Martin Roebel

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.

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.

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.

Temporal modeling demonstrates preserved overlearning processes in schizophrenia: An fMRI study

Working memory (WM) deficits are a core feature of schizophrenia. However, it has not been examined whether these deficits are related to altered temporal dynamics of information acquisition and changes in executive cognitive control. Therefore, the present study intended to quantify and model the dynamic process of information acquisition during continuous overlearning of WM information. It also aimed at investigating the relation between overlearning-associated change in behavioral performance and brain activity. Thirteen schizophrenic patients and 13 healthy volunteers were studied with functional magnetic resonance imaging (fMRI) while performing a recently developed overlearning paradigm [Koch K, Wagner G, von Consbruch K, Nenadic I, Schultz C, Ehle C, Reichenbach J, Sauer H, Schlösser R (2006) Temporal changes in neural activation during practice of information retrieval from short-term memory: An fMRI study. Brain Res 1107:140-150]. Consistent with the earlier study, short-term learning of stimulus material was associated with significant performance improvements and exponential signal decreases in a fronto-parieto-cerebellar network both in schizophrenic patients and in healthy volunteers. Against expectation patients exhibited stronger signal decreases relative to controls in anterior cingulate (Brodmann area (BA) 32), middle and superior temporal (BA 37, BA 22), superior frontal (BA 8/9, BA 6) and posterior parietal regions (BA 40). Furthermore, the individually modeled exponential decay rate of the blood oxygenation level-dependent signal in the right dorsolateral prefrontal cortex was significantly correlated with exponential decrease in mean behavioral response times in healthy controls while a statistical trend emerged in patients. A relative hyperactivation in the patient group was observable only at the start of the learning process and diminished with continued overlearning. This effect might indicate a gradual reduction of recruited neuronal resources and a practice-associated activation normalization in patients with schizophrenia. Our data suggest that in subacute patients learning and associated decreases in cerebral activation brought about by short-term practice are left unimpaired.

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.