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.

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.

Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial.

Interventional studies suggest that changes in physical fitness affect brain function and structure. We studied the influence of high intensity physical exercise on hippocampal volume and metabolism in 17 young healthy male adults during a 6-week exercise program compared with matched controls. We further aimed to relate these changes to hypothesized changes in exercised-induced brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). We show profound improvement of physical fitness in most subjects and a positive correlation between the degree of fitness improvement and increased BDNF levels. We unexpectedly observed an average volume decrease of about 2%, which was restricted to right hippocampal subfields CA2/3, subiculum, and dentate gyrus and which correlated with fitness improvement and increased BDNF levels negatively. This result indicates that mainly those subjects who did not benefit from the exercise program show decreased hippocampal volume, reduced BDNF levels, and increased TNF-α concentrations. While spectroscopy results do not indicate any neuronal loss (unchanged N-acetylaspartate levels) decreased glutamate-glutamine levels were observed in the right anterior hippocampus in the exercise group only. Responder characteristics need to be studied in more detail. Our results point to an important role of the inflammatory response after exercise on changes in hippocampal structure.

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.

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.

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.

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.

ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies.

Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes.

Altered emotional and BOLD responses to negative, positive and ambiguous performance feedback in OCD.

While abnormal processing of performance feedback has been associated with obsessive-compulsive disorder (OCD), neural responses to different kinds of feedback information, especially to ambiguous feedback are widely unknown. Using fMRI and a performance adaptive time-estimation task, we acquired blood oxygenation level-dependant responses and emotional ratings to positive, negative and ambiguous performance feedback in patients and healthy controls. Negative and ambiguous feedback led to increased levels of anxiety, guilt and shame in patients. Both negative and ambiguous feedback, as compared to positive feedback, induced increased activation of the insular cortex in patients. Furthermore, patients showed no differential activation to negative feedback in the putamen and to ambiguous feedback in the ventromedial prefrontal cortex (VMPFC). Finally, negative feedback induced increased activation in the midcingulate cortex in patients compared to controls. Findings indicate that both negative and ambiguous performance feedbacks are associated with abnormal negative emotions and altered brain activation, in particular increased insula activation, while activation in the putamen and VMPFC does not differentiate between feedback types in OCD patients. This suggests a parallel pattern of increased and decreased neural sensitivity to different kinds of feedback information and a general emotional hyperresponsivity to negative and ambiguous performance feedback in OCD.

Structural basis of the fronto-thalamic dysconnectivity in schizophrenia: A combined DCM-VBM study.

Several lines of evidence suggest that cognitive control deficits may be regarded as a connecting link between reported impairments in different cognitive domains of schizophrenia. However, the precise interplay within the fronto-cingulo-thalamic network known to be involved in cognitive control processes and its structural correlates has only been sparsely investigated in schizophrenia. The present multimodal study was therefore designed to model cognitive control processes within the fronto-cingulo-thalamic network. A disruption in effective connectivity in patients in association with abnormal white matter (WM) structure in this network was hypothesized. 36 patients with schizophrenia and 36 healthy subjects participated in the present study. Using functional magnetic resonance imaging (fMRI) a Stroop task was applied in an event-related design. For modeling effective connectivity dynamic causal modeling (DCM) was used. Voxel-based morphometry (VBM) was employed to study WM abnormalities. In the fMRI analysis, the patients demonstrated a significantly decreased BOLD signal in the fronto-cingulo-thalamic network. In the DCM analysis, a significantly decreased bilateral endogenous connectivity between the mediodorsal thalamus (MD) and the anterior cingulate cortex (ACC) was detected in patients in comparison to healthy controls, which was negatively correlated with the Stroop interference score. Furthermore, an increased endogenous connectivity between the right DLPFC and the right MD was observed in the patients. WM volume decreases were observed in the patients in the MD and the frontal cortex. The present results provide strong evidence for the notion that an abnormal fronto-cingulo-thalamic effective connectivity may represent the basis of cognitive control deficits in schizophrenia. Moreover, the data indicate that disrupted white matter connectivity in the mediodorsal thalamus and in the fronto-cingulo-thalamic network may constitute the determining cause of fronto-cingulo-thalamic dysconnectivity.

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.

The visual cortex in schizophrenia: alterations of gyrification rather than cortical thickness--a combined cortical shape analysis.

In light of bottom-up models of disrupted cognition in schizophrenia, visual processing deficits became a key feature for the pathophysiology of schizophrenia. However, morphometric studies focusing on the visual cortex are limited. Thus, the present study sought to provide a combined cortical shape analysis (cortical thickness, folding) of visual areas, which were implicated to be involved in disturbed visual processing in schizophrenia. A group of 72 patients with schizophrenia according to DSM-IV and 72 age- and gender-matched healthy control subjects were included. All participants underwent high-resolution T1-weighted MRI scans on a 1.5-T scanner. Cortical thickness and mean curvature of the V1, V2 and V5/MT+ visual cortex were estimated using an automated computerized algorithm (Freesurfer Software). A GLM controlling for the effect of age was used to estimate differences of cortical shape parameters between the study groups. Significantly increased gyrification of the V1, V2 and the V5/MT+ visual area bilaterally was detected. Conversely, cortical thickness was reduced in patients with schizophrenia only for the V5/MT+ area. This study is the first providing direct in vivo evidence for a disturbed cortical shape of central visual areas in schizophrenia. The present findings of hypergyria are highly indicative for a disrupted corticogenesis of these visual key regions and might constitute a relevant anatomical basis for visual processing deficits in schizophrenia.

