Matthias F. Nitschke

Motor Memory Consolidation in Sleep Shapes More Effective Neuronal Representations

Learning a motor skill involves a latent process of consolidation that develops after training to enhance the skill in the absence of any practice and crucially depends on sleep. Here, we show that this latent consolidation during sleep changes the brain representation of the motor skill by reducing overall the neocortical contributions to the representation. Functional magnetic resonance brain imaging was performed during initial training and 48 h later, at retesting, on a sequential finger movement task with training followed by either a night of regular sleep or sleep deprivation. An additional night of sleep for all subjects served to rule out unspecific effects of sleep loss at retrieval testing. Posttraining sleep, but not sleep deprivation, led to improved motor skill performance at retrieval. This sleep-dependent improvement was linked to greatly reduced brain activation in prefrontal, premotor, and primary motor cortical areas, along with a stronger involvement of left parietal cortical regions. Our findings indicate that storing a motor skill during sleep reorganizes its brain representation toward enhanced efficