Christian Gaser

Abstract: Genetics of the variability of normal and diseased brain structure largely remains to be elucidated. Expansions of certain trinucleotide repeats cause neurodegenerative disorders of which Huntington's disease constitutes the most common example. Here, we test the hypothesis that variation within the IT15 gene on chromosome 4, whose expansion causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we determined CAG repeat length within the IT15 gene on chromosome 4 and analyzed high-resolution T1-weighted magnetic resonance images by the use of voxel-based morphometry. We found an increase of GM with increasing long CAG repeat and its interaction with age within the pallidum, which is involved in Huntington's disease. Our study demonstrates that a certain trinucleotide repeat influences normal brain structure in humans. This result may have important implications for the understanding of both the healthy and diseased brain.

Abstract: In Multiple Sclerosis (MS), detection of T2-hyperintense white matter (WM) lesions on magnetic resonance imaging (MRI) has become a crucial criterion for diagnosis and predicting prognosis in early disease. Automated lesion detection is not only desirable with regard to time and cost effectiveness but also constitutes a prerequisite to minimize user bias. Here, we developed and evaluated an algorithm for automated lesion detection requiring a three-dimensional (3D) gradient echo (GRE) T1-weighted and a FLAIR image at 3 Tesla (T). Our tool determines the three tissue classes of gray matter (GM) and WM as well as cerebrospinal fluid (CSF) from the T1-weighted image, and, then, the FLAIR intensity distribution of each tissue class in order to detect outliers, which are interpreted as lesion beliefs. Next, a conservative lesion belief is expanded toward a liberal lesion belief. To this end, neighboring voxels are analyzed and assigned to lesions under certain conditions. This is done iteratively until no further voxels are assigned to lesions. Herein, the likelihood of belonging to WM or GM is weighed against the likelihood of belonging to lesions. We evaluated our algorithm in 53 MS patients with different lesion volumes, in 10 patients with posterior fossa lesions, and 18 control subjects that were all scanned at the same 3T scanner (Achieva, Philips, Netherlands). We found good agreement with lesions determined by manual tracing (R2 values of over 0.93 independent of FLAIR slice thickness up to 6mm). These results require validation with data from other protocols based on a conventional FLAIR sequence and a 3D GRE T1-weighted sequence. Yet, we believe that our tool allows fast and reliable segmentation of FLAIR-hyperintense lesions, which might simplify the quantification of lesions in basic research and even clinical trials.

Abstract: Several cortical regions are reported to vary in meditation practitioners. However, prior analyses have focused primarily on examining gray matter or cortical thickness. Thus, additional effects with respect to other cortical features might have remained undetected. Gyrification (the pattern and degree of cortical folding) is an important cerebral characteristic related to the geometry of the brain's surface. Thus, exploring cortical gyrification in long-term meditators may provide additional clues with respect to the underlying anatomical correlates of meditation. This study examined cortical gyrification in a large sample (n = 100) of meditators and controls, carefully matched for sex and age. Cortical gyrification was established by calculating mean curvature across thousands of vertices on individual cortical surface models. Pronounced group differences indicating larger gyrification in meditators were evident within the left precentral gyrus, right fusiform gyrus, right cuneus, as well as left and right anterior dorsal insula (the latter representing the global significance maximum). Positive correlations between gyrification and the number of meditation years were similarly pronounced in the right anterior dorsal insula. Although the exact functional implications of larger cortical gyrification remain to be established, these findings suggest the insula to be a key structure involved in aspects of meditation. For example, variations in insular complexity could affect the regulation of well-known distractions in the process of meditation, such as daydreaming, mind-wandering, and projections into past or future. Moreover, given that meditators are masters in introspection, awareness, and emotional control, increased insular gyrification may reflect an integration of autonomic, affective, and cognitive processes. Due to the cross-sectional nature of this study, further research is necessary to determine the relative contribution of nature and nurture to links between cortical gyrification and meditation.

Abstract: Surface reconstruction methods allow advanced analysis of structural and functional brain data beyond what can be achieved using volumetric images alone. Automated generation of cortical surface meshes from 3D brain MRI often leads to topological defects and geometrical artifacts that must be corrected to permit subsequent analysis. Here, we propose a novel method to repair topological defects using a surface reconstruction that relies on spherical harmonics. First, during reparameterization of the surface using a tiled platonic solid, the original MRI intensity values are used as a basis to select either a "fill" or "cut" operation for each topological defect. We modify the spherical map of the uncorrected brain surface mesh, such that certain triangles are favored while searching for the bounding triangle during reparameterization. Then, a low-pass filtered alternative reconstruction based on spherical harmonics is patched into the reconstructed surface in areas that previously contained defects. Self-intersections are repaired using a local smoothing algorithm that limits the number of affected points to less than 0.1% of the total, and as a last step, all modified points are adjusted based on the T1 intensity. We found that the corrected reconstructions have reduced distance error metrics compared with a "gold standard" surface created by averaging 12 scans of the same brain. Ninety-three percent of the topological defects in a set of 10 scans of control subjects were accurately corrected. The entire process takes 6-8 min of computation time. Further improvements are discussed, especially regarding the use of the T1-weighted image to make corrections.

Abstract: There is increasing evidence for hormone-dependent modification of function and behavior during the menstrual cycle, but little is known about associated short-term structural alterations of the brain. Preliminary studies suggest that a hormone-dependent decline in brain volume occurs in postmenopausal, or women receiving antiestrogens, long term. Advances in serial MR-volumetry have allowed for the accurate detection of small volume changes of the brain. Recently, activity-induced short-term structural plasticity of the brain was demonstrated, challenging the view that the brain is as rigid as formerly believed.

Abstract: From longitudinal voxel-based morphometry (VBM) studies we know that relatively short periods of training can increase regional grey matter volume in trained cortical areas. In 14 right-handed patients with writer's cramp, we employed VBM to test whether suppression (i.e., immobilization) or enhancement (i.e., training) of manual activity lead to opposing changes in grey matter in the contralateral primary motor hand area (M1(HAND)). We additionally used transcranial magnetic stimulation (TMS) to evaluate concurrent changes in regional excitability. Patients were recruited from a clinical trial which was designed to improve handwriting-associated dystonia. Initially the dystonic hand was immobilized for 4 weeks with the intention to reverse faulty plasticity. After immobilization, patients accomplished a motor re-training for 8 weeks. T1-weighted MRIs of the whole brain and single-pulse TMS measurements of the resting motor threshold (RMT) were performed every 4 weeks. Immobilization of the right hand resulted in a relative grey matter decrease in the contralateral left M1(HAND) along with a decrease in corticomotor excitability as indexed by an increase in RMT. Subsequent training reversed the effects of immobilization, causing an increase in regional grey matter density and excitability of left M1(HAND). The relative changes in grey matter correlated with the relative shifts in RMT. This prospective within-subject VBM study in task-specific hand dystonia shows that the grey matter density of M1(HAND) is dynamically shaped by the level of manual activity. This bi-directional structural plasticity is functionally relevant as local grey matter changes are mirrored by changes in regional excitability.

Abstract: Background: Although mostly conceptualized as a neurodevelopmental disorder, there is an increasing interest in progressive changes of cognitive deficits and brain structure and function in schizophrenia across the life span. Methods: In this study, we investigated age-related changes in regional gray matter using voxel-based morphometry in a sample of 99 patients (age range 18-65 years) with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia and 113 healthy controls (age range 19-59 years) using a cross-sectional design. Results: We found steeper age-related decline in gray matter in patients in a cluster comprising the left superior temporal cortex and adjacent inferior parietal lobule. We then divided the schizophrenia sample in 3 subgroups based on a 3-factor model of psychopathology ratings. Age-related changes were markedly different in each of the 3 subgroups (compared with healthy controls). While patients with predominantly paranoid symptoms showed stronger age-related progression in the left superior temporal cortex and right inferior frontal gyrus, those of the disorganized subgroup had stronger gray matter loss in the left lateral cerebellum, while the predominantly negative subgroup showed minor effects in the left superior temporal gyrus. Conclusions: Our findings show that differences in brain structural changes associated with aging diverge between schizophrenia patients and healthy subjects and that different subgroups within a patient sample might be at higher risk of age-related regional gray matter loss.

Abstract: Parosmia is a common olfactory disorder. In this condition, odors are perceived in a different quality than usual. This distorted olfactory percept is typically reported to be unpleasant. Little is known about the pathophysiology of this phenomenon. Previous studies demonstrated smaller volumes of the olfactory bulbs in patients with parosmia compared to subjects without parosmia. In order to investigate structural brain alterations in areas beyond the olfactory bulb, in the current study voxel-based morphometry was applied. A group of 22 parosmic patients was compared with control subjects matched for age- and sex, who exhibited a similar performance in olfactory tests. Performing a whole brain analysis, we found profound gray matter volume loss in the left anterior insula in parosmic patients. In an additional volume of interest analysis including primary and secondary olfactory areas, we also found volume loss in the right anterior insula, the anterior cingulate cortex, the hippocampus bilaterally, and the left medial orbitofrontal cortex. Many of these areas are critically involved in olfactory quality discrimination and odor memory. The present results indicate that reduced gray matter volume in brain regions supporting odor discrimination and memory is related to disturbed olfactory sensation in parosmia.

Abstract: In Alzheimer's disease (AD), brain atrophy has been proposed to be left lateralized. Here, we reinvestigated the asymmetry and lateralization (i.e., asymmetry directed toward one hemisphere) of grey-matter (GM) distribution in 35 patients with AD, 24 patients with amnestic mild cognitive impairment (aMCI, a state of increased risk for AD), and 30 age-matched healthy controls (HC). We analyzed GM distribution by applying voxel-based morphometry (VBM) including analyses for asymmetry and lateralization. When comparing MCI with AD patients, VBM revealed GM loss in the entorhinal, temporoparietal, dorsofrontal, and occipital cortices as well as in the precuneus; when comparing HCs with MCI patients, we found similar differences, which were less pronounced especially within the temporoparietal cortex and precuneus. Analyses of regional asymmetry and regional lateralization as well as global lateralization did not yield significant results. However, lobar asymmetry of the temporal, parietal, and occipital lobes increased from HC to AD. Moreover, in aMCI and AD patients, performance of language-based neuropsychological tests correlated with lateralization of GM loss to the left hemisphere. We conclude that, in principle, brain atrophy in AD is asymmetric rather than lateralized. At the individual level however, asymmetry contributes to cognitive deficits.

