TDP-43 and Cytoskeletal Proteins in ALS Oberstadt, Moritz; Claßen, Joseph; Arendt, Thomas ...
Molecular neurobiology,
04/2018, Volume:
55, Issue:
4
Journal Article
Peer reviewed
Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease and is characterized by a degeneration of motor neurons. Motor neurons are particularly susceptible to ...selective and early degeneration because of their extended axon length and their dependency on the cytoskeleton for its stability, signaling, and axonal transport. The motor neuron cytoskeleton comprises actin filaments, neurofilaments like peripherin, and microtubules. The
Transactivating Response Region
(TAR)
DNA Binding Protein
(TDP-43) forms characteristic cytoplasmic aggregates in motor neurons of ALS patients, and at least in part, the pathogenesis of ALS seems to be driven by toxic pTDP-43 aggregates in cytoplasm, which lead to a diminished axon formation and reduced axon length. Diminished axon formation and reduced axon length suggest an interaction of TDP-43 with the cytoskeleton of motor neurons. TDP-43 interacts with several cytoskeletal components, e.g., the microtubule-associated protein 1B (MAP1B) or the neurofilament light chain (NFL) through direct binding to its RNA. From a clinical perspective, cytoskeletal biomarkers like phosphorylated neurofilament heavy chain (pNFH) and NFL are already clinically used in ALS patients to predict survival, disease progression, and duration. Thus, in this review, we focus on the interaction of TDP-43 with the different cytoskeleton components such as actin filaments, neurofilaments, and microtubules as well as their associated proteins as one aspect in the complex pathogenesis of ALS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The cerebellum and its interaction with cortical areas play a key role in our ability to flexibly adapt a motor program in response to sensory input. Current knowledge about specific neural ...mechanisms underlying the process of visuomotor adaptation is however lacking. Using a novel placement of EEG electrodes to record electric activity from the cerebellum, we studied local cerebellar activity, as well as its coupling with neocortical activity to obtain direct neurophysiological markers of visuomotor adaptation in humans. We found increased theta (4–8 Hz) power in “cerebellar” as well as cortical electrodes, when subjects first encountered a visual manipulation. Theta power decreased as subjects adapted to the perturbation, and rebounded when the manipulation was suddenly removed. This effect was observed in two distinct locations: a cerebellar cluster and a central cluster, which were localized in left cerebellar crus I (lCB) and right supplementary motor area (rSMA) using linear constrained minimum variance beamforming. Importantly, we found that better adaptation was associated with increased theta power in left cerebellar electrodes and a right sensorimotor cortex electrode. Finally, increased rSMA -> lCB connectivity was significantly decreased with adaptation. These results demonstrate that: (1) cerebellar theta power is markedly modulated over the course of visuomotor adaptation and (2) theta oscillations could serve as a key mechanism for communication within a cortico-cerebellar loop.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•TMS primarily targets the gyri at the hemispheric surface due to limited depth penetration.•The direct response to TMS is complex, involving a mixture of neuronal populations.•Myelinated axon ...terminals of pyramidal cells and inhibitory interneurons in the crown of the gyri constitute low-threshold targets for TMS.•Neuronal excitation propagates along axons and across synapses from the primary stimulation site to connected regions in a state-dependent fashion.•TMS always causes substantial peripheral somatosensory and auditory co-stimulation.
Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The neural substrate of bodily ownership can be disclosed by the rubber hand illusion (RHI); namely, the illusory self-attribution of an artificial hand that is induced by synchronous tactile ...stimulation of the subject's hand that is hidden from view. Previous studies have pointed to the premotor cortex (PMC) as a pivotal area in such illusions. To investigate the effective connectivity between – and within – sensory and premotor areas involved in bodily perceptions, we used dynamic causal modeling of touch-evoked responses in 13 healthy subjects. Each subject's right hand was stroked while viewing their own hand (“REAL”), or an artificial hand presented in an anatomically plausible (“CONGRUENT”) or implausible (“INCONGRUENT”) position. Bayesian model comparison revealed strong evidence for a differential involvement of the PMC in the generation of touch-evoked responses under the three conditions, confirming a crucial role of PMC in bodily self-attribution. In brief, the extrinsic (forward) connection from left occipital cortex to left PMC was stronger for CONGRUENT and INCONGRUENT as compared to REAL, reflecting the augmentation of bottom-up visual input when multisensory integration is challenged. Crucially, intrinsic connectivity in the primary somatosensory cortex (S1) was attenuated in the CONGRUENT condition, during the illusory percept. These findings support predictive coding models of the functional architecture of multisensory integration (and attenuation) in bodily perceptual experience.
