Resilience and cortical thickness: a MRI study.

Resilience is defined as the psychological resistance which enables the processing of stress and adverse life events and thus constitutes a key factor for the genesis of psychiatric illness. However, little is known about the morphological correlates of resilience in the human brain. Hence, the aim of this study is to examine the neuroanatomical expression of resilience in healthy individuals. 151 healthy subjects were recruited and had to complete a resilience-specific questionnaire (RS-11). All of them underwent a high-resolution T1-weighted MRI in a 3T scanner. Fine-grained cortical thickness was analyzed using FreeSurfer. We found a significant positive correlation between the individual extent of resilience and cortical thickness in a right hemispherical cluster incorporating the lateral occipital cortex, the fusiform gyrus, the inferior parietal cortex as well as the middle and inferior temporal cortex, i.e., a reduced resilience is associated with a decreased cortical thickness in these areas. We lend novel evidence for a direct linkage between psychometric resilience and local cortical thickness. Our findings in a sample of healthy individuals show that a lower resilience is associated with a lower cortical thickness in anatomical areas are known to be involved in the processing of emotional visual input. These regions have been demonstrated to play a role in the pathogenesis of stress and trauma-associated disorders. It can thus be assumed that neuroanatomical variations in these cortical regions might modulate the susceptibility for the development of stress-related disorders.

Evidence for alterations of cortical folding in anorexia nervosa.

Anorexia nervosa (AN) is highly heritable, and the perspective on the etiology of AN has changed from a behavioral to a neurobiological and neurodevelopmental view. However, cortical folding as an important marker for deviations in brain development has yet rarely been explored in AN. Hence, in order to determine potential cortical folding alterations, we investigated fine-grained cortical folding in a cohort of 26 patients with AN, of whom 6 patients were recovered regarding their weight at the time point of MRI measurement. MRI-derived cortical folding was computed and compared between patients and healthy controls at about 150,000 points per hemisphere using a surface-based technique (FreeSurfer). Patients with AN exhibited highly significant increased cortical folding in a right dorsolateral prefrontal cortex region (DLPFC). Furthermore, a statistical trend in the same direction was found in the right visual cortex. We did not find a correlation of local cortical folding and current symptoms of the disease. In conclusion, our analyses provide first evidence that altered DLPFC cortical folding plays a role in the etiology of AN. The absence of correlations with clinical parameters implicates a relatively independence of cortical folding alterations from the current symptomatology and might thus be regarded as a trait characteristic of the disease potentially related to other neurobiological features of AN.

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.

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.

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.

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.

Checking and washing rituals are reflected in altered cortical thickness in obsessive-compulsive disorder.

There is growing evidence for structural brain alterations in obsessive-compulsive disorder (OCD). The overall picture is however rather heterogeneous. To detect meaningful associations between clinical symptom profiles and structural alterations, we applied a classification approach, the k-means cluster analysis on clinical data, i.e., the Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire. 73 OCD patients were assigned to three distinct symptom profiles. Using structural MRI and surface-based morphometric analysis (SBM), we compared cortical thickness between all OCD patients and 69 matched healthy subjects as well as among patients according to three symptom profiles. The total sample of OCD patients exhibited a thicker cortex in the pre-supplementary motor cortex (pre-SMA), dorsomedial prefrontal (DMPFC), anterior cingulate cortex and in the right anterior insula. Comparing patients of the three symptom clusters, a subgroup of OCD patients with a specific symptom profile was identified, which showed a thicker cortex in pre-SMA/DMPFC and in the contralateral primary motor cortex. In contrast to both other subgroups, patients in this group were mainly characterized by the predominance of a combination of checking and washing rituals. The other two OCD symptom subgroups showed comparable cortical thickness to healthy controls. Higher cortical thickness in regions of the motor circuitry seems to be related to motor activity-induced neuroplasticity in a specific group of OCD patients. Thicker anterior insular cortex in the total sample of patients points toward a more general pathophysiological process in OCD and potentially indicates abnormal interoceptive processing in OCD.

White matter abnormalities and brain activation in schizophrenia: a combined DTI and fMRI study.