Abstract: Altered cortical surface complexity and gyrification differences may be a potentially sensitive marker for several neurodevelopmental disorders. We propose to use spherical harmonic (SPH) constructions to measure cortical surface folding complexity. First, we demonstrate that the complexity measure is accurate, by applying our SPH approach and the more traditional box-counting method to von Koch fractal surfaces with known fractal dimension (FD) values. The SPH approach is then applied to study complexity differences between 87 patients with DSM-IV schizophrenia (with stable psychopathology and treated with antipsychotic medication; 48 male/39 female; mean age=35.5 years, SD=11.0) and 108 matched healthy controls (68 male/40 female; mean age=32.1 years, SD=10.0). The global FD for the right hemisphere in the schizophrenia group was significantly reduced. Regionally, reduced complexity was also found in temporal, frontal, and cingulate regions in the right hemisphere, and temporal and prefrontal regions in the left hemisphere. These results are discussed in terms of previously published findings. Finally, the anatomical implications of a reduced FD are highlighted through comparison of two subjects with vastly different complexity maps.

Abstract: Background: Neuropsychological deficits predate overt psychosis and overlap with the impairments in the established disease. However, to date, no single neurocognitive measure has shown sufficient power for a prognostic test. Thus, it remains to be determined whether multivariate neurocognitive pattern classification could facilitate the diagnostic identification of different at-risk mental states (ARMS) for psychosis and the individualized prediction of illness transition. Methods: First, classification of 30 healthy controls (HC) vs 48 ARMS individuals subgrouped into 20 "early," 28 "late" ARMS subjects was performed based on a comprehensive neuropsychological test battery. Second, disease prediction was evaluated by categorizing the neurocognitive baseline data of those ARMS individuals with transition (n = 15) vs non transition (n = 20) vs HC after 4 years of follow-up. Generalizability of classification was estimated by repeated double cross-validation. RESULTS: The 3-group cross-validated classification accuracies in the first analysis were 94.2% (HC vs rest), 85.0% (early at-risk subjects vs rest), and, 91.4% (late at-risk subjects vs rest) and 90.8% (HC vs rest), 90.8% (converters vs rest), and 89.0% (nonconverters vs rest) in the second analysis. Patterns distinguishing the early or late ARMS from HC primarily involved the verbal learning/memory domains, while executive functioning and verbal IQ deficits were particularly characteristic of the late ARMS. Disease transition was mainly predicted by executive and verbal learning impairments. CONCLUSIONS: Different ARMS and their clinical outcomes may be reliably identified on an individual basis by evaluating neurocognitive test batteries using multivariate pattern recognition. These patterns may have the potential to substantially improve the early recognition of psychosis.

Abstract: OBJECT: To investigate the potential of a clinical 3 T scanner to perform MRI of small rodents. MATERIALS AND METHODS: Different dedicated small animal coils and several imaging sequences were evaluated to optimize image quality with respect to SNR, contrast and spatial resolution. As an application, optimal grey-white-matter contrast and resolution were investigated for rats. Furthermore, manganese-enhanced MRI was applied in mice with unilateral crush injury of the optic nerve to investigate coil performance on topographic mapping of the visual projection. RESULTS: Differences in SNR and CNR up to factor 3 and more were observed between the investigated coils. The best grey-white matter contrast was achieved with a high resolution 3D T (2)-weighted TSE (SPACE) sequence. Delineation of the retino-tectal projection and detection of defined visual pathway damage on the level of the optic nerve could be achieved by using a T (1)-weighted, 3D gradient echo sequence with isotropic resolution of (0.2 mm)(3). CONCLUSIONS: Experimental studies in small rodents requiring high spatial resolution can be performed by using a clinical 3 T scanner with appropriate dedicated coils.

Abstract: 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.

Abstract: The aim of this large-sample cross-sectional voxel-based morphometry (VBM) study of anatomical brain data was to investigate linear and nonlinear age-related trajectories of grey matter volume in the human brain during the adult lifespan. To date, there are only a few structural brain studies investigating local nonlinear aspects at the voxel level, i.e., without using anatomical ROIs as a priori hypothesis. Therefore, we analyzed 547 T1-weighted MR images of healthy adult brains with an age range of 19 to 86 years, including 161 scans of subjects with ages 60 and older. We found that the gray matter volume in some regions did not linearly decrease over time, but rather exhibited a delayed decline. Nonlinear age trajectories were observed in the medial temporal lobe regions, the basal ganglia, and parts of the cerebellum. Their trajectories indicated a preservation of grey matter volume during the early adult lifespan. Interestingly, we found nonlinear grey matter structural dynamics specifically in parts of the brain that have been extensively discussed in the context of learning and memory. We propose a hypothesis in relation to the functional role of these brain regions that may explain these results. Hum Brain Mapp, 2011. © 2011 Wiley-Liss, Inc.

Abstract: Previous neuroimaging studies in the field of motor learning have shown that learning a new skill induces specific changes of neural gray and white matter in human brain areas necessary to control the practiced task. Former longitudinal studies investigating motor skill learning have used strict training protocols with little ecological validity rather than physical leisure activities, although there are several retrospective and cross-sectional studies suggesting neuroprotective effects of physical leisure activities. In the present longitudinal MRI study, we used voxel-based morphometry to investigate training-induced gray matter changes in golf novices between the age of 40 and 60 years, an age period when an active life style is assumed to counteract cognitive decline. As a main result, we demonstrate that 40 h of golf practice, performed as a leisure activity with highly individual training protocols, are associated with gray matter increases in a task-relevant cortical network encompassing sensorimotor regions and areas belonging to the dorsal stream. A new and striking result is the relationship between training intensity (time needed to complete the 40 training hours) and structural changes observed in the parieto-occipital junction. Thus, we demonstrate that a physical leisure activity induces training-dependent changes in gray matter and assume that a strict and controlled training protocol is not mandatory for training-induced adaptations of gray matter.

Abstract: A spherical map of a cortical surface is often used for improved brain registration, for advanced morphometric analysis (eg, of brain shape), and for surface-based analysis of functional signals recorded from the cortex. Furthermore, for intersubject analysis, it is usually necessary to reparameterize the surface mesh into a common coordinate system. An isometric map conserves all angle and area information in the original cortical mesh; however, in practice, spherical maps contain some distortion. Here, we propose fast new algorithms to reduce the distortion of initial spherical mappings generated using one of three common spherical mapping methods. The algorithms iteratively solve a nonlinear optimization problem to reduce distortion. Our results demonstrate that our correction process is computationally inexpensive and the resulting spherical maps have improved distortion metrics. We show that our corrected spherical maps improve reparameterization of the cortical surface mesh, such that the distance error measures between the original and reparameterized surface are significantly decreased.

Abstract: Alterations in the central nervous system in patients with a loss of sense of smell are well documented for the olfactory bulb (OB). Here we present a voxel-based morphometry (VBM) study on cerebral alterations in the gray matter of patients with anosmia above the OB. 3-Tesla MRI datasets were obtained from 17 patients with anosmia as well as from 17 normosmic controls. Data processing and evaluation was performed using the SPM5 software package (Wellcome Department of Imaging Neuroscience Group, London, UK) and the implemented VBM5 toolbox. Patients with anosmia showed a significant volume decrease in the gray matter in the primary olfactory cortex as well as in secondary olfactory areas (insular cortex, orbitofrontal cortex, cingulate cortex and hippocampus). Furthermore, volume decreases in areas like the nucleus accumbens with adjacent subcallosal gyrus and the dorsolateral prefrontal cortex were found. Longer disease duration was associated with more profound alterations in the gray matter. VBM is appropriate to document brain alterations in patients with olfactory disorders.

Abstract: The purpose of this study was to investigate whether enhancement of tactile resolution (measured with Grating Orientation Task) can be demonstrated for patients undergoing regional anesthesia during hand surgery compared with surgery in general anesthesia and nonoperative controls. Regional anesthesia (nine patients) induced a significant improvement in contralateral tactile resolution at 10 and 24 h after the operation (P<0.01 and <0.05) compared with baseline. In the general anesthesia group (10 patients), tactile resolution improved significantly over time, but to a lesser extent than in the regional anesthesia group. When comparing with the control group (10 individuals), only the regional anesthesia group showed significantly increased tactile resolution at both the time points (P<0.01 and P<0.05), postoperatively.

Abstract: Cortical surface complexity is a potential structural marker for certain diseases such as schizophrenia. In this study, we developed a measure of fractal dimension (FD) calculated from lowpass-filtered spherical harmonic brain surface reconstructions. A local FD measure was also computed at each vertex in a cortical surface mesh, visualizing local variations in surface complexity over the brain surface. We analyzed the surface complexity for 87 patients with DSM-IV schizophrenia (with stable psychopathology and treated with antipsychotic medication) and 108 matched healthy controls. The global FD for the right hemisphere in the schizophrenic group was significantly lower than that in controls. Local FD maps showed that the lower complexity was mainly due to differences in the prefrontal cortex.

Abstract: The early identification of brain anatomy deviating from the normal pattern of growth and atrophy, such as in Alzheimer's disease (AD), has the potential to improve clinical outcomes through early intervention. Recently, Davatzikos et al. (2009) supported the hypothesis that pathologic atrophy in AD is an accelerated aging process, implying accelerated brain atrophy. In order to recognize faster brain atrophy, a model of healthy brain aging is needed first. Here, we introduce a framework for automatically and efficiently estimating the age of healthy subjects from their T(1)-weighted MRI scans using a kernel method for regression. This method was tested on over 650 healthy subjects, aged 19-86 years, and collected from four different scanners. Furthermore, the influence of various parameters on estimation accuracy was analyzed. Our age estimation framework included automatic preprocessing of the T(1)-weighted images, dimension reduction via principal component analysis, training of a relevance vector machine (RVM; Tipping, 2000) for regression, and finally estimating the age of the subjects from the test samples. The framework proved to be a reliable, scanner-independent, and efficient method for age estimation in healthy subjects, yielding a correlation of r=0.92 between the estimated and the real age in the test samples and a mean absolute error of 5 years. The results indicated favorable performance of the RVM and identified the number of training samples as the critical factor for prediction accuracy. Applying the framework to people with mild AD resulted in a mean brain age gap estimate (BrainAGE) score of +10 years.

Abstract: Spinocerebellar ataxia (SCA17) is a rare genetic disorder characterized by a variety of neuropsychiatric symptoms. Recently, using magnetic resonance imaging (MRI) voxel-based morphometry (VBM), several specific functional-structural correlations comprising differential degeneration related to motor and psychiatric symptoms were reported in patients with SCA17. To investigate gray matter volume (GMV) changes over time and its association to clinical neuropsychiatric symptomatology, nine SCA17 mutation carriers and nine matched healthy individuals underwent a detailed neuropsychiatric clinical examination and a high-resolution T1-weighted volume MRI scan, both at baseline and follow-up after 18 months. Follow-up images revealed a progressive GMV reduction in specific degeneration patterns. In contrast to healthy controls, SCA17 patients showed a greater atrophy not only in cerebellar regions but also in cortical structures such as the limbic system (parahippocampus, cingulate) and parietal precuneus. Clinically, progression of motor symptoms was more pronounced than that of psychiatric symptoms. Correlation with the clinical motor scores revealed a progressive reduction of GMV in cerebellar and cerebral motor networks, whereas correlation with psychiatric scores displayed a more widespread GMV impairment in frontal, limbic, parietal, and also cerebellar structures. Interestingly, changes in global functioning were correlated with bilateral atrophy within the para-/hippocampus. While there was a good temporal association between worsening of motor symptoms and progression in cerebral and cortical neurodegeneration, the progression in psychiatric related neurodegeneration seemed to be more widespread and complex, showing progressive atrophy that preceded the further development of clinical psychiatric symptoms.

Abstract: 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.

Abstract: Brain morphological changes are among the best-studied potential endophenotypes in schizophrenia and linked to genetic liability and expression of disease phenotype. Yet, there is considerable heterogeneity across individual subjects making its use as a disease-specific marker difficult. In this study we consider psychopathological variability of disease phenotype to delineate subsyndromes of schizophrenia, link them to distinct brain morphological patterns, and use a classification approach to test specificity of achieved discrimination. We first applied voxel-based morphometry (VBM) to compare 99 patients with DSM-IV schizophrenia (stable psychopathology and antipsychotic medication) with 113 matched healthy controls, then delineated three subgroups within the patient cohort based on psychopathology pattern and compared differential patterns of grey matter abnormalities. Finally, we tested accuracy of assigning any individual MRI scan to either the control group or any of the three patient subgroups. While VBM analysis showed overlap of brain structural deficits mostly in prefrontal areas, the disorganised subsyndrome showed stronger deficits in medial temporal and cerebellar regions, the paranoid/hallucinatory subsyndrome showed additional effects in the superior temporal cortex, and the negative subsyndrome showed stronger deficits in the thalamus. Using an automated algorithm, we achieved 95.8% accuracy classifying any given scan to one of the subgroups. Patterns of psychopathology are meaningful parameters in reducing heterogeneity of brain morphological endophenotypes in schizophrenia.

Abstract: Regional structural brain changes are among the most robust biological findings in schizophrenia, yet the underlying pathophysiological changes remain poorly understood. Recent evidence suggests that abnormal neuronal/dendritic plasticity is related to alterations in membrane lipids. We examined whether serum activity of membrane lipid remodelling/repairing cytosolic phospholipase A(2) (PLA(2)) were related to regional brain structure in magnetic resonance images (MRI). The study involved 24 schizophrenia patients, who were either drug-naïve or off antipsychotic medication, and 25 healthy controls. Using voxel-based morphometry (VBM) analysis of T1-high-resolution MRI-images, we correlated both gray matter and white matter changes with serum PLA(2)-activity. PLA(2) activity was increased in patients, consistent with previous findings. VBM group comparison of patients vs. controls showed abnormalities of frontal and medial temporal cortices/hippocampus, and left middle/superior temporal gyrus in first-episode patients. Group comparison of VBM/PLA(2)-correlations revealed a distinct pattern of disease-related interactions between gray/white matter changes in patients and PLA(2)-activity: in first-episode patients (n=13), PLA(2)-activity was associated with structural alterations in the left prefrontal cortex and the bilateral thalamus. Recurrent-episode patients (n=11) showed a wide-spread pattern of associations between PLA(2)-activity and structural changes in the left (less right) prefrontal and inferior parietal cortex, the left (less right) thalamus and caudate nucleus, the left medial temporal and orbitofrontal cortex and anterior cingulum, and the cerebellum. Our findings demonstrate a potential association between membrane lipid biochemistry and focal brain structural abnormalities in schizophrenia. Differential patterns in first-episode vs. chronic patients might be related to PLA(2)-increase at disease-onset reflecting localized regenerative activity, whereas correlations in recurrent-episode patients might point to less specific neurodegenerative aspects of disease progression.

Abstract: Chronic olfactory disorders, including the complete loss of the sense of smell (anosmia), are common. Using voxel-based morphometry (VBM) in magnetic resonance imaging (MRI), structural changes in the cerebral gray matter (GM) of a group of patients with anosmia compared with a normosmic, healthy control group were evaluated. Patients with anosmia presented a significant decrease of GM volume mainly in the nucleus accumbens with adjacent subcallosal gyrus, in the medial prefrontal cortex (MPC) including the middle and anterior cingulate cortices, and in the dorsolateral prefrontal cortex (dlPFC). These areas are part of the limbic loop of the basal ganglia and except the dlPFC secondary olfactory areas. They also play an important role in many neurological diseases. Furthermore, volume decreases in smaller areas like the piriform cortex, insular cortex, orbitofrontal cortex, hippocampus, parahippocampal gyrus, supramarginal gyrus, and cerebellum could be seen. Longer disease duration was associated with a stronger atrophy in the described areas. No local increases in the GM volume could be observed. A comparison with results of an additionally executed functional MRI study on olfaction in healthy subjects was performed to evaluate the significance of the observed atrophy areas in cerebral olfactory processing. To our knowledge, this is the first study on persisting structural changes in cortical GM volume after complete olfactory loss.

Abstract: The at-risk mental state for psychosis (ARMS) has been associated with abnormal structural brain dynamics underlying disease transition or non-transition. To date, it is unknown whether these dynamic brain changes can be predicted at the single-subject level prior to disease transition using MRI-based machine-learning techniques.

Abstract: 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.

Abstract: Deficits in executive functioning have been described as a core feature of schizophrenia and have been linked to patterns of fronto-temporo-limbic brain alterations. To date, such structure-cognition relationships have not been explored in a clinically defined at-risk mental state (ARMS) for psychosis using whole-brain neuroimaging techniques. Therefore, we used voxel-based morphometry in 40 ARMS and 30 matched healthy control (HC) individuals to investigate whether gray and white matter volumes (1) correlated with the performance in the Trail-Making Test B (TMT-B), an established measure of executive functioning, and (2) were volumetrically linked to the ventromedial prefrontal cortex (VMPFC), found to be associated with TMT-B in the ARMS during the first analysis step. We found the ARMS subjects to be specifically impaired in their TMT-B performance versus HC. Brain-cognition associations involving the insular cortices were observed in the HC, but not in the ARMS individuals. Conversely, TMT-B correlations in the VMPFC, the cerebellum, the fronto-callosal white matter were detected in the ARMS, but not the HC group. The VMPFC was linked to the temporo-limbic cortices in HC, whereas the connectivity pattern in the ARMS involved the left temporal and dorsolateral prefrontal cortex, the cerebellum, the right SMA and extended portions of the fronto-callosal white matter. These findings suggest that executive deficits are already present in the ARMS for psychosis and may be subserved by structurally altered networks of interconnected cortical and subcortical brain regions in line with the disconnectivity hypothesis of schizophrenia.

Abstract: The absence of olfactory input causes structural brain remodelling in humans. Mainly, the olfactory bulb and cortical olfactory areas are involved in this process. The aim of our study was to investigate volume changes of the gray and white matter in a group of subjects with an impaired but not complete loss of olfaction (hyposmia). Magnetic resonance images of hyposmic subjects and an age- and sex-matched control group were acquired on a 3T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. The analysis revealed significant gray matter volume loss in the insular cortex, anterior cingulate cortex, orbitofrontal cortex, cerebellum, fusiform gyrus, precuneus, middle temporal gyrus and piriform cortex. In the VBM white matter analysis areas of volume loss were found underneath the insular cortex, in the cerebellum and middle frontal gyrus. All areas of white matter atrophy were spatially connected to areas of gray matter volume loss except the middle frontal gyrus alterations. No significant gray or white matter volume increases could be observed. The pattern of gray matter alterations was similar to that known from anosmic subjects with a lower extent. To our knowledge, we report here for the first time on white matter volume alterations in patients with olfactory deficit.

Abstract: A brain surface reconstruction allows advanced analysis of structural and functional brain data that is not possible using volumetric data alone. However, the generation of a brain surface mesh from MRI data often introduces topological defects and artifacts that must be corrected. We show that it is possible to accurately correct these errors using spherical harmonics. Our results clearly demonstrate that brain surface meshes reconstructed using spherical harmonics are free from topological defects and large artifacts that were present in the uncorrected brain surface. Visual inspection reveals that the corrected surfaces are of very high quality. The spherical harmonic surfaces are also quantitatively validated by comparing the surfaces to an "ideal" brain based on a manually corrected average of twelve scans of the same subject. In conclusion, the spherical harmonics approach is a direct, computationally fast method to correct topological errors.

Abstract: Age-related structural brain changes have been demonstrated repeatedly but data on the effect of gender on age-related structural brain changes are conflicting. Using high-resolution T1-weighted magnetic resonance imaging and voxel-based morphometry, we examined a population of 133 healthy adults (women, 73; men, 60; age range, 29-80 years) focusing on differential aging between men and women (i.e., interaction of age and gender). Compared to women, men showed accelerated age-related gray matter (GM) loss in the posterior putamen. Our data may constitute the structural substrate for age-related differences in motor function between men and women such as the higher incidence and earlier onset of Parkinson's disease in men.

Abstract: Identification of individuals at high risk of developing psychosis has relied on prodromal symptomatology. Recently, machine learning algorithms have been successfully used for magnetic resonance imaging-based diagnostic classification of neuropsychiatric patient populations.

Abstract: BACKGROUND AND PURPOSE: Voxel-based morphometry (VBM) has proved a powerful method to detect subtle changes of gray matter (GM) at the group level but the role of VBM for the detection of GM changes in single subjects, especially in those with suspected neurodegenerative disorder, remains uncertain. Here, we performed single subject analyses in 22 patients in early stages of Huntington disease (HD), a neurodegenerative disorder with a well-known and characteristic pattern of GM loss. MATERIALS AND METHODS: We applied an ANCOVA with age and gender as covariates and corrected for multiple statistical tests by false discovery rate (P < 0.05). Each patient was compared to 133 healthy controls. The same procedure was applied to 22 of the controls matched for age and gender in a pair-wise manner. RESULTS: Our analyses yielded biologically plausible results in HD patients in which GM decrease within the caudate nucleus could be identified in 15 of the 16 most affected patients while GM decrease was found in only 1 control subject. Lowering the size of the control group yielded comparable results with 99 and 66 control subjects whereas sensitivity decreased with 33 control subjects. CONCLUSIONS: Our pilot study demonstrates a potential role of VBM for the detection of cerebral GM changes in single subjects with suspected neurodegenerative disorder.

Abstract: Although the systematic study of meditation is still in its infancy, research has provided evidence for meditation-induced improvements in psychological and physiological well-being. Moreover, meditation practice has been shown not only to benefit higher-order cognitive functions but also to alter brain activity. Nevertheless, little is known about possible links to brain structure. Using high-resolution MRI data of 44 subjects, we set out to examine the underlying anatomical correlates of long-term meditation with different regional specificity (i.e., global, regional, and local). For this purpose, we applied voxel-based morphometry in association with a recently validated automated parcellation approach. We detected significantly larger gray matter volumes in meditators in the right orbito-frontal cortex (as well as in the right thalamus and left inferior temporal gyrus when co-varying for age and/or lowering applied statistical thresholds). In addition, meditators showed significantly larger volumes of the right hippocampus. Both orbito-frontal and hippocampal regions have been implicated in emotional regulation and response control. Thus, larger volumes in these regions might account for meditators' singular abilities and habits to cultivate positive emotions, retain emotional stability, and engage in mindful behavior. We further suggest that these regional alterations in brain structures constitute part of the underlying neurological correlate of long-term meditation independent of a specific style and practice. Future longitudinal analyses are necessary to establish the presence and direction of a causal link between meditation practice and brain anatomy.

Abstract: A bilateral compensatory increase of basal ganglia (BG) gray matter value (GMV) was recently demonstrated in asymptomatic Parkin mutation carriers, who likely have an increased risk to develop Parkinson's disease (PD). We hypothesized BG morphological changes in symptomatic Parkin mutation carriers (sPARKIN-MC) and idiopathic PD patients (iPD) after the occurrence of PD symptoms, reflecting the breakdown of compensatory mechanisms. Nine sPARKIN-MC, 14 iPD, and 24 controls were studied clinically and with voxel-based morphometry. Analysis of variance revealed mainly BG decrease of GMV in sPARKIN-MC and to a lesser extent in iPD. However, a slight increase in GMV was also found in the right globus pallidus externus in sPARKIN-MC and in the right putamen in iPD. This may reflect a structural correlate of functional compensation that can only partially be maintained when nigrostriatal neurodegeneration becomes manifest. Simple regression analyses with the UPDRS-III and disease duration score revealed a distinct more bilateral linear decrease of BG GMV in sPARKIN-MC than in iPD that may correspond to previous findings showing a symmetric reduction in putaminal (18)F-DOPA-uptake and bilateral manifestation of symptoms in sPARKIN-MC. In symptomatic PD, BG are subject to a progressive atrophy, which gradually increases with disease severity and duration.

Abstract: Structural brain abnormalities have been described in individuals with an at-risk mental state for psychosis. However, the neuroanatomical underpinnings of the early and late at-risk mental state relative to clinical outcome remain unclear.

Abstract: The different brain anatomy of men and women is both a classic and continuing topic of major interest. Among the most replicated and robust sex differences are larger overall brain dimensions in men, and relative increases of global and regional gray matter (GM) in women. However, the question remains whether sex-typical differences in brain size (i.e., larger male and smaller female brains) or biological sex itself account for the observed sex effects on tissue amount and distribution. Exploring cerebral structures in men and women with similar brain size may clarify the true contribution of biological sex. We thus examined a sample of 24 male and 24 female subjects with brains identical in size, in addition to 24 male and 24 female subjects with considerable brain size differences. Using this large set of brains (n = 96), we applied a well validated and automated voxel-based approach to examine regional volumes of GM. While we revealed significant main effects of sex, there were no significant effects of brain size (and no significant interactions between sex and brain size). When conducting post hoc tests, we revealed a number of regions where women had larger GM volumes than men. Importantly, these sex effects remained evident when comparing men and women with the same brain size. Altogether, our findings suggest that the observed increased regional GM volumes in female brains constitute sex-dependent redistributions of tissue volume, rather than individual adjustments attributable to brain size.

Abstract: Processing pediatric neuroimaging data is a challenge due to pervasive morphological changes that occur in the human brain during normal development. This is of special relevance when reference data is used as part of the processing approach, as in spatial normalization and tissue segmentation. Current approaches construct reference data (templates) by averaging brain images from a control group of subjects, or by creating custom templates from the group under study. In this technical note, we describe a new, and generalized method of constructing such appropriate reference data by statistically analyzing a large sample (n=404) of healthy children, as acquired during the NIH MRI study of normal brain development. After eliminating non-contributing demographic variables, we modeled the effects of age (first, second, and third-order terms) and gender, for each voxel in gray matter and white matter. By appropriate weighting with the parameter estimates from these analyses, complete tissue maps can be generated automatically from this database to match a pediatric population selected for study. The algorithm is implemented in the form of a toolbox for the SPM5 image data processing suite, which we term Template-O-Matic. We compare the performance of this approach with the current method of template generation and discuss the implications of our approach.

Abstract: Spatial normalization and segmentation of infant brain MRI data based on adult or pediatric reference data may not be appropriate due to the developmental differences between the infant input data and the reference data. In this study we have constructed infant templates and a priori brain tissue probability maps based on the MR brain image data from 76 infants ranging in age from 9 to 15 months. We employed two processing strategies to construct the infant template and a priori data: one processed with and one without using a priori data in the segmentation step. Using the templates we constructed, comparisons between the adult templates and the new infant templates are presented. Tissue distribution differences are apparent between the infant and adult template, particularly in the gray matter (GM) maps. The infant a priori information classifies brain tissue as GM with higher probability than adult data, at the cost of white matter (WM), which presents with lower probability when compared to adult data. The differences are more pronounced in the frontal regions and in the cingulate gyrus. Similar differences are also observed when the infant data is compared to a pediatric (age 5 to 18) template. The two-pass segmentation approach taken here for infant T1W brain images has provided high quality tissue probability maps for GM, WM, and CSF, in infant brain images. These templates may be used as prior probability distributions for segmentation and normalization; a key to improving the accuracy of these procedures in special populations.

Abstract: BACKGROUND: Mutations in the PINK1 gene can cause Parkinson's disease and are frequently associated with psychiatric symptoms that might even precede motor signs. METHODS: To determine whether specific gray matter degeneration of limbic and frontal structures might be liable to different psychiatric symptoms in PINK1 mutation carriers, observer-independent voxel-based morphometry was applied to high-resolution magnetic resonance images of 14 PINK1 mutation carriers from a large German family and 14 age- and gender-matched healthy control subjects. RESULTS: Psychiatric diagnoses in PINK1 mutation carriers comprised major depression without psychotic symptoms and schizophrenia-spectrum, panic, adjustment, and obsessive-compulsive personality disorders. As hypothesized, the categorical comparison between all PINK1 mutation carriers and control subjects demonstrated atrophy of limbic structures, especially the hippocampus and parahippocampus. More specifically, multiple regression analysis considering all psychiatric subscores simultaneously displayed different frontal (prefrontal, dorsolateral, and premotor cortex) and limbic (parahippocampus and cingulate) degeneration patterns. The duration of the psychiatric disease was also correlated with the extent of limbic and frontal gray matter volume decrease. CONCLUSIONS: Our results support the hypothesis that limbic and frontal gray matter alterations could explain various psychiatric symptoms observed in PINK1 mutation carriers. Factors determining individual susceptibility to degeneration of certain brain areas remain to be elucidated in future studies.

Abstract: The pronounced convolution of the human cortex may be a morphological substrate that supports some of our species' most distinctive cognitive abilities. Therefore, individual intelligence within humans might be modulated by the degree of folding in certain cortical regions. We applied advanced methods to analyze cortical convolution at high spatial resolution and correlated those measurements with intelligence quotients. Within a large sample of healthy adult subjects (n = 65), we detected the most prominent correlations in the left medial hemisphere. More specifically, intelligence scores were positively associated with the degree of folding in the temporo-occipital lobe, particularly in the outermost section of the posterior cingulate gyrus (retrosplenial areas). Thus, this region might be an important contributor toward individual intelligence, either via modulating pathways to (pre)frontal regions or by serving as a location for the convergence of information. Prominent gender differences within the right frontal cortex were observed; females showed uncorrected significant positive correlations and males showed a nonsignificant trend toward negative correlations. It is possible that formerly described gender differences in regional convolution are associated with differences in the underlying architecture. This might lead to the development of sexually dimorphic information processing strategies and affect the relationship between intelligence and cortical convolution.

