Max Planck Institute for Neurological Research
Max Planck Institute for Neurological Research
Zempel H.,German Center for Neurodegenerative Diseases |
Mandelkow E.,German Center for Neurodegenerative Diseases |
Mandelkow E.,Max Planck Institute for Neurological Research
Trends in Neurosciences | Year: 2014
Tau is a microtubule-associated-protein that is sorted into neuronal axons in physiological conditions. In Alzheimer disease (AD) and other tauopathies, Tau sorting mechanisms fail and Tau becomes missorted into the somatodendritic compartment. In AD, aberrant amyloid-β (Aβ) production might trigger Tau missorting. The physiological axonal sorting of Tau depends on the developmental stage of the neuron, the phosphorylation state of Tau and the microtubule cytoskeleton. Disease-associated missorting of Tau is connected to increased phosphorylation and aggregation of Tau, and impaired microtubule interactions. Disease-causing mechanisms involve impaired transport, aberrant kinase activation, non-physiological interactions of Tau, and prion-like spreading. In this review we focus on the physiological and pathological (mis)sorting of Tau, the underlying mechanisms, and effects in disease. © 2014 Elsevier Ltd.
Knosche T.R.,Max Planck Institute for Human Cognitive and Brain Sciences |
Tittgemeyer M.,Max Planck Institute for Neurological Research
Frontiers in Systems Neuroscience | Year: 2011
This review focuses on the role of long-range connectivity as one element of brain structure that is of key importance for the functional-anatomical organization of the cortex. In this context, we discuss the putative guiding principles for mapping brain function and structure onto the cortical surface. Such mappings reveal a high degree of functional-anatomical segregation. Given that brain regions frequently maintain characteristic connectivity profiles and the functional repertoire of a cortical area is closely related to its anatomical connections, long-range connectivity may be used to define segregated cortical areas. This methodology is called connectivity-based parcellation. Within this framework, we investigate different techniques to estimate connectivity profiles with emphasis given to non-invasive methods based on diffusion magnetic resonance imaging (dMRI) and diffusion tractography. Cortical parcellation is then defined based on similarity between diffusion tractograms, and different clustering approaches are discussed. We conclude that the use of non-invasively acquired connectivity estimates to characterize the functional-anatomical organization of the brain is a valid, relevant, and necessary endeavor. Current and future developments in dMRI technology, tractography algorithms, and models of the similarity structure hold great potential for a substantial improvement and enrichment of the results of the technique. © 2011 Knösche and Tittgemeyer.
Adamczak J.,Max Planck Institute for Neurological Research
Progress in Brain Research | Year: 2012
The therapeutic potential of stem cells for regeneration after cerebral lesion has become of great interest. This is particularly so for neurodegenerative diseases as well as for stroke. Contrary to more conventional, cerebroprotective treatment approaches, the focus of regeneration lies in a longer time window during the chronic phase of the lesion evolution. Thus, in order to assess the true potential of a treatment strategy and to investigate the underlying mechanisms, observation of the temporal profile of both the cell dynamics as well as the organ response to the treatment is of paramount importance. This need for intraindividual longitudinal studies can be optimally met by the application of noninvasive imaging modalities. This chapter presents in breadth the potential of noninvasive imaging modalities for cell tracking with application focus to experimental stroke. While the lion's share of discussed studies is based on MRI, we have also included the contributions of positron emission tomography and of the increasingly important optical imaging modality. © 2012 Elsevier B.V.
Wurm M.F.,Max Planck Institute for Neurological Research |
Schubotz R.I.,University of Munster
NeuroImage | Year: 2012
Most every day actions take place in domestic rooms that are specific for certain classes of actions. Contextual information derived from domestic settings may therefore influence the efficiency of action recognition. The present studies investigated whether action recognition is modulated by compatibility of the context an action is embedded in. To this end, subjects watched video clips of actions performed in compatible, incompatible, and neutral contexts. Recognition was significantly slower when actions took place in an incompatible as compared to a compatible or a neutral context (Experiment 1). Functional MRI revealed increased activation for incompatible context in Brodmann Areas (BA) 44, 45, and 47 of the left ventrolateral prefrontal cortex (vlPFC; Experiment 2). Results suggest that contextual information - even when task-irrelevant - informs a high processing level of action analysis. In particular, the functional profiles assigned to these prefrontal regions suggest that contextual information activates associated action representations as a function of (in-)compatibility. Thus, incompatibility effects may reflect the attempt to resolve the conflict between action and context by embedding the presented action step into an overarching action that is again compatible with the provided context. © 2011 Elsevier Inc.
