patients with non-high risk for suicide and 30 matched healthy controls participated in the study. We applied the voxel-based morphometry protocol to structural T1-weighted volumes. Patients with high risk for suicide showed significantly decreased gray matter density in a fronto-striato-limbic network in contrast to matched healthy controls and in caudate and rostral anterior cingulate cortex in contrast to non-high risk patients. In the latter patient group no significant gray matter alterations were detected. This new finding provides evidence for structural brain alterations in depressed patients with high risk for suicide in a brain network strongly involved in emotional and motivational control reflecting a potentially distinct neurobiological entity.

Neural activation and radial diffusivity in schizophrenia: combined fMRI and diffusion tensor imaging study.

BACKGROUND: Schizophrenia is associated with often widespread changes in white matter structure. Most studies have investigated changes in fractional anisotropy, whereas alterations in radial or axial diffusivity have barely been investigated until now. AIMS: To investigate radial diffusivity as a potential marker of dysmyelination in direct relation to abnormalities in neural activation. METHOD: Neural activation in association with decision-making under uncertainty was investigated in 19 people with schizophrenia and 20 healthy controls and linked to radial diffusivity as measured by diffusion tensor imaging. RESULTS: Decision-making under uncertainty was associated with a significantly decreased activation in a frontostriatocingulate network in the schizophrenia group. Structurally, they exhibited increased radial diffusivity in temporal white matter that was negatively correlated with activation in parts of the frontostriatocingulate network. CONCLUSIONS: Present data indicate that altered diffusivity within relevant white matter networks may be closely linked to abnormal neural activation in schizophrenia.

ADC changes in schizophrenia: a diffusion-weighted imaging study.

Studies using diffusion tensor imaging (DTI) have shown multifocal reduction in anisotropy of white matter fibre tracts in schizophrenia, and a few of these also suggest changes in apparent diffusion coefficient (ADC). In this study, we assessed ADC in 18 patients with schizophrenia and 18 healthy controls using a voxel-based approach. We did not find evidence of statistically significant changes in ADC in either direction at P < 0.05 (FDR corrected) using different smoothing filter sizes; only at an uncorrected threshold of P < 0.001 did we find an increase in a small right prefrontal area close to our previous FA finding. Our findings therefore do not support ADC changes to be a marker of white matter or grey matter abnormalities in schizophrenia. Changes in other parameters like fractional anisotropy (FA) might be a more sensitive indicator of white matter pathology in this disorder.

Altered activation in association with reward-related trial-and-error learning in patients with schizophrenia.

In patients with schizophrenia, the ability to learn from reinforcement is known to be impaired. The present fMRI study aimed at investigating the neural correlates of reinforcement-related trial-and-error learning in 19 schizophrenia patients and 20 healthy volunteers. A modified gambling paradigm was applied where each cue indicated a subsequent number which had to be guessed. In order to vary predictability, the cue-number associations were based on different probabilities (50%, 81%, 100%) which the participants were not informed about. Patients' ability to learn contingencies on the basis of feedback and reward was significantly impaired. While in healthy volunteers increasing predictability was associated with decreasing activation in a fronto-parietal network, this decrease was not detectable in patients. Analysis of expectancy-related reinforcement processing yielded a hypoactivation in putamen, dorsal cingulate and superior frontal cortex in patients relative to controls. Present results indicate that both reinforcement-associated processing and reinforcement learning might be impaired in the context of the disorder. They moreover suggest that the activation deficits which patients exhibit in association with the processing of reinforcement might constitute the basis for the learning deficits and their accompanying activation alterations.

Fronto-cingulate effective connectivity in obsessive compulsive disorder: a study with fMRI and dynamic causal modeling.

Evidence suggests that obsessive compulsive disorder (OCD) is associated with an overactive error control system. A key role in error detection and control has been ascribed to the fronto-cingulate system. However, the exact functional interplay between the single components of this network in OCD is largely unknown. Therefore, the present study combined a univariate data analysis and effective connectivity analysis using dynamic causal modeling (DCM) to examine error control in 21 patients with OCD and 21 matched healthy controls. All subjects performed an adapted version of the Stroop color-word task while undergoing fMRI scans. Enhanced activation in the fronto-cingulate system could be detected in OCD patients during the incongruent task condition. Additionally, task-related modulation of effective connectivity from the dorsal ACC to left DLPFC was significantly stronger in OCD patients. These findings are consistent with an overactive error control system in OCD subserving suppression of prepotent responses during decision-making.