Abstract: Structural neuroimaging has substantially advanced the neurobiological research of schizophrenia by describing a range of focal brain alterations as possible neuroanatomical underpinnings of the disease. Despite this progress, a considerable heterogeneity of structural findings persists that may reflect the phenomenological diversity of schizophrenia. It is unclear whether the range of possible clinical disease manifestations relates to a core structural brain deficit or to distinct structural correlates. Therefore, gray matter density (GMD) differences between 175 schizophrenic patients (SZ) and 177 matched healthy control subjects (HC) were examined in a three-step approach using cross-sectional and conjunctional voxel-based morphometry (VBM): (1) analysis of structural alterations irrespective of symptomatology; (2) subdivision of the patient sample according to a three-dimensional factor model of the PANSS and investigation of structural differences between these subsamples and healthy controls; (3) analysis of a common pattern of structural alterations present in all patient subsamples compared to healthy controls. Significant GMD reductions in patients compared to controls were identified within the prefrontal, limbic, paralimbic, temporal and thalamic regions. The disorganized symptom dimension was associated with bilateral alterations in temporal, insular and medial prefrontal cortices. Positive symptoms were associated with left-pronounced alterations in perisylvian regions and extended thalamic GMD losses. Negative symptoms were linked to the most extended alterations within orbitofrontal, medial prefrontal, lateral prefrontal and temporal cortices as well as limbic and subcortical structures. Thus, structural heterogeneity in schizophrenia may relate to specific patterns of GMD reductions that possibly share a common prefrontal-perisylvian pattern of structural brain alterations.

Abstract: BACKGROUND: Recently, activation-dependant structural brain plasticity in humans has been demonstrated in adults after three months of training a visio-motor skill. Learning three-ball cascade juggling was associated with a transient and highly selective increase in brain gray matter in the occipito-temporal cortex comprising the motion sensitive area hMT/V5 bilaterally. However, the exact time-scale of usage-dependant structural changes occur is still unknown. A better understanding of the temporal parameters may help to elucidate to what extent this type of cortical plasticity contributes to fast adapting cortical processes that may be relevant to learning. PRINCIPAL FINDINGS: Using a 3 Tesla scanner and monitoring whole brain structure we repeated and extended our original study in 20 healthy adult volunteers, focussing on the temporal aspects of the structural changes and investigated whether these changes are performance or exercise dependant. The data confirmed our earlier observation using a mean effects analysis and in addition showed that learning to juggle can alter gray matter in the occipito-temporal cortex as early as after 7 days of training. Neither performance nor exercise alone could explain these changes. CONCLUSION: We suggest that the qualitative change (i.e. learning of a new task) is more critical for the brain to change its structure than continued training of an already-learned task.

Abstract: It has been suggested that learning is associated with a transient and highly selective increase in brain gray matter in healthy young volunteers. It is not clear whether and to what extent the aging brain is still able to exhibit such structural plasticity. We built on our original study, now focusing on healthy senior citizens. We observed that elderly persons were able to learn three-ball cascade juggling, but with less proficiency compared with 20-year-old adolescents. Similar to the young group, gray-matter changes in the older brain related to skill acquisition were observed in area hMT/V5 (middle temporal area of the visual cortex). In addition, elderly volunteers who learned to juggle showed transient increases in gray matter in the hippocampus on the left side and in the nucleus accumbens bilaterally.

Abstract: Forty Untreated high-risk (HR) individuals for psychosis and 75 healthy control subjects (HC) matched for age, gender, handedness and educational level were investigated by structural MRI. HR subjects were recruited at the Early Detection and Intervention Centre for Mental Crises (FETZ) of the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Germany. Measurements of gray matter volumes were performed by voxel-based morphometry using SPM5. The sample of HR subjects showed GM volume reductions in frontal, lateral temporal and medial temporal regions compared to the healthy control group. These regions are compatible with structural findings in the clinically apparent disease of schizophrenia.

Abstract: The neurophysiological basis of practice-induced gray matter increase is unclear. To study the relationship of practice-induced gray matter changes and neural activation, we conducted a combined longitudinal functional and morphometric (voxel-based morphometry) magnetic resonance imaging (MRI) study on mirror reading. Compared with normal reading, mirror reading resulted in an activation of the dorsolateral occipital cortex, medial occipital cortex, superior parietal cortex, medial and dorsolateral prefrontal cortex, as well as anterior insula and cerebellum. Daily practice of 15 min for 2 weeks resulted in an increased performance of mirror reading. After correction for pure performance effects, we found a practice-related decrease of activation at the right superior parietal cortex and increase of activation at the right dorsal occipital cortex. The longitudinal voxel-based morphometry analysis yielded an increase of gray matter in the right dorsolateral occipital cortex that corresponded to the peak of mirror-reading-specific activation. This confirms that short-term gray matter signal increase corresponds to task-specific processing. We speculate that practice-related gray matter signal changes in MRI are primarily related to synaptic remodeling within specific processing areas.

Abstract: BACKGROUND: Mutations in the Parkin and PINK1 genes can cause parkinsonism. Since asymptomatic carriers of a single mutant allele of the Parkin or PINK1 gene display a presynaptic dopaminergic dysfunction in the striatum, they provide a unique in vivo model to study structural and functional reorganization in response to latent nigrostriatal dysfunction. We hypothesized that subclinical nigrostriatal neurodegeneration caused by these mutations would induce morphologic changes in the dysfunctional striatal gray matter. METHODS: In asymptomatic carriers of a heterozygous Parkin (n = 13) or PINK1 (n = 10) mutation and 23 age-and sex-matched individuals without a mutation, we applied observer independent region-of-interest and voxel-based morphometry to high-resolution structural MRIs. RESULTS: Relative to controls without a mutation, Parkin and PINK1 mutation carriers displayed a bilateral increase in gray matter volume in the putamen and the internal globus pallidus. In 8 of the 13 Parkin mutation carriers, the presynaptic dopaminergic function was studied with (18)F-DOPA PET. The metabolic-morphometric regression analysis revealed that the linear decrease in individual presynaptic striatal (18)F-DOPA uptake was linked to a reciprocal decrease in the striatal gray matter volume in the putamen bilaterally and in the left caudate nucleus. CONCLUSIONS: The alternative causes of the increased striatal gray matter volume may be either due to excessive levels of neuronal activity caused by chronic dopaminergic dysfunction or due to long-term adaptation to chronic nigrostriatal dysfunction actively compensating for the dopaminergic denervation. In any case, the results indicate that a genetically driven regional dysfunction may be imprinted in the structure of the dysfunctional brain region, for example in the striatum.

Abstract: OBJECTIVE: The brain regions that are critically involved in the pathophysiology of anorexia nervosa have not been clearly elucidated. Moreover, decrease in cerebral tissue during extreme malnutrition has been demonstrated repeatedly in anorexia nervosa, but data regarding the reversibility of this cerebral tissue decrease are conflicting. The authors examined region-specific gray matter changes and global cerebral volumes in recovered patients with anorexia nervosa. METHOD: High-resolution, T1-weighted magnetic resonance imaging (MRI) and voxel-based morphometry were performed in 22 recovered women with anorexia nervosa and in 37 healthy comparison women. Recovery was defined as a body mass index above 17.0 kg/m(2) and regular menses for at least 6 months. RESULTS: The global volumes of gray matter (but not white matter) were decreased in patients with anorexia nervosa by approximately 1%. Analyses of region-specific gray matter changes revealed a gray matter decrease bilaterally in the anterior cingulate cortex of approximately 5%, which remained significant after correction for global effects. This gray matter decrease correlated significantly with the lowest body mass index of lifetime but not with other clinical variables. CONCLUSIONS: In anorexia nervosa, part of the global gray matter loss persists over the long run. Region-specific gray matter loss in the anterior cingulate cortex is directly related to the severity of anorexia nervosa, indicating an important role of this area in the pathophysiology of the disorder. Further research is warranted to determine the cause, specificity, and functional consequences of this structural brain change in anorexia nervosa.

Abstract: In Huntington's disease (HD), the distribution of pathological changes throughout the brain is incompletely understood. Some studies have identified leftward-biased lateralization, whereas others did not. We performed magnetic resonance imaging and a voxel-based asymmetry analysis in 44 right-handed HD gene carriers (presymptomatic, n = 5; stage I, n = 28; stage II, n = 11) and 44 right-handed healthy controls. The group comparison revealed leftward-biased gray matter loss in the striatum. Further analyses showed no indication of asymmetry in presymptomatic HD patients but an increase in asymmetry in the course of the HD stages under examination. Our study demonstrates and discusses leftward-biased gray matter loss in HD.

Abstract: In Huntington disease (HD), both the genetic defect and mutant gene product huntington are known but the exact mechanisms that lead to neuronal loss are poorly understood. Until now, the distribution of tissue loss throughout the brain has been investigated intensively. Here we searched for areas that, antipodal to the striatum, display grey-matter (GM) preservation. We performed high resolution T1-weighted magnetic resonance imaging and voxel-based morphometry in 46 patients in early HD and 46 healthy controls. We applied an analysis of covariance (ANCOVA) model with the total GM volume of each participant as covariate. In accordance with earlier reports, group comparisons revealed GM decrease in the striatum, insula, and thalamus as well as in dorsolateral frontal and occipital areas. In contrast, the limbic prefrontal cortex displayed GM preservation. Our findings support hypotheses that postulate differential involvement of frontosubcortical circuits in the pathophysiology of HD.

Abstract: Structural neuroimaging studies have reported a variety of brain alterations between groups of obsessive-compulsive disorder (OCD) patients and healthy controls. However, the large heterogeneity in discrete anatomical measures that exists among patients prevents a clear discrimination of single patients from healthy subjects. This reduces the potential clinical applicability of structural neuroimaging studies. In the present study we assessed the feasibility of identifying OCD patients on the basis of whole-brain anatomical alterations. Whole-brain magnetic resonance images were collected from two consecutive samples of OCD outpatients (n=72 and n=30), and control subjects (n=72 and n=30). We computed the whole-brain (voxel-wise) pattern of structural difference between OCD patients and control subjects at the group level. A single expression value of this difference pattern was calculated for each subject, expressing their degree of 'OCD-like' anatomical alteration. Accuracy of patient classification based on these expression values was assessed using two validation approaches. Firstly, using a cross-validation method, we obtained a high classification accuracy (average of the sensitivity and specificity indices) of 93.1%. In a second assessment, which classified new groups of OCD patients and control subjects, overall accuracy was lower at 76.6%. Individual expression values for OCD patients were significantly correlated with overall symptom severity as measured by the Y-BOCS scale. Our results suggest that OCD patients can be identified on the basis of whole-brain structural alterations, although the accuracy of our approach may be limited by the inherent variability of psychiatric populations. Nevertheless, the anatomical characterization of individual patients may ultimately provide the psychiatrist with relevant biological information.