•The rubber hand illusion (RHI) relies on multisensory integration of contradictory input.•Dynamic causal modeling highlights the role of bottom-up visual input for the RHI.•Intrinsic connectivity in S1 is specifically attenuated during the illusion condition.•Attenuation of proprioceptive input may be a basic prerequisite for the RHI.•The findings are in line with predictive coding models of multisensory integration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Falls are a major cause of morbidity and mortality in neurological disorders. Technical means of detecting falls are of high interest as they enable rapid notification of caregivers and emergency ...services. Such approaches must reliably differentiate between normal daily activities and fall events. A promising technique might be based on the classification of movements based on accelerometer signals by machine-learning algorithms, but the generalizability of classifiers trained on laboratory data to real-world datasets is a common issue. Here, three machine-learning algorithms including Support Vector Machine (SVM), k-Nearest Neighbors (kNN), and Random Forest (RF) were trained to detect fall events. We used a dataset containing intentional falls (SisFall) to train the classifier and validated the approach on a different dataset which included real-world accidental fall events of elderly people (FARSEEING). The results suggested that the linear SVM was the most suitable classifier in this cross-dataset validation approach and reliably distinguished a fall event from normal everyday activity at an accuracy of 93% and similarly high sensitivity and specificity. Thus, classifiers based on linear SVM might be useful for automatic fall detection in real-world applications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Motor skills emerge when practicing individual movements enables the motor system to extract building instructions that facilitate the generation of future diverse movements. Here we asked ...how practicing stereotyped movements for minutes affects motor synergies that encode human motor skills acquired over years of training. Participants trained a kinematically highly constrained combined index-finger and thumb movement. Before and after training, finger movements were evoked at rest by transcranial magnetic stimulation (TMS). Post-training, the angle between posture vectors describing TMS-evoked movements and the training movements temporarily decreased, suggesting the presence of a short-term memory for the trained movement. Principal component analysis was used to identify joint covariance patterns in TMS-evoked movements. The quality of reconstruction of training or grasping movements from linear combinations of a small subset of these TMS-derived synergies was used as an index of neural efficiency of movement generation. The reconstruction quality increased for the trained movement but remained constant for grasping movements. These findings suggest that the motor system rapidly reorganizes to enhance the coding efficiency of a difficult movement without compromising the coding efficiency of overlearned movements. Practice of individual movements may drive an unsupervised bottom-up process that ultimately shapes synergistic neuronal organization by constant competition of action memories.
•Alpha coherence between premotor cortex and cerebellum decreases during learning.•Following 10Hz cerebellar stimulation we found: (1) decreased learning.•(2) Increased alpha power in premotor ...cortex.•(3) Increased alpha coherence between premotor cortex and cerebellum.•Alpha underlies information transfer in premotor-cerebellar loop during learning.