Differential effects of serotonergic and noradrenergic antidepressants on brain activity during a cognitive control task and neurofunctional prediction of treatment outcome in patients with depression.

BACKGROUND: We investigated the differential effects of serotonergic and noradrenergic antidepressants on brain activation in patients with major depressive disorder during a Stroop task. We predicted that pretreatment hyperactivity in the rostral anterior cingulate cortex would predict better treatment outcomes. METHODS: In total, 20 patients underwent naturalistic open-label clinical treatment with citalopram (n = 12) or reboxetine (n = 8). We performed functional magnetic resonance imaging at baseline and after 6 weeks of treatment. RESULTS: There were no significant group differences in clinical characteristics, treatment outcomes or baseline fMRI activations. The group by time interaction revealed significant voxels in the right amygdala-hippocampus complex (p < 0.05, family-wise error corrected by use of the bilateral amygdala and hippocampus mask image as a small volume), indicating a posttreatment blood oxygen level- dependent signal decrease in the citalopram group. Pretreatment hyperactivity in the rostral anterior cingulate cortex was not related to symptom improvement. LIMITATIONS: Our study was a nonrandomized clinical trial. CONCLUSION: These results indicate that serotonergic and noradrenergic antidepressants have a differential effect on brain activity, especially in the amygdala and hippocampus.

Complex pattern of cortical thinning in schizophrenia: results from an automated surface based analysis of cortical thickness.

A considerable body of evidence from structural brain imaging studies suggests that patients with schizophrenia have significant alterations of gray matter density. Additionally, recently developed surface-based analysis approaches demonstrate reduced cortical thickness in patients with schizophrenia. However, the number of studies employing this relatively new method is still limited. Specifically, little is known about changes in cortical thickness in schizophrenia patients whose duration of illness is relatively short. Therefore, the present study sought to examine cortical thickness in a large sample of patients with adult onset schizophrenia and an average duration of illness of 4.4 years, using an automated analysis method over the entire cortex. A significantly decreased cortical thickness in prefrontal and temporolimbic regions as well as parieto-occipital cortical areas was hypothesized. A sample of 58 patients with schizophrenia and 58 age- and sex-matched healthy controls was investigated using high-resolution magnetic resonance imaging (MRI) and an automated algorithm for extraction of the cortical surface in order to assess local cortical thinning across the entire cerebrum. Significant reduction of cortical thickness in schizophrenia was found in a spatially complex pattern of focal anatomical regions. This pattern comprised the dorsolateral prefrontal cortex as well as the medial prefrontal cortex, lateral temporal cortices, left entorhinal cortex, posterior cingulate cortex, precuneus and lingual cortex, bilaterally. A complex fronto-temporo-parietal pattern of reduced cortical thickness in schizophrenia was observed. This pattern is consistent with a disruption of neurofunctional networks previously implicated in the pathophysiology of schizophrenia.

Disrupted white matter integrity of corticopontine-cerebellar circuitry in schizophrenia.

Evidence for white matter abnormalities in patients with schizophrenia is increasing. Decreased fractional anisotropy (FA) in interhemispheric commissural fibers as well as long-ranging fronto-parietal association fibers belongs to the most frequent findings. The present study used tract-based spatial statistics to investigate white matter integrity in 35 patients with schizophrenia and 35 healthy volunteers. We found that patients exhibited significantly decreased FA relative to healthy subjects in the corpus callosum, the cerebral peduncle, the left inferior fronto-occipital fasciculus, the anterior thalamic radiation, the right posterior corona radiata, the middle cerebellar peduncle, and the right superior longitudinal fasciculus. Increased FA was detectable in the inferior sections of the corticopontine-cerebellar circuit. Present data indicate extended cortical-subcortical alterations of white matter integrity in schizophrenia using advanced data analysis strategies. They corroborate preceding findings of white matter structural deficits in mainly long-ranging association fibers and provide first evidence for neuroplastic changes in terms of an increased directionality in more inferior fiber tracts.