Abstract: BACKGROUND: Primary blepharospasm is a focal dystonia characterised by excessive involuntary closure of the eyelids. The pathophysiology of primary blepharospasm is unresolved. AIM: To pinpoint grey-matter changes that are associated with primary blepharospasm. METHODS: 16 right-handed patients with primary blepharospasm (mean age 67.4 (SD 4.3) years; 12 women) were compared with 16 healthy volunteers matched for sex and age. High-resolution T1-weighted magnetic resonance imaging of each participant was obtained and analysed by voxel-based morphometry, a method to detect regionally specific differences in grey matter between patients and control group. To evaluate whether the identified grey-matter changes were correlated with the duration of primary blepharospasm or botulinum neurotoxin treatment (BoNT), separate regression analyses were carried out. RESULTS: In patients with primary blepharospasm, grey-matter increase in the putamina was observed, whereas regression analyses did not indicate a correlation between grey-matter increases and the duration of primary blepharospasm or BoNT. Grey-matter decrease was detected in the left inferior parietal lobule; here regression analyses of grey-matter decrease showed a significant (p = 0.013) correlation of grey-matter decrease with the duration of BoNT. CONCLUSIONS: The data suggest structural changes in primary blepharospasm and point to a crucial role of the putamen for the pathophysiology of this focal dystonia.

Abstract: The hippocampus is discussed as one of the key regions in the pathogenesis of Posttraumatic Stress Disorder (PTSD). MRI results concerning the volume of the hippocampus are, however, inconsistent. This may be due to the heterogeneity of patients' traumata or postprocessing of the imaging data. To overcome these problems, the present study investigates volume changes in well-characterized chronic PTSD patients in comparison to controls using two different evaluation methods. MATERIAL AND METHODS: 15 patients with chronic PTSD, traumatized at the same air show plane crash in 1988 (Ramstein, Germany), and 15 matched healthy controls participated in this study. All patients suffered from significant impairment by the PTSD; none had a history of drug or alcohol abuse. Hippocampus volume changes were processed by a semi-automated standard procedure performed with BRAINS2 as well as the voxel based morphometry (VBM) using SPM2. RESULTS: No differences in total brain grey or white matter were detected between patients and controls. No differences in total hippocampal volume or in right and left parts were seen, even when hippocampal volumes were corrected by total brain volume or correlated with clinical data. Finally, no significant differences were detected between patients and controls in hippocampal regions using VBM. DISCUSSION: This is the first study examining long-term changes in hippocampal volumes in chronic PTSD patients compared to matched controls using two different evaluation methods. Neither conventional volumetry nor VBM could detect any differences in the volume and structure. This supports the hypothesis that previously described hippocampal volume reduction is not necessarily due to PTSD or at least that, after 15 years, volume changes have been restored or have not yet developed.

Abstract: Functional activation patterns of an auditory working memory task were examined prior to and after 5 days of training (1 h/day). A control group with no training was scanned twice at the same intervals to assess test-retest effects. Based on behavioral improvement scores, the training group (n = 14) was divided into "Strong-Learners (SL)" and "Weak-Learners (WL)". No significant functional or structural brain differences were seen between the SL and WL groups prior to training. Imaging contrasts comparing post- with pre-training sessions showed a significant signal increase in the left Heschl's gyrus (HG) as well as in the left posterior superior temporal and supramarginal gyrus for the SL group, while the WL group showed significant signal increases in the left HG and anterior insular cortex as well as in a lingual-orbitofrontal-parahippocampal network. The test-retest analysis in the control group revealed only minimal signal increases in a right dorsolateral prefrontal region. A random effects analysis comparing the SL group with the WL group using the post- and pre-training contrast images showed increased activation only in the left supramarginal gyrus but not in HG. The importance of HG in pitch discrimination has been established in previous studies. The pitch memory component differentiated our task from a straight pitch discrimination task. It is most likely that the activation of the SMG reflects its importance in the short-term storage of auditory material, and it was this activation that best differentiated between subjects' levels of performance.

Abstract: Applying a recently developed method to analyze gyrification with excellent spatial resolution across thousands of points across the lateral and medial cortical surface, we mapped differences in cortical surface anatomy between subjects with Williams syndrome (WS; n=42) and an age-matched sample of healthy subjects (n=40). WS subjects showed increased gyrification bilaterally in occipital regions and over the cuneus. Differences were more pronounced in the left hemisphere than in the right, with additional regions of increased gyrification in WS in the left precuneus, posterior and anterior cingulate, paracentral and mesial frontal lobe. No cortical area was significantly more convoluted in healthy subjects relative to the WS subjects. On the lateral surfaces, the direction and pattern of gyrification asymmetries were similar in WS subjects and controls; posterior brain regions had greater gyrification in the left hemisphere, while anterior brain regions showed greater gyrification in the right hemisphere. On the medial surfaces, control subjects and WS individuals differed considerably with respect to the degree but also direction of gyrification asymmetry. Our findings confirm and extend previous studies measuring cortical complexity at the global whole-brain or hemispheric levels. The observed gyrification abnormalities in individuals with WS might be related to dysfunctions in neuronal circuits and consequently contribute to the distinct cognitive and behavioral profile accompanying the disorder.

Abstract: Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapyramidal, pyramidal as well as psychiatric signs. The pathoanatomical basis of this disorder is still not well known. A total of 12 patients and 12 age- and sex-matched controls were examined by in vivo MRI voxel-based morphometry (VBM). Besides general patterns of disease-related brain atrophy, characteristic syndrome-related morphological changes in SCA17 patients were studied. In comparison with normal controls, SCA17 patients showed a pattern of degeneration of the grey matter centred around mesial cerebellar structures, occipito-parietal structures, the anterior putamen bilaterally, the thalamus and other parts of the motor network, reflecting the cerebellar, pyramidal and extrapyramidal signs. A correlation analysis revealed a clear association between the clinical cerebellar, extrapyramidal and psychiatric scores and degeneration in specific areas. Two degeneration patterns were found as follows: regarding motor dysfunction, atrophy of the grey matter involved mainly the cerebellum and other motor networks, in particular the basal ganglia. In contrast, correlations with psychiatric scores revealed grey matter degeneration patterns in the frontal and temporal lobe, the cuneus and cingulum. Most interestingly, there was a highly significant correlation between the clinical Mini-Mental State Examination scores and atrophy of the nucleus accumbens, probably accounting for the leading psychiatric signs.

Abstract: OBJECTIVE: To investigate cerebellar gray matter volume in patients with essential tremor (ET). METHODS: We used voxel-based morphometry (VBM) based on high-resolution T1-weighted MRI to compare gray and white matter density between 27 patients with ET and 27 age- and sex-matched healthy control subjects. Fourteen patients had only postural tremor, whereas 13 patients showed additional intention tremor. RESULTS: VBM failed to demonstrate regional decreases in gray and white matter volume in patients with ET. There was, however, an expansion in gray matter depending on the type of tremor. Compared with age-matched control groups, patients with intention tremor showed a relative expansion of gray matter bilaterally in the region of the temporoparietal junction and the right middle occipital cortex. CONCLUSIONS: The lack of a consistent decrease in gray and white matter density argues against a progressive neurodegenerative process in essential tremor that leads to a substantial decrease in cerebellar gray matter volume. Patients with predominant intention tremor show a relative expansion of gray matter areas involved in higher order visuospatial processing, which might represent a long-term result of adaptive reorganization compensating the higher demands on the visuospatial control of skilled movements in case of trembling.

Abstract: The current view regarding human long-term memory as an active process of encoding and retrieval includes a highly specific learning-induced functional plasticity in a network of multiple memory systems. Voxel-based morphometry was used to detect possible structural brain changes associated with learning. Magnetic resonance images were obtained at three different time points while medical students learned for their medical examination. During the learning period, the gray matter increased significantly in the posterior and lateral parietal cortex bilaterally. These structural changes did not change significantly toward the third scan during the semester break 3 months after the exam. The posterior hippocampus showed a different pattern over time: the initial increase in gray matter during the learning period was even more pronounced toward the third time point. These results indicate that the acquisition of a great amount of highly abstract information may be related to a particular pattern of structural gray matter changes in particular brain areas.

Abstract: Tinnitus is a common but poorly understood disorder characterized by ringing or buzzing in the ear. Central mechanisms must play a crucial role in generating this auditory phantom sensation as it persists in most cases after severing the auditory nerve. One hypothesis states that tinnitus is caused by a reorganization of tonotopic maps in the auditory cortex, which leads to an overrepresentation of tinnitus frequencies. Moreover, the participation of the limbic system in generating tinnitus has been postulated. Here we aimed at identifying brain areas that display structural change in tinnitus. We compared tinnitus sufferers with healthy controls by using high-resolution magnetic resonance imaging and voxel-based morphometry. Within the auditory pathways, we found gray-matter increases only at the thalamic level. Outside the auditory system, gray-matter decrease was found in the subcallosal region including the nucleus accumbens. Our results suggest that reciprocal involvement of both sensory and emotional areas are essential in the generation of tinnitus.