Diffusion tensor imaging (DTI) studies of schizophrenia have revealed white matter abnormalities in several areas of the brain. The functional impact on either psychopathology or cognition remains, however, poorly understood. Here we analysed both functional MRI (during a working memory task) and DTI data sets in 18 patients with schizophrenia and 18 controls. Firstly, DTI analyses revealed reductions of fractional anisotropy (FA) in the right medial temporal lobe adjacent to the right parahippocampal gyrus, likely to contain fibres of the inferior cingulum bundle, and in the right frontal lobe. Secondly, functional MRI revealed prefrontal, superior parietal and occipital relative hypoactivation in patients with the main effect of task. This was accounted for by reduced prefrontal activation during the encoding phase of the task, but not during maintenance or retrieval phases. Thirdly, we found a direct correlation in patients between the frontal FA reduction (but not medial temporal reductions) and fMRI activation in regions in the prefrontal and occipital cortex. Our study combining fMRI and DTI thus demonstrates altered structure-function relationships in schizophrenia. It highlights a potential relationship between anatomical changes in a frontal-temporal anatomical circuit and functional alterations in the prefrontal cortex.

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.

Structural and functional dysconnectivity of the fronto-thalamic system in schizophrenia: a DCM-DTI study.

Evidence suggests that cognitive deficits are a core feature of schizophrenia. The concept of "cognitive dysmetria" has been introduced to characterize disintegration of fronto-thalamic-cerebellar circuitry which constitutes a key network for a variety of neuropsychological symptoms in schizophrenia. The present multimodal study aimed at investigating effective and structural connectivity of the fronto-thalamic circuitry in schizophrenia. fMRI effective connectivity analysis using dynamic causal modeling (DCM) and diffusion tensor imaging (DTI) were combined to examine cognitive control processes in 38 patients with schizophrenia and 40 matched healthy controls. Significantly lower fractional anisotropy (FA) was detected in patients in the right anterior limb of the internal capsule (ALIC), the right thalamus and the right corpus callosum. During Stroop task performance patients demonstrated significantly lower activation relative to healthy controls in a predominantly right lateralized fronto-thalamo-cerebellar network. An abnormal effective connectivity was observed in the right connections between thalamus, anterior cingulate and dorsolateral prefrontal cortex. FA in the ALIC was significantly correlated with the thalamic BOLD signal, cognitive performance and fronto-thalamic effective connectivity in patients. Present data provide evidence for the notion of a structural and functional defect in the fronto-thalamo-cerebellar circuitry, which may be the basis of specific cognitive impairments in schizophrenia.

Disrupted white matter connectivity is associated with reduced cortical thickness in the cingulate cortex in schizophrenia.

INTRODUCTION: Both impaired white matter connectivity and alterations in gray matter morphometry have repeatedly been reported in schizophrenia. Neurodevelopmental models propose a close linkage between gray matter alterations and white matter deficits. However, there are no studies investigating alterations in cortical thickness in relation to white matter connectivity changes. METHODS: This combined diffusion tensor imaging (DTI) - surface based morphometry study examined a potential linkage between disruption in white matter connectivity and alterations in cortical thickness. Cortical thickness was analyzed using the FreeSurfer software package (version 4.0.5, http://surfer.nmr.harvard.edu) in a sample of 19 patients with schizophrenia and 20 healthy controls. RESULTS: Whole brain node-by-node correlational analysis revealed a highly significant association ( r= -.8, p < .0001) between disturbed white matter connectivity in the superior temporal cortex and diminished cortical thickness in the posterior part of the cingulate cortex (Brodmann area 23/31). CONCLUSIONS: This result indicates a significant linkage between disturbed white matter connectivity and reduced cortical thickness in a relevant node of the default mode network that is held to be of high pathophysiological relevance in schizophrenia. The result moreover provides support for the assumption of a neurodevelopmental pathogenesis of the disorder.

Age-dependent visuomotor performance and white matter structure: a DTI study.

The Trail Making Test (TMT), which assesses motor performance, selective attention, working memory and cognitive flexibility is highly sensitive to age-related performance differences. However, the structural basis of this age-performance association is largely unknown. This DTI study examined the influence of white matter characteristics on the association between TMT performance (i.e., speed of processing) and age in a sample of 86 healthy, middle-aged subjects (mean age 27.9 years, range 18-55). Voxel-wise correlation yielded a significant negative association between FA in the body of the corpus callosum (CC) and TMT-A performance (i.e., time taken to complete the test). There was also a significant association between age and TMT-A performance. However, this association between age and TMT-A performance was neither mediated nor moderated by FA in the CC. Results suggest that fast motor performance is strongly dependent on individual white matter characteristics of the CC. This indicates that interindividual variations in white matter of the CC known to be relevant for interhemispheric motor signal transduction critically influence speed of motor processing. However, these interindividual variations do not explain the observed association between age and TMT performance.