Psychopathological correlates of the entorhinal cortical shape in schizophrenia.

Animal experiments have shown that early developmental lesions of the entorhinal cortex lead, after a prolonged interval, to an enhanced mesolimbic dopamine release and an increased locomotor activity in rats. Hence, disturbed shape of the entorhinal cortex might indicate maturational abnormalities relevant for psychotic symptoms in schizophrenia. We used an automated surface-based MRI method to perform a region of interest analysis of entorhinal cortical surface area, folding and thickness in 59 patients with schizophrenia and 59 healthy controls. We postulated the entorhinal cortical surface area, folding index, and thickness to be significantly smaller in patients with schizophrenia. Additionally, we expected the complexity of the entorhinal cortical shape to be associated with psychotic symptoms in schizophrenia. Our ROI analysis showed a significant thinner left entorhinal cortex. In addition, our data demonstrate a positive correlation between left entorhinal cortical surface area and folding index and severity of psychotic symptoms. In conclusion, we present new evidence for the involvement of the entorhinal cortex in the pathogenesis of schizophrenia. As cortical folding is a stable neuroanatomical parameter terminated in early neonatal stages, our data give reason to assume that the vulnerability to develop psychotic symptoms might be manifest at an early level of brain maturation.

The neural correlates of reward-related trial-and-error learning: an fMRI study with a probabilistic learning task.

This fMRI study investigated the neural correlates of reward-related trial-and-error learning in association with changing degrees of stimulus-outcome predictabilities. We found that decreasing predictability was associated with increasing activation in a frontoparietal network. Only maximum predictability was associated with signal decreases across the learning process. The receipt of monetary reward revealed activation in the striatum and associated frontoparietal regions. Present data indicate that during reward-related learning, high uncertainty forces areas relevant for cognitive control to remain activated. In contrast, learning on the basis of predictable stimulus-outcome associations enables the brain to reduce resources in association with the processes of prediction.

Inefficient executive cognitive control in schizophrenia is preceded by altered functional activation during information encoding: an fMRI study.

Working memory deficits are a core feature of schizophrenia. Previous working memory studies suggest a load dependent storage deficit. However, explicit studies of higher executive working memory processes are limited. Moreover, few studies have examined whether subcomponents of working memory such as encoding and maintenance of information are differentially affected by these deficits. Therefore, the aim of the present study was to examine the neural substrates of working memory subprocesses requiring stimulus encoding, maintenance and higher executive processing. Using functional magnetic resonance imaging a modified Sternberg working memory task involving verbal stimulus material was applied. The event-related design enabled the segregation of encoding, active maintenance and executive manipulation of information. Forty-one patients with schizophrenia and 41 healthy subjects were included. Relative to normal controls, schizophrenic patients demonstrated a significantly stronger activation pattern in a fronto-parietal network during executive information manipulation. Additionally, significant relative hypoactivity was detectable in the thalamus. Conversely, during stimulus encoding the patients demonstrated lower activation relative to controls in the prefrontal cortex and the anterior cingulate gyrus. The present findings indicate a pronounced prefrontal functional hyperactivation within the neural network subserving higher executive working memory control processes in schizophrenia. Moreover, they suggest that these altered activations during executive control are related to a preceding abnormality of information encoding. During encoding, a reduced activation in mainly dorsolateral prefrontal and anterior cingulate regions was observed. These results could be explained by increased top-down control processing from prefrontal cortex as a compensation for functional deficits occurring during encoding.

Enhanced rostral anterior cingulate cortex activation during cognitive control is related to orbitofrontal volume reduction in unipolar depression.