Abstract: Using magnetic resonance imaging and a new method to analyze local surface shape, we examined the effects of gender on gyrification in a large and well-matched sample of healthy subjects. Unlike traditional 2D methods that produce whole-brain measurements of cortical complexity or more sophisticated 3D parametric mesh-based techniques that allow only different sections (lobes) of the cortex to be investigated, we employed a novel approach with increased spatial resolution. Although our method is sensitive to similar cortical features like the classic whole-brain gyrification index (depths of sulci and heights of gyri), we are now able to provide detailed and regionally specific estimates of cortical convolution at thousands of points across the cortical surface without introducing any bias through the rater or the selected orientation of the slices. We revealed pronounced gender differences, showing increased gyrification in frontal and parietal regions in females compared to males that agree with recent regions-of-interest findings. In addition, we detected higher female gyrification in temporal and occipital cortices that was not previously identified in studies using more global measures. No cortical area was significantly more convoluted in males compared to females. Our results demonstrate the sensitivity of this automated approach for identifying very local changes in gyrification. This technique may serve to isolate regionally specific changes in fissuration/gyrification in neurodevelopmental or neuropsychiatric disorders.

Abstract: PURPOSE OF REVIEW: In contrast to traditional anatomical and pathological methods, magnetic resonance morphometry of the brain allows the in-vivo study of temporal changes in brain morphology and the correlation of brain morphology with brain function. Magnetic resonance morphometry has thereby recently emerged as one of the most promising fields in clinical neuroscience. This review covers the last 3 years, which have witnessed remarkable progress in this alluring new field. RECENT FINDINGS: Next to the detection of structural differences in grey and white matter in a number of brain diseases, a very important recent finding of magnetic resonance-based morphometry is the discovery of the brain's ability to alter its shape within weeks, reflecting structural adaptation to physical and mental activity. Consequently, magnetic resonance morphometry promises to be a powerful method to study disease states of the brain and to track the effects of novel therapies. SUMMARY: Despite these fascinating prospects, the results of morphometric studies are still dependent on the properties of the individual magnetic resonance scanner, which renders pooling of data almost impossible. It is also not known what the structural plasticity is based on at the histological or cellular level. Once these obstacles are overcome, magnetic resonance-based morphometry will become a powerful method for multicenter and therapeutic trials of several brain diseases.

Abstract: Auditory hallucinations are a frequent symptom in schizophrenia. While functional imaging studies have suggested the association of certain patterns of brain activity with sub-syndromes or single symptoms (e.g. positive symptoms such as hallucinations), there has been only limited evidence from structural imaging or post-mortem studies. In this study, we investigated the relation of local brain structural deficits to severity of auditory hallucinations, particularly in perisylvian areas previously reported to be involved in auditory hallucinations. In order to overcome certain limitations of conventional volumetric methods, we used deformation-based morphometry (DBM), a novel automated whole-brain morphometric technique, to assess local gray and white matter deficits in structural magnetic resonance images of 85 schizophrenia patients. We found severity of auditory hallucinations to be significantly correlated (P < 0.001) with volume loss in the left transverse temporal gyrus of Heschl (primary auditory cortex) and left (inferior) supramarginal gyrus, as well as middle/inferior right prefrontal gyri. This demonstrates a pattern of distributed structural abnormalities specific for auditory hallucinations and suggests hallucination-specific alterations in areas of a frontotemporal network for processing auditory information and language.

Abstract: Voxel-based morphometry (VBM) was used to analyze gray matter (GM) asymmetries in a large sample (n = 60) of male and female professional musicians with and without absolute pitch (AP). We chose to examine these particular groups because previous studies using traditional region-of-interest (ROI) analyses have shown differences in hemispheric asymmetry related to AP and gender. Voxel-based methods may have advantages over traditional ROI-based methods since the analysis can be performed across the whole brain with minimal user bias. After determining that the VBM method was sufficiently sensitive for the detection of differences in GM asymmetries between groups, we found that male AP musicians were more leftward lateralized in the anterior region of the planum temporale (PT) than male non-AP musicians. This confirmed the results of previous studies using ROI-based methods that showed an association between PT asymmetry and the AP phenotype. We further observed that male non-AP musicians revealed an increased leftward GM asymmetry in the postcentral gyrus compared to female non-AP musicians, again corroborating results of a previously published study using ROI-based methods. By analyzing hemispheric GM differences across our entire sample, we were able to partially confirm findings of previous studies using traditional morphometric techniques, as well as more recent, voxel-based analyses. In addition, we found some unusually pronounced GM asymmetries in our musician sample not previously detected in subjects unselected for musical training. Since we were able to validate gender- and AP-related brain asymmetries previously described using traditional ROI-based morphometric techniques, the results of our analyses support the use of VBM for examinations of GM asymmetries.

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Abstract: OBJECTIVE: Enlargement of the lateral ventricles is among the most frequently reported macroscopic brain structural changes in schizophrenia, although variable in extent and localization. The authors investigated whether ventricular enlargement is related to regionally specific volume loss. METHOD: High-resolution magnetic resonance imaging scans from 39 patients with schizophrenia were analyzed with deformation-based morphometry, a voxel-wise whole brain morphometric technique. RESULTS: Significant negative correlations with the ventricle-brain ratio were found for voxels in the left and right thalamus and posterior putamen and in the left superior temporal gyrus and insula. CONCLUSIONS: Thalamic shrinkage, especially of medial nuclei and the adjacent striatum and insular cortex, appear to be important contributors to ventricular enlargement in schizophrenia.

Abstract: Auditory functional magnetic resonance imaging tasks are challenging since the MR scanner noise can interfere with the auditory stimulation. To avoid this interference a sparse temporal sampling method with a long repetition time (TR = 17 s) was used to explore the functional anatomy of pitch memory. Eighteen right-handed subjects listened to a sequence of sine-wave tones (4.6 s total duration) and were asked to make a decision (depending on a visual prompt) whether the last or second to last tone was the same or different as the first tone. An alternating button press condition served as a control. Sets of 24 axial slices were acquired with a variable delay time (between 0 and 6 s) between the end of the auditory stimulation and the MR acquisition. Individual imaging time points were combined into three clusters (0-2, 3-4, and 5-6 s after the end of the auditory stimulation) for the analysis. The analysis showed a dynamic activation pattern over time which involved the superior temporal gyrus, supramarginal gyrus, posterior dorsolateral frontal regions, superior parietal regions, and dorsolateral cerebellar regions bilaterally as well as the left inferior frontal gyrus. By regressing the performance score in the pitch memory task with task-related MR signal changes, the supramarginal gyrus (left>right) and the dorsolateral cerebellum (lobules V and VI, left>right) were significantly correlated with good task performance. The SMG and the dorsolateral cerebellum may play a critical role in short-term storage of pitch information and the continuous pitch discrimination necessary for performing this pitch memory task.

Abstract: Temporal information processing is a fundamental brain function, which might include central timekeeping mechanisms independent of sensory modality. Psychopharmacological and patient studies suggest a crucial role of the basal ganglia in time estimation. In this study, functional magnetic resonance imaging (fMRI) was applied in 15 healthy right-handed male subjects performing an auditory time estimation task (duration discrimination of tone pairs in the range of 1,000-1,400 ms) and frequency discriminations (tone pairs differing in pitch, around 1,000 Hz) as an active control task. Task difficulty was constantly modulated by an adaptive algorithm (weighted up-down method) reacting on individual performance. Time estimation (vs rest condition) elicited a distinct pattern of cerebral activity, including the right medial and both left and right dorsolateral prefrontal cortices (DLPFC), thalamus, basal ganglia (caudate nucleus and putamen), left anterior cingulate cortex, and superior temporal auditory areas. Most activations showed lateralisation to the right hemisphere and were similar in the frequency discrimination task. Comparing time and frequency tasks, we isolated activation in the right putamen restricted to time estimation only. This result supports the notion of central processing of temporal information associated with basal ganglia activity. Temporal information processing in the brain might thus be a distributed process of interaction between modality-dependent sensory cortical function, the putamen (with a timing-specific function), and additional prefrontal cortical systems related to attention and memory. Further investigations are needed to delineate the differential contributions of the striatum and other areas to timing.

Abstract: Musicians learn complex motor and auditory skills at an early age and practice these specialized skills extensively from childhood through their entire careers. Using a voxel-by-voxel morphometric technique, we found gray matter volume differences in motor as well as auditory and visuospatial brain regions comparing professional musicians (keyboard players) with matched amateur musicians and nonmusicians. These multiregional differences might represent structural adaptations in response to long-term skill learning and repetitive rehearsal of these skills. This is supported by finding a strong association between structural differences, musician status, and practice intensity as well as by a wealth of supporting animal data showing structural changes in response to long-term motor training.

Abstract: From an early age, musicians learn complex motor and auditory skills (e.g., the translation of visually perceived musical symbols into motor commands with simultaneous auditory monitoring of output), which they practice extensively from childhood throughout their entire careers. Using a voxel-by-voxel morphometric technique, we found gray matter volume differences in motor, auditory, and visual-spatial brain regions when comparing professional musicians (keyboard players) with a matched group of amateur musicians and non-musicians. Although some of these multiregional differences could be attributable to innate predisposition, we believe they may represent structural adaptations in response to long-term skill acquisition and the repetitive rehearsal of those skills. This hypothesis is supported by the strong association we found between structural differences, musician status, and practice intensity, as well as the wealth of supporting animal data showing structural changes in response to long-term motor training. However, only future experiments can determine the relative contribution of predisposition and practice.

Abstract: The disturbance of somatosensory perception and bodily experiences, including somatosensory hallucinations, are main features of the coenaesthesia sub-syndrome of schizophrenia. We used functional MRI to study a coenaesthesia patient with rapidly fluctuating painful somatosensory hallucinatory perceptions. Transient brain activations accompanying hallucinations were similar to the pattern elicited in a control experiment (non-painful tactile stimulation). However, an area in the medial parietal cortex, including parts of the precuneus and previously characterised as a supplementary sensory area, was activated significantly stronger during hallucinations than the control condition. This finding demonstrates elevated brain activity in a somatosensory area accompanying painful somatic hallucinations.

Abstract: Difficulties in phonological processing are currently considered one of the major causes for dyslexia. Nine dyslexic children and eight control children were investigated using functional magnetic resonance imaging (fMRI) during non-oral reading of German words. All subjects silently read words and pronounceable non-words in an event related potentials (ERP) investigation, as well. The fMRI showed a significant difference in the activation in the left inferior frontal gyrus between the dyslexic and control groups, resulting from a hyperactivation in the dyslexics. The ERP scalp distribution showed a significant distinction between the two groups concerning the topographic difference for left frontal electrodes in a time window 250-600 ms after stimulus onset for non-word reading. Both the fMRI and the ERP results support differences in phonological processing between dyslexic and normal-reading children.