Self-referential processing influences functional activation during cognitive control: an fMRI study.

Rostral anterior cingulate cortex (rACC) plays a central role in the pathophysiology of major depressive disorder (MDD). As we reported in our previous study (Wagner et al., 2006), patients with MDD were characterized by an inability to deactivate this region during cognitive processing leading to a compensatory prefrontal hyperactivation. This hyperactivation in rACC may be related to a deficient inhibitory control of negative self-referential processes, which in turn may interfere with cognitive control task execution and the underlying fronto-cingulate network activation. To test this assumption, a functional magnetic resonance imaging study was conducted in 34 healthy subjects. Univariate and functional connectivity analyses in statistical parametric mapping software 8 were used. Self-referential stimuli and the Stroop task were presented in an event-related design. As hypothesized, rACC was specifically engaged during negative self-referential processing (SRP) and was significantly related to the degree of depressive symptoms in participants. BOLD signal in rACC showed increased valence-dependent (negative vs neutral SRP) interaction with BOLD signal in prefrontal and dorsal anterior cingulate regions during Stroop task performance. This result provides strong support for the notion that enhanced rACC interacts with brain regions involved in cognitive control processes and substantiates our previous interpretation of increased rACC and prefrontal activation in patients during Stroop task.

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.

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.

Glutamate receptor δ 1 (GRID1) genetic variation and brain structure in schizophrenia.

Common genetic variation in the promoter region of the glutamate receptor delta 1 (GRID1) gene has recently been shown to confer increased risk for schizophrenia in several independent large samples. We analysed high-resolution magnetic resonance imaging (MRI) data from 62 patients with schizophrenia and 54 healthy controls using voxel-based morphometry (VBM) to assess the effect of single nucleotide polymorphism rs3814614 (located in the GRID1 promoter region), of which the T allele was identified as a risk factor in a previous association study. There were no effects of genotype or group × genotype interactions on total brain grey matter or white matter, but on regional grey matter. In healthy subjects, we identified a significant effect of rs3814614 genotype in the anterior thalamus (bilaterally), superior prefrontal cortex, and orbitofrontal cortex - in all cases with the homozygous risk genotype TT resulting in higher grey matter density. We did not find this association within the schizophrenia sample, where rs3814614 variation was only associated with grey matter reduction in TT homozygous subjects in medial parietal cortex and increased grey matter in right medial cerebellum. For white matter, we did not find significant genotype effects in healthy controls, and only minor effects within schizophrenia patients in the posterior temporal lobe white matter. Our data indicate that GRID1 rs3814614 genotype is related to grey matter variation in prefrontal and anterior thalamic brain areas in healthy subjects, but not in patients indicating a potential role of this schizophrenia candidate gene in thalamo-cortical functioning.

Prefrontal cortical thickness in depressed patients with high-risk for suicidal behavior.

Major depressive disorder (MDD) is associated with an increased risk for suicide. There is considerable evidence that a predisposition to suicidal behavior may exist which is independent of the MDD itself. Recent studies suggest a familial transmission of the diathesis for suicidal behavior, reflected in the observation of suicide aggregation in families and higher rate of suicidal behavior in first-degree relatives of suicide attempters with MDD. One of these transmission factors may be neurobiological alterations. The main goal of the present study was therefore to study abnormalities in cortical thickness in the hypothesized fronto-cingulate network in depressed patients with high risk for suicide. 15 MDD patients with documented own suicidal behavior and/or with suicidal behavior in first-degree relatives (high risk group), 15 depressed patients with non-high risk for suicide and 30 matched healthy controls participated in the study. Using an automated surface based approach (FreeSurfer) structural T1-weighted volumes were analyzed for differences in cortical thickness on a node by node basis covering the entire cortex. Patients with high risk for suicide showed significantly thinner cortex in the left dorsolateral, ventrolateral prefrontal cortex and the anterior cingulate in contrast to non-high risk patients. Together with previous morphometric results of our group, this new finding provides strong evidence for structural brain alterations in depressed patients with high risk for suicide in the fronto-cingulo-striatal network, which is strongly involved in reward processing and behavioral/emotional control. This alteration may constitute the neurobiological basis for an increased predisposition to suicidal behavior.

Aberrant anterior cingulate activation in obsessive-compulsive disorder is related to task complexity.

OBJECTIVES: Evidence for working memory (WM) deficits in obsessive-compulsive disorder (OCD) is increasing. However, findings regarding the underlying neural substrates are heterogeneous. Moreover, the influence of cognitive demand on the severity of these deficits and associated activation alterations is a matter of debate. METHODS: To further address this question the present fMRI study examined a sample of 21 predominantly medication-free inpatients with OCD and 21 matched healthy volunteers using a parametric verbal n-back task. RESULTS: In agreement with earlier studies patients exhibited focused activation alterations that could be found to be critically dependent on WM demands: There were no differences in activation between patients and healthy volunteers under low cognitive demands. However, patients exhibited a significantly decreased activation in the dorsal anterior cingulate cortex (dACC) in association with increasing task demands. While dACC activation in controls showed a linear increase with increasing task demands, this linearity was not detectable in patients with OCD. CONCLUSIONS: Present findings provide further support for the relevance of the anterior cingulate in OCD and illustrate that both task demands and task processes are of major influence in this context.