OBJECTIVE: In patients with major depressive disorder (MDD), enhanced activation of the rostral anterior cingulate cortex (rACC) during conflict resolution has been demonstrated with the use of functional magnetic resonance imaging (fMRI), which suggests dysregulation of the affective compartment of the ACC associated with error monitoring and cognitive control. Moreover, several previous studies have reported disrupted structural integrity in limbic brain areas and the orbitofrontal cortex in MDD. However, the relation between structural and functional alterations remains unclear. Therefore, the present study sought to investigate whether structural brain aberrations in terms of grey matter decreases directly in the medial frontal regions or in anatomically closely connected areas might be related to our previously reported functional alterations. METHODS: A sample of 16 female, drug-free patients with an acute episode of MDD and 16 healthy control subjects matched for age, sex and education were examined with structural high-resolution T(1)-weighted MRI; fMRI images were obtained in the same session. RESULTS: Voxel-based morphometry (VBM) revealed grey matter decreases in the orbitofrontal and subgenual cortex, in the hippocampus-amygdala complex and in the middle frontal gyrus. The relative hyperactivation of the rACC in terms of inability to deactivate this region during the Stroop Color-Word Test showed an inverse correlation with grey matter reduction in the orbitofrontal cortex. CONCLUSION: The present study provides strong evidence for an association between structural alterations in the orbitofrontal cortex and disturbed functional activation in the emotional compartment of the ACC in patients with MDD during cognitive control.

Increased white matter radial diffusivity is associated with prefrontal cortical folding deficits in schizophrenia.

The neuronal underpinnings of cortical folding alterations in schizophrenia remain unclear. Theories on the physiological development of cortical folds stress the importance of white matter fibers for this process and disturbances of fiber tracts might be relevant for cortical folding alterations in schizophrenia. Nine-teen patients with schizophrenia and 19 healthy subjects underwent T1-weighted MRI and DTI. Cortical folding was computed using a surface based approach. DTI was analyzed using FSL and SPM 5. Radial diffusivity and cortical folding were correlated covering the entire cortex in schizophrenia. Significantly increased radial diffusivity of the superior longitudinal fasciculus (SLF) in the left superior temporal region was negatively correlated with cortical folding of the left dorsolateral prefrontal cortex (DLPFC) in patients, i.e. higher radial diffusivity, as an indicator for disturbed white matter fiber myelination, was associated with lower cortical folding of the left DLPFC. Patients with pronounced alterations of the SLF showed significantly reduced cortical folding in the left DLPFC. Our study provides novel evidence for a linkage between prefrontal cortical folding alterations and deficits in connecting white matter fiber tracts in schizophrenia and supports the notion that the integrity of white matter tracts is crucial for intact morphogenesis of the cortical folds.

Pronounced prefronto-temporal cortical thinning in schizophrenia: Neuroanatomical correlate of suicidal behavior?

Schizophrenia is characterized by increased mortality for which suicidality is the decisive factor. An analysis of cortical thickness and folding to further elucidate neuroanatomical correlates of suicidality in schizophrenia has not yet been performed. We searched for relevant brain regions with such differences between patients with suicide-attempts, patients without any suicidal thoughts and healthy controls. 37 schizophrenia patients (14 suicide-attempters and 23 non-suicidal) and 50 age- and gender-matched healthy controls were included. Suicidality was documented through clinical interview and chart review. All participants underwent T1-weighted MRI scans. Whole brain node-by-node cortical thickness and folding were estimated (FreeSurfer Software) and compared. Additionally a three group comparison for prefrontal regions-of-interest was performed in SPSS using a multifactorial GLM. Compared with the healthy controls patients showed a typical pattern of cortical thinning in prefronto-temporal regions and altered cortical folding in the right medial temporal cortex. Patients with suicidal behavior compared with non-suicidal patients demonstrated pronounced (p<0.05) cortical thinning in the right DLPFC and the superior temporal cortex. Comparing cortical thickness in suicidal patients with non-suicidal patients significant (p<0.05) cortical thinning was additionally found in the right superior and middle temporal, temporopolar and insular cortex. Our findings extend the evidence for neuroanatomical underpinnings of suicidal behaviour in schizophrenia. We identified cortical thinning in a network strongly involved in regulation of impulsivity, emotions and planning of behaviour in suicide attempters, which might lead to neuronal dysregulation in this network and consequently to a higher risk of suicidal behavior.