Abstract: Deformation-based morphometry (DBM) is a useful technique to detect morphological differences over the entire brain since it analyses positional differences between every voxel and a standard brain. In this report we compare DBM to semimanual tracing of brain ventricles in a population of 39 patients with schizophrenia. High-resolution T(1)-weighted magnetic resonance images were obtained and processed with DBM and interactive tracing software. We evaluate the validity of the DBM in two different approaches. First, we divide subjects into two groups based on the mean ventricular/brain ratios and compute statistical maps of displacement vectors and their spatial derivatives. This analysis demonstrates a striking consistency of the DBM and visual tracing results. We show that restricting the information about the deformation fields by computing the local Jacobian determinant (as a measure of volume change) provides evidence of the shape of ventricular deformation which is unavailable from ventricular volume measures alone. Second, we compute a mean measure of the Jacobian values over the entire ventricles and observe a correlation of r = 0.962 with visual tracing based ventricular/brain ratios. The results support the usefulness and validity of DBM for the local and global examination of brain morphology.

Abstract: fMRI was performed in nine male schizophrenia patients and 15 healthy male controls during an auditory time estimation (timing), a frequency (i.e. pitch) discrimination task, and rest. An adaptive psychophysical approach, the weighted up-down method, was used to adjust individual performance to a level of 75% probability for correct answers. Although performing on the same level of individual difficulty, schizophrenia patients revealed less activations in prefrontal cortex and caudate nucleus, comparing time vs rest. Timing specific differences (i.e. timing vs pitch) between patients and controls were found in the posterior putamen, anterior thalamus, and right medial prefrontal cortex, with patients showing relative hypoactivity. Impairment in time estimation in schizophrenia might be mediated by specific fronto-thalamo-striatal dysfunction.

Abstract: Functional neuroimaging findings of "hypofrontality" in schizophrenic patients - as tested with the Wisconsin Card Sorting Test (WCST) - are still controversial, mainly due to methodological aspects and the heterogeneity of the patient samples. To measure WCST specific and reproducible reduced cerebral activations in schizophrenic patients, we revised the study design and patient recruitment, respectively. For this purpose, we used an adequate active control task instead of an undefined rest condition to determine exclusively WCST specific cerebral activations. In addition, we focused on the investigation of modified activations between a selected group of neuroleptic-naive schizophrenic patients and carefully matched healthy controls by means of functional magnetic resonance imaging. The results indicate that neuroleptic-naive schizophrenic patients show reduced activations in the right frontal and left temporal lobe, as well as in the left cerebellum. By utilizing an active control task all unwanted activations are suppressed. Furthermore the influence of different task performances is reduced. The findings are in line with previous PET and SPECT studies and confirm the "hypofrontality" hypothesis. The findings suggest that "hypofrontality" is not caused by neuroleptic medication.

Abstract: Using functional magnetic resonance imaging and single slice FLASH technique, we investigated reorganization of the hand representation of the primary sensorimotor cortex (SMC) in 16 patients with upper extremity amputation. Patients were asked to perform finger tapping with the intact hand, repetitive eye closing and anteflexion of the amputation stump or intact shoulder. Six normal volunteers served as control. In the normal volunteers activations during shoulder anteflexion, finger tapping and eye closure were located within the central sulcus in a medio-lateral fashion. Patients demonstrated invasion of the face or shoulder representation into the hand representation of the amputated limb. Eight phantom limb pain patients showed significantly greater activation in SMC and supplementary motor area (SMA) in contrast to eight patients without phantom limb pain. We conclude, that different parts of the motor system are affected in patients with phantom limb pain--possibly in the sense of an up-regulation of excitability.

Abstract: The aim of the study was to investigate whether there is any structural evidence for the model of 'cognitive dysmetria' in schizophrenia if an automatic whole-brain analysis method is used. High-resolution magnetic resonance scans were obtained for 75 schizophrenic patients and 75 controls. These data were analysed using the recently developed deformation-based morphometry allowing the assessment of volumetric differences without a priori definition of regions of interest. When compared with controls, we found reduced volumes in patients with schizophrenia in the frontal lobe (gyrus frontalis superior, medius and medialis), the temporal lobe (gyrus temporalis superior and inferior), the thalamus, the left cerebellar hemisphere and the right cerebellar vermis. There was an increase in volume in the right putamen. To date, this is the first structural magnetic resonance imaging study to demonstrate that the three key-elements of the model of cognitive dysmetria--frontal lobe, thalamus, and cerebellum--are reduced in volume in schizophrenic patients. This highlights the importance of this concept for future investigations.

Abstract: This paper describes a new method for detecting structural brain differences based on the analysis of deformation fields. Deformations are obtained by an intensity-based nonlinear registration routine that transforms one brain onto another one. We present a general multivariate statistical approach to analyze deformation fields in different subjects. This method was applied to the brains of 85 schizophrenic patients and 75 healthy volunteers to examine whether low frequency deformations are sufficiently sensitive to detect regional deviations in the brains of both groups. We observed significant changes caused by volume reduction in brains of schizophrenics bilaterally in the thalamus and in the superior temporal gyrus. On the left side, the superior frontal gyrus and precentral gyrus are found to be changed, while on the right side, the middle frontal gyrus was altered. In addition, there were significant changes in the occipital lobe (left lingual gyrus) and in the left cerebellum. Volume enlargement in brains of schizophrenics was observed in the right putamen and in the adjacent white matter of the thalamic region. Our data suggest a disturbance in the nodes of a prefrontal-thalamic-cerebellar circuitry. This provides further support for the model of "cognitive dysmetria," which postulates a disruption in these nodes. We have demonstrated the application of deformation-based morphometry by detecting structural changes in the whole brain. This technique is fully automatic, thus allowing for the inclusion of large samples, with no user bias or a priori-defined regions of interest.

Abstract: The Continuous Performance Test (CPT) has become an essential constituent of the neuropsychological investigation of schizophrenia. Also, a vast number of brain imaging studies, mostly PET investigations, have employed the CPT as a cognitive challenge and established a relative hypofrontality in schizophrenics compared to controls. The aim of the present investigation was to clarify whether this predescribed hypofrontality could also be verified using functional magnetic resonance imaging (fMRI). 20 healthy volunteers and 14 schizophrenics on stable neuroleptic medication were included. Imaging was performed using the CPT-double-T-version and a clinical 1.5 T MRI-scanner with a single slice technique and a T(2)*-weighted gradient-echo-sequence. The schizophrenics exhibited a decreased activation in the right mesial prefrontal cortex, the right cingulate and the left thalamus compared to controls. These results obtained by fMRI are discussed in relation to published findings using PET.

Abstract: Combining the Continuous Performance Test (CPT) with a modern functional imaging technique provides a powerful tool for investigating neurophysiological processes in the human brain. There is increasing evidence from single photon emission tomography (SPECT), positron emission tomography (PET) and presently also functional magnetic resonance imaging (fMRI) studies proposing the existence of a distributed large-scale attentional network, mediated by the dorsolateral prefrontal and mesial frontal cortex, thalamus, basal ganglia and posterior parietal and superior temporal lobe. The aim of this study is to show that fMRI is a useful tool for in vivo localization of attentional tasks and to compare the results with established imaging techniques. Functional MRI was performed on a clinical 1.5-T system using gradient-echo acquisition. For data processing, the Statistical Parametric Mapping (SPM96) package was used. A right lateralized activation pattern in the dorsolateral prefrontal and mesial frontal cortex, the thalamus and the basal ganglia was found in a group of 12 male subjects. These findings support theories suggesting right hemispheric dominance of human attention.

Abstract: PURPOSE: To determine whether functional magnetic resonance (MR) imaging can demonstrate a specific pattern of cerebral activation during cognitive stimulation by using a high-level cognitive task such as the Wisconsin Card Sorting Test. MATERIALS AND METHODS: Thirty-one healthy volunteers underwent functional MR imaging with a 1.5-T MR imager with a standard head coil (100/50 [repetition time msec/echo time msec], 230-mm field of view, 40 degrees flip angle, 256 x 256 matrix). For stimulation, a personal computer version of the Wisconsin Card Sorting Test was used. Image analysis was done off-line, and cross-correlation coefficients between the stimulus function and the signal intensity response were calculated on a pixel-by-pixel basis and overlaid onto the corresponding anatomic MR image for each volunteer. RESULTS: Stimulation resulted in strongly frontal activation, which included the mesial and the dorsolateral prefrontal cortexes, interconnected with Brodmann areas 44, 45, and 46. While activation was often bilateral, the largest area of activation was in the right hemisphere. Activation also was found in the basal ganglia and the mesial thalamic nuclei. CONCLUSION: Functional MR imaging can demonstrate a specific pattern during activation with a cognitive task. Functional MR imaging has promise for more precise anatomic and functional imaging studies of brain interaction than have other imaging modalities.

Abstract: It has been demonstrated by single photon emission computed tomography (SPECT) and positron emission tomography (PET) that frontal brain regions are stimulated during performance of the Wisconsin Card Sorting Test (WCST). The WCST is also regarded as one of the standard tests for the assessment of frontal activity in brain imaging studies of schizophrenia. In this study cerebral activation was assessed by means of functional magnetic resonance imaging (fMRI). In healthy volunteers WCST stimulation resulted in a right lateralized frontal activation. In 13 chronic schizophrenics on stable neuroleptic medication, a lack of activation in the right prefrontal cortex and--as a trend--an increased left temporal activity during execution of the WCST was noted compared to controls. Since a one-slice technique was used, no information about the activation pattern in adjacent brain regions was obtained. However, as fMRI possesses a superior spatial resolution compared to SPECT and PET, the anatomical localization of the activation effect in the measured slice can be defined more precisely. Beside these methodological considerations, the results are discussed in relation to prior findings of a reduced ability of schizophrenics to coordinate cerebral function.

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