Claus Zimmer

Selective changes of resting-state networks in individuals at risk for Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n = 16) and patients with amnestic mild cognitive impairment (aMCI) (n = 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of resting-state fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs.

An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis

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.

Gray Matter Increase Induced by Practice Correlates with Task-Specific Activation: A Combined Functional and Morphometric Magnetic Resonance Imaging Study

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.

Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder.

&NA; Idiopathic chronic pain conditions with a mismatch between anatomical abnormalities and symptoms can be categorized as somatoform pain disorder according to the DSM‐IV criteria. A dysfunction of pain processing circuits has been suggested as one underlying pathophysiological factor. There is accumulating evidence for a crucial role of affect regulating brain structures such as the medial frontal cortex in this context. We investigated the cerebral processing of noxious heat stimuli as objective marker for pain sensation in 12 right handed women with somatoform pain disorder fulfilling DSM‐IV criteria and 13 age‐matched healthy volunteers using functional MRI. The average ratings for experimentally induced pain were not significantly different between controls and patients concerning pain intensity and pain unpleasantness. Comparing patients with controls a pain related hypoactive state of the ventromedial prefrontal/orbitofrontal cortex (BA 10/11) and a hyperactive state of the parahippocampal gyrus, amygdala and anterior insula were found in the patient group. Our findings of an altered cerebral processing of experimentally induced pain in patients with somatoform pain disorder support the hypothesis of dysfunctional pain processing, especially in affect regulating regions.

Patients with pain disorder show gray-matter loss in pain-processing structures: a voxel-based morphometric study.

Objective: To investigate whether the functional changes in pain disorder might be reflected by structural brain changes. Pain disorder assessed with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria is characterized by persistent and distressing chronic pain at one or more body sites which cannot be fully explained by a physiological process or somatic disorder. Psychological factors are thought to play a major role. Recent neuroimaging studies evidenced altered pain processing in patients suffering from this disorder. Methods: Fourteen right-handed women fulfilling the DSM-IV criteria for pain disorder and 25 healthy age-matched women were investigated with magnetic resonance imaging. In the voxel-based morphometry analysis, we compared both groups for changes of gray-matter density. We included age and Beck Depression Inventory scores as nuisance variables to minimize possible confounding effects of age or depressive comorbidity. Results: In the patient group, we found significant gray-matter decreases in the prefrontal, cingulate, and insular cortex. These regions are known to be critically involved in the modulation of subjective pain experiences. Conclusions: In the context of similar results in patients with other functional pain syndromes, such as fibromyalgia and chronic back pain, we suggest that structural changes in fronto-limbic brain circuits represent not only an objective marker of these pain syndromes but also constitute a critical pathophysiological element. These findings represent a further proof of the important role of central changes in pain disorder. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision; VBM = voxel-based morphometry; fMRI = functional magnetic resonance imaging; GM = gray matter; WM = white matter; CSF = cerebrospinal fluid; BDI = Beck Depression Inventory; MNI = standardized reference space defined by the Montreal Neurological Institute; SOMS = screening for somatoform symptoms; PPS = Pain Perception Scale; SCID = Structured Clinical Interview for DSM-IV disorders.

Endovascular treatment of acute intracerebral artery occlusions with the solitaire stent: single-centre experience with 108 recanalization procedures.

Background and Purpose: Stent retrievers are currently displacing ‘classical’ thrombectomy devices for recanalization in acute ischaemic stroke. The aim of our study was to show the procedural efficacy and safety of the Solitaire stent retriever as part of our multimodality endovascular approach in the treatment of ischaemic stroke. Methods: Between March 2008 and December 2009, 104 patients [53 females (51%), 51 males (49%), mean age 67.3 years (range 31–96)] with 108 territorial occlusions were treated with the Solitaire stent alone or in conjunction with other endovascular stroke devices. All patients were referred to our service after clinical evaluation by a team of stroke neurologists as part of our standard treatment algorithm with 0.9 mg/kg i.v. recombinant tissue-type plasminogen activator and endovascular continuation of treatment in CT angiography-proven main branch occlusion. The time of angiography was defined as the moment of groin puncture. Final reperfusion success was rated according to the Thrombolysis in Cerebral Infarction (TICI) scale; the first persistent Thrombolysis in Myocardial Infarction (TIMI) 2/3 reperfusion was used for time-to-reperfusion measures. Results: Fifty-eight patients were treated in conjunction with intravenous lysis, 32/104 received intra-arterial lytics. Twenty-five territories were treated with the Solitaire alone; the remaining 83 were treated with a combination of mechanical thrombectomy devices or aspiration thrombectomy followed by or in conjunction with the Solitaire. The most frequent combination was a proximal aspiration/distal access catheter and Solitaire (62/108). In 15/108 procedures, temporary stenting without thrombectomy was performed. Eighty-three successful thrombectomy attempts were performed in the remaining 93 territories. The mean number of Solitaire passes was 2.46 (median 2, max. 12). The mean time from onset to reperfusion was 265 min (range 56–1,031), median 230 min; the mean angio-to-reperfusion time was 47 min (5–186), median 38.5 min. A subanalysis showed a significant reduction of the angio-to-reperfusion time when the Solitaire was used (48.7 vs. 68 min). The rate of final TICI 2b/3 reperfusion was 79% for the anterior and 77.9% for the posterior circulation (TIMI 2/3 for both: 92.5%). During or after the first deployment of the Solitaire, 72.8% showed TIMI 2/3 reperfusion. The mean National Institute of Health Stroke Scale score on admission was 15.3 and decreased by 7.8 points at clinical discharge. The overall mortality at discharge was 16% in the anterior and 47.8% in the posterior circulation group. There were 2 cases of periprocedural intracranial haemorrhage, unrelated to the Solitaire, 6 patients had evidence of subarachnoid haemorrhage, 2 potentially related to the Solitaire deployment. In 4/108 territories, thrombus migration to previously unaffected territories was noted. Vasospasm was seen in 13% of the target vessels. One device was inadvertently detached during retrieval. All these complications had no clinical consequence. Conclusions: Our single-centre experience proves the technical feasibility and safety of the Solitaire for the treatment of acute intracranial vessel occlusion and approves previous reports with smaller patient numbers. Further multicentre studies with a randomized and prospective design will be necessary to verify the results.

Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity

Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results.

Simultaneous Electroencephalographic and Functional Magnetic Resonance Imaging Indicate Impaired Cortical Top–Down Processing in Association with Anesthetic-induced Unconsciousness

Background: In imaging functional connectivity (FC) analyses of the resting brain, alterations of FC during unconsciousness have been reported. These results are in accordance with recent electroencephalographic studies observing impaired top–down processing during anesthesia. In this study, simultaneous records of functional magnetic resonance imaging (fMRI) and electroencephalogram were performed to investigate the causality of neural mechanisms during propofol-induced loss of consciousness by correlating FC in fMRI and directional connectivity (DC) in electroencephalogram. Methods: Resting-state 63-channel electroencephalogram and blood oxygen level–dependent 3-Tesla fMRI of 15 healthy subjects were simultaneously registered during consciousness and propofol-induced loss of consciousness. To indicate DC, electroencephalographic symbolic transfer entropy was applied as a nonlinear measure of mutual interdependencies between underlying physiological processes. The relationship between FC of resting-state networks of the brain (z values) and DC was analyzed by a partial correlation. Results: Independent component analyses of resting-state fMRI showed decreased FC in frontoparietal default networks during unconsciousness, whereas FC in primary sensory networks increased. DC indicated a decline in frontal–parietal (area under the receiver characteristic curve, 0.92; 95% CI, 0.68–1.00) and frontooccipital (0.82; 0.53–1.00) feedback DC (P < 0.05 corrected). The changes of FC in the anterior default network correlated with the changes of DC in frontal–parietal (rpartial = +0.62; P = 0.030) and frontal–occipital (+0.63; 0.048) electroencephalographic electrodes (P < 0.05 corrected). Conclusion: The simultaneous propofol-induced suppression of frontal feedback connectivity in the electroencephalogram and of frontoparietal FC in the fMRI indicates a fundamental role of top–down processing for consciousness.

Increased Intrinsic Brain Activity in the Striatum Reflects Symptom Dimensions in Schizophrenia

Striatal dysfunction is thought to be a fundamental element in schizophrenia. Striatal dopamine dysfunction impacts on reward processing and learning and is present even at rest. Here, we addressed the question whether and how spontaneous neuronal activity in the striatum is altered in schizophrenia. We therefore assessed intrinsic striatal activity and its relation with disorder states and symptom dimensions in patients with schizophrenia. We performed resting-state functional (rs-fMRI) and structural magnetic resonance imaging as well as psychometric assessment in 21 schizophrenic patients during psychosis. On average 9 months later, we acquired follow-up data during psychotic remission and with comparable levels of antipsychotic medication. Twenty-one age- and sex-matched healthy controls were included in the study. Independent component analysis of fMRI data yielded spatial maps and time-courses of coherent ongoing blood-oxygen-level-dependent signal fluctuations, which were used for group comparisons and correlation analyses with scores of the positive and negative syndrome scale. During psychosis, coherent intrinsic activity of the striatum was increased in the dorsal part and correlated with positive symptoms such as delusion and hallucination. In psychotic remission of the same patients, activity of the ventral striatum was increased and correlated with negative symptoms such as emotional withdrawal and blunted affect. Results were controlled for volumetric and medication effects. These data provide first evidence that in schizophrenia intrinsic activity is changed in the striatum and corresponds to disorder states and symptom dimensions.

Spatiotemporal reconfiguration of large-scale brain functional networks during propofol-induced loss of consciousness.

Applying graph theoretical analysis of spontaneous BOLD fluctuations in functional magnetic resonance imaging (fMRI), we investigated whole-brain functional connectivity of 11 healthy volunteers during wakefulness and propofol-induced loss of consciousness (PI-LOC). After extraction of regional fMRI time series from 110 cortical and subcortical regions, we applied a maximum overlap discrete wavelet transformation and investigated changes in the brains intrinsic spatiotemporal organization. During PI-LOC, we observed a breakdown of subcortico-cortical and corticocortical connectivity. Decrease of connectivity was pronounced in thalamocortical connections, whereas no changes were found for connectivity within primary sensory cortices. Graph theoretical analyses revealed significant changes in the degree distribution and local organization metrics of brain functional networks during PI-LOC: compared with a random network, normalized clustering was significantly increased, as was small-worldness. Furthermore we observed a profound decline in long-range connections and a reduction in whole-brain spatiotemporal integration, supporting a topological reconfiguration during PI-LOC. Our findings shed light on the functional significance of intrinsic brain activity as measured by spontaneous BOLD signal fluctuations and help to understand propofol-induced loss of consciousness.