Alpha oscillations (8-13 Hz) have been suggested to play an important role in dynamic neural processes underlying learning and memory. The goal of this study was to scrutinize the role of alpha oscillations in communication within a cortico-cerebellar network implicated in motor sequence learning. To this end, we conducted two EEG experiments using a serial reaction time task. In the first experiment, we explored changes in alpha power and cross-channel alpha coherence as subjects learned a motor sequence. We found a gradual decrease in spectral alpha power over left premotor cortex (PMC) and sensorimotor cortex (SM1) during learning blocks. In addition, alpha coherence between left PMC/SM1 and left cerebellar crus I was specifically decreased during sequence learning, possibly reflecting a functional decoupling in the broader motor learning network. In the second experiment in a different cohort, we applied 10Hz transcranial alternating current stimulation (tACS), a method shown to entrain local oscillatory activity, to left M1 (lM1) and right cerebellum (rCB) during sequence learning. We observed a tendency for diminished learning following rCB tACS compared to sham, but not following lM1 tACS. Learning-related alpha power following rCB tACS was increased in left PMC, possibly reflecting increase in local inhibitory neural activity. Importantly, learning-specific alpha coherence between left PMC and right cerebellar lobule VIIb was enhanced following rCB tACS. These findings provide strong evidence for a causal role of alpha oscillations in controlling information transfer in a premotor-cerebellar loop during motor sequence learning. Our findings are consistent with a model in which sequence learning may be impaired by enhancing premotor cortical alpha oscillation via external modulation of cerebellar oscillations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The feeling of body-ownership can be experimentally manipulated using the rubber hand illusion (RHI) paradigm. Participants experience a sense of ownership over an artificial hand when their hidden ...real hand and the visible artificial hand are synchronously stroked. Using lesion masks and behavioral data from a previous study on RHI failure in acute stroke patients, we here employed lesion network-symptom-mapping (LNSM) based on normative functional connectome data to identify lesion-dependent network connectivity related to the experience of self-attribution of an artificial hand in the RHI paradigm. We found that failure to experience the RHI was associated with higher normative lesion-dependent network connectivity to the right temporoparietal junction (rTPJ), right anterior Insula (raI) and right inferior frontal gyrus (rIFG). Since these areas were spared by the infarction in most patients with RHI failure (89% for rTPJ and 94% for raI/rIFG), the analysis suggests that remote dysfunction in rTPJ, raI, and rIFG accounted for RHI failure. These results highlight the potential role of rTPJ, raI, and rIFG in bodily self-consciousness. LNSM is a powerful tool capable of delineating the architecture of functional networks underlying complex cognitive function.
•Normative functional connectome data can be utilized to indirectly map networks affected by focal brain lesions.•Using this method, connections to several cortical regions were associated with failure to induce the rubber hand illusion.•These regions included the right temporoparietal junction, inferior frontal gyrus and anterior insula.•This highlights the potential role of these regions in bodily self-consciousness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The rubber hand illusion (RHI) paradigm—in which illusory bodily ownership is induced by synchronous tactile stimulation of a participant's (hidden) hand and a (visible) surrogate—allows one to ...investigate how the brain resolves conflicting multisensory evidence during perceptual inference. To identify the functional anatomy of the RHI, we used multichannel EEG, acquired under three conditions of tactile stimulation. Evoked potentials were averaged from EEG signals registered to the timing of brushstrokes to the participant's hand. The participant's hand was stroked either in the absence of an artificial hand (REAL) or synchronously with an artificial hand, which either lay in an anatomically plausible (CONGRUENT) or impossible (INCONGRUENT) position. The illusion was reliably elicited in the CONGRUENT condition. For right-hand stimulation, significant differences between conditions emerged at the sensor level around 55 msec after the brushstroke at left frontal and right parietal electrodes. Response amplitudes were smaller for illusory (CONGRUENT) compared with nonillusory (INCONGRUENT and REAL) conditions in the contralateral perirolandic region (pre- and postcentral gyri), superior and inferior parietal lobule, whereas veridical perception of the artificial hand (INCONGRUENT) amplified responses at a scalp region overlying the contralateral postcentral gyrus and inferior parietal lobule compared with the remaining two conditions. Left-hand stimulation produced similar contralateral patterns. These results are consistent with predictive coding models of multisensory integration and may reflect the attenuation of somatosensory precision that is required to resolve perceptual hypotheses about conflicting multisensory input.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • We review investigations of whether tDCS can facilitate motor skill learning and adaptation. • We identify several caveats in the existing literature and propose solutions for addressing ...these. • Open Science efforts will improve standardization, reproducibility and quality of future research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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