Claudia Schachtzabel

Reduced cortical thickness in first episode schizophrenia

OBJECTIVE Previous morphometric studies are suggesting altered cortical thickness mainly in prefronto-temporal regions in first episode schizophrenia. In an extension of these earlier studies, we used an entire cortex vertex-wise approach and an automated clustering for the detection and exact quantification of cortical thickness alterations in first episode schizophrenia. METHODS A group of 54 patients with first episode schizophrenia according to DSM-IV and 54 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 was estimated as the distance between the gray-white matter border and the pial surface using an automated computerized algorithm (Freesurfer Software). Statistical cortical maps were created to estimate differences of cortical thickness between groups based on this entire cortex analysis. RESULTS Significant cortical thinning was observed in first episode schizophrenia patients relative to controls in a number of cortical areas including the dorsolateral and frontopolar cortices, the anterior cingulate cortex, a ventrolateral-orbitofrontal cluster, as well as the superior temporal cortices and superior parietal lobe. Cortical thinning within these regions was on average 4.4-5.7% with strongest reductions in orbitofrontal regions (7.1%). CONCLUSIONS The present findings suggest widespread reduction of cortical thickness, mostly in heteromodal cortices of fronto-temporal networks to be present at an early stage of schizophrenia. Taken together, the present morphometric data in first episode schizophrenia provide further evidence for potential neurodevelopmental deficits and disruption of cortical maturation in this disorder.

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.

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. Hum Brain Mapp, 2010.

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.

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.

FRONTO-STRIATAL HYPOACTIVATION DURING CORRECT INFORMATION RETRIEVAL IN PATIENTS WITH SCHIZOPHRENIA : AN fMRI STUDY

Working memory (WM) deficits are core symptoms of schizophrenia. Differing behavioral performance is known to represent a potent moderating variable when investigating the neural correlates of working memory in patients with schizophrenia compared with healthy controls. The present functional magnetic resonance imaging study examined performance-matched cerebral activity during correct WM retrieval by balancing the mean number of correct responses as well as the mean response times between patients and controls and analyzing remaining correct trials. Forty-one schizophrenia patients and 41 healthy controls performed an event-related Sternberg task allowing for analysis of correctly remembered trials. Correct retrieval was associated with activation in a bilateral fronto-parieto-occipital network comprising mainly the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex and superior parietal cortex in controls and, to a weaker degree, in patients. Direct group comparison revealed significantly decreased activations in patients in the posterior (Brodmann area (BA) 31) and anterior (BA 32) cingulate cortex (ACC) and the medial caudate bilaterally when matching for performance. When matching for performance and response speed there was additional hypoactivation in the insula. Mean response times were negatively correlated with cingulate and caudate activation only in controls. Present findings suggest that during efficient WM retrieval processing patients exhibit only slightly impaired activation in a task-specific network containing mainly prefrontal and superior parietal areas. However, hypoactivation of areas predominantly responsible for cognitive control and response execution seems to remain even under performance-matched conditions. Given the relevant role of the caudate and the ACC in dopaminergically mediated executive processing, the results bear crucial implications for the psychopathology of schizophrenia.

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.

Increased parahippocampal and lingual gyrification in first-episode schizophrenia

OBJECTIVE Cerebral gyrification is attributed to a large extent to genetic and intrauterine/perinatal factors. Hence, investigating gyrification might offer important evidence for disturbed neurodevelopmental mechanisms in schizophrenia. As an extension of recent ROI analyses of gyrification in schizophrenia the present study is the first to compare on a node-by-node basis mean curvature as a sensitive parameter for the identification of local gyrification changes of the whole cortex in first-episode schizophrenia. METHODS A group of 54 patients with first-episode schizophrenia according to DSM-IV and 54 age and gender matched healthy control subjects were included. All participants underwent high-resolution T1-weighted MRI scans on a 1.5 T scanner. Mean curvature was calculated dividing the sum of the principal curvatures by two at each point of the curved surface as implemented in the Freesurfer Software package. Statistical cortical maps were created to estimate gyrification differences between groups based on a clustering approach. RESULTS A significantly increased gyrification was observed in first-episode schizophrenia patients relative to controls in a right parahippocampal-lingual cortex area. The cluster encompassed a surface area of 750 mm². A further analysis of cortical thickness of this cluster demonstrated concurrent significant reduced cortical thickness of this area. CONCLUSIONS This is the first study to reveal an aberrant gyrification of the medial surface in first-episode schizophrenia. This finding is in line with substantial evidence showing medial temporal lobe abnormalities in schizophrenia. The present morphometric data provide further support for an early disruption of cortical maturation in schizophrenia.

Reduced cortical thickness is associated with the glutamatergic regulatory gene risk variant DAOA Arg30Lys in schizophrenia.

In light of current etiological concepts the glutamatergic system plays an essential role for the pathophysiology of the disorder, offering multiple options for new treatment strategies. The D-amino oxidase activator (DAOA) gene is closely connected to the glutamatergic system and its therapeutic and pathophysiological relevance for schizophrenia is therefore intensively debated. In a further step to shed light on the role of DAOA in schizophrenia, we aimed to investigate the association of the functional DAOA Arg30Lys (rs2391191) variant and cortical thickness in schizophrenia. Cortical thickness was computed by an automated surface-based technique (FreeSurfer) in 52 genotyped patients with schizophrenia and 42 healthy controls. Cortical thickness of the entire cortex was compared between risk carriers and non-risk carriers regarding the Arg30Lys polymorphism in patients and healthy controls on the basis of a node-by-node procedure and an automated clustering approach. Risk carriers with schizophrenia show significantly thinner cortex in two almost inversely arranged clusters on the left and right hemisphere comprising middle temporal, inferior parietal, and lateral occipital cortical areas. The clusters encompass an area of 1174 mm2 (left) and 1156 mm2 (right). No significant effect was observed in healthy controls.The finding of our study that the Arg30Lys risk variant is associated with a distinct cortical thinning provides new evidence for the pathophysiological impact of DAOA in schizophrenia. The affected areas are mostly confined to cortical regions with a crucial role in the ToM network and visual processing, which both can be influenced by glutamatergic modulation. Our finding thus underlines the importance of DAOA and related glutamatergic processes as a putative target for therapeutic interventions in schizophrenia.

White matter structure and symptom dimensions in obsessive–compulsive disorder

There is evidence that the different symptom dimensions in obsessive-compulsive disorder (OCD) may be mediated by partially distinct neural systems. This DTI study investigated the relationship between symptom dimensions and white matter microstructure. Fractional anisotropy (FA), axial and radial diffusivity was analyzed in relation to the main OCD symptom dimensions. Symptom severity on the obsessing dimension was negatively correlated with FA in the corpus callosum and the cingulate bundle. Severity on the ordering dimension was negatively correlated with FA in, amongst others, the right inferior fronto-occipital fasciculus and the right optic radiation. All correlations were ascribable to alterations in radial diffusivity while there was no association between symptoms and axial diffusivity. Present results illustrate an association between alterations in visual processing tracts and ordering symptoms which are characterized by altered visual processing and increased attention towards irrelevant detail. They also indicate an association between obsessive thoughts and alterations in structures known to be relevant for cognitive control and inhibition. Hence, different symptom dimensions must be taken into account in order to disentangle the neurobiological underpinnings of OCD.