Heiss W.-D.,Max Planck Institute for Neurological Research
European Journal of Neurology | Year: 2012
Advances in resuscitation and critical care management have resulted in the survival of many patients despite severe brain damage. These patients may remain in coma or in vegetative state. The probability of recovery of conscious function is dependent on the extent of structural brain damage, which is difficult to assess by clinical, laboratory or functional tests. Positron emission tomography (PET) of 18F-fluordeoxyglucose (FDG) can be used to investigate metabolic and functional impairment of the brain. In acute vegetative state (AVS, duration<1month), overall glucose utilization was significantly reduced in comparison with age-matched controls. In a few cases with locked-in syndrome, cortical metabolism was in the normal range. 11C-Flumazenil (FMZ) measures the density of benzodiazepine receptors (BZRs) and thereby furnishes an estimate of neuronal integrity. PET with this tracer demonstrated a considerable reduction in BZRs in cortical areas, but indicated that the cerebellum was spared from neuronal loss. The comparison of FDG- and FMZ-PET findings in AVS demonstrates that alterations of cerebral glucose consumption do not represent mere functional inactivation, but also irreversible structural damage. In some cases with minimally conscious state, auditory stimuli with emotional valence induced more brain activation (investigated by H215O-PET) than meaningless noise; such studies can be used to detect residual cortical function. To improve prognostication of chances for recovery, a combination of functional activation studies and assessment of the extent of neuronal damage might be the optimal procedure and should be tested in larger cohorts of patients with comatose states of different severity. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.
Heiss W.-D.,Max Planck Institute for Neurological Research
Annals of the New York Academy of Sciences | Year: 2012
An ischemic penumbra has the potential for functional recovery provided that local blood flow can be reestablished, but irreversible damage will develop without sufficient reperfusion, depending on the interaction of severity and duration of ischemia. With acute flows below the threshold required for maintenance of basic housekeeping, injury in the core is established within a few minutes. During the subacute phase, the irreversible damage expands into the penumbra: multiple electrical and biological signals are triggered by periinfarct, spreading depression-like depolarizations leading to hypoxia and stepwise increase in lactate. Usually within 6 to 8 hours, all the penumbra are converted into irreversible infarcts. In a delayed phase, secondary phenomena may cause additional tissue damage: disruption of the tight junctions results in vasogenic edema, leading to increase of water content and damage expansion. Neutrophils and cytokinins cause secondary inflammation, inducing further damage in periinfarct regions and connecting fiber tracts. Multimodal imaging might be able to differentiate among the tissue compartments affected by acute, subacute, or delayed ischemic damage, and thereby might provide the basis for phase-specific treatment strategies. © 2012 New York Academy of Sciences.
Wessel J.R.,University of California at San Diego |
Wessel J.R.,Max Planck Institute for Neurological Research
Frontiers in Human Neuroscience | Year: 2012
From its discovery in the early 1990s until this day, the error-related negativity (ERN) remains the most widely investigated electrophysiological index of cortical error processing. When researchers began addressing the electrophysiology of subjective error awareness more than a decade ago, the role of the ERN, alongside the subsequently occurring error positivity (Pe), was an obvious locus of attention. However, the first two studies explicitly addressing the role of error-related event-related brain potentials (ERPs) would already set the tone for what still remains a controversy today: in contrast to the clear-cut findings that link the amplitude of the Pe to error awareness, the association between ERN amplitude and error awareness is vastly unclear. An initial study reported significant differences in ERN amplitude with respect to subjective error awareness, whereas the second failed to report this result, leading to a myriad of follow-up studies that seemed to back up or contradict either view. Here, I review those studies that explicitly dealt with the role of the error-related ERPs in subjective error awareness, and try to explain the differences in reported effects of error awareness on ERN amplitude. From the point of view presented here, different findings between studies can be explained by disparities in experimental design and data analysis, specifically with respect to the quantification of subjective error awareness. Based on the review of these results, I will then try to embed the error-related negativity into a widely known model of the implementation of access consciousness in the brain, the global neuronal workspace (GNW) model, and speculate as the ERN's potential role in such a framework. At last, I will outline future challenges in the investigation of the cortical electrophysiology of error awareness, and offer some suggestions on how they could potentially be addressed. © 2012 Wessel.
Hossmann K.-A.,Max Planck Institute for Neurological Research
Journal of Cerebral Blood Flow and Metabolism | Year: 2012
Brain injury after focal ischemia evolves along two basically different pathophysiologies, depending on the severity of the primary flow reduction and the dynamics of postischemic recirculation. In permanent and gradually reversed focal ischemia as after thromboembolic occlusion, primary core injury is irreversible but the expansion of the core into the penumbra can be alleviated by hemodynamic and molecular interventions. Such alleviation can only be achieved within 3 hours after the onset of ischemia because untreated core injury expands to near maximum size during this interval. In promptly reversed transient ischemia as after mechanical vascular occlusion, primary core injury may recover but a secondary delayed injury evolves after a free interval of as long as 6 to 12 hours. This injury can be alleviated throughout the free interval but the longer window is without clinical relevance because transient mechanical vascular occlusion is not a model of naturally occurring stroke. As this difference is widely ignored in stroke research, most clinical trials have been designed with a far too long therapeutic window, which explains their failure. Transient mechanical vascular occlusion models should, therefore, be eliminated from the repertoire of preclinical stroke research. © 2012 ISCBFM All rights reserved.
Ullsperger M.,Max Planck Institute for Neurological Research
Brain structure & function | Year: 2010
To detect erroneous action outcomes is necessary for flexible adjustments and therefore a prerequisite of adaptive, goal-directed behavior. While performance monitoring has been studied intensively over two decades and a vast amount of knowledge on its functional neuroanatomy has been gathered, much less is known about conscious error perception, often referred to as error awareness. Here, we review and discuss the conditions under which error awareness occurs, its neural correlates and underlying functional neuroanatomy. We focus specifically on the anterior insula, which has been shown to be (a) reliably activated during performance monitoring and (b) modulated by error awareness. Anterior insular activity appears to be closely related to autonomic responses associated with consciously perceived errors, although the causality and directions of these relationships still needs to be unraveled. We discuss the role of the anterior insula in generating versus perceiving autonomic responses and as a key player in balancing effortful task-related and resting-state activity. We suggest that errors elicit reactions highly reminiscent of an orienting response and may thus induce the autonomic arousal needed to recruit the required mental and physical resources. We discuss the role of norepinephrine activity in eliciting sufficiently strong central and autonomic nervous responses enabling the necessary adaptation as well as conscious error perception.
Heiss W.-D.,Max Planck Institute for Neurological Research
Cerebrovascular Diseases | Year: 2011
The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed 'penumbra', and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. However, in further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and duration of critically reduced blood flow was established - proving that the lower the flow, the shorter the time for efficient reperfusion. Therefore, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The propagation of irreversible tissue damage is characterized by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusional disturbances. Waves of depolarizations, the peri-infarct spreading depression-like depolarizations, inducing activation of ion pumps and liberation of excitatory transmitters, have dramatic consequences as drastically increased metabolic demand cannot be satisfied in regions with critically reduced blood supply. The translation of experimental concept into the basis for efficient treatment of stroke requires non-invasive methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue that can benefit from therapeutic interventions. Positron emission tomography (PET) allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction. From these variables, clear definitions of irreversible tissue damage and critically perfused but potentially salvageable tissue (i.e. the penumbra) can be achieved in animal models and stroke patients. Additionally, further tracers can be used for early detection of irreversible tissue damage, e.g. by the central benzodiazepine receptor ligand flumazenil. However, PET is a research tool and its complex logistics limit clinical routine applications. As a widely applicable clinical tool,perfusion/diffusion-weighted (PW/DW) MRI is used, and the 'mismatch' between the PW and the DW abnormalities serve as an indicator of the penumbra. However, comparative studies of PW/DW-MRI and PET have pointed to an overestimation of the core of irreversible infarction as well as of the penumbra by MRI modalities. Some of these discrepancies can be explained by unselective application of relative perfusionthresholds, which might be improved by more complex analytical procedures. Heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of PW/DW-MRI for the selection of patients for clinical trials. As long as a validation of the mismatch selection paradigm is lacking, its use as a surrogate marker of outcome is limited. Copyright © 2011 S. Karger AG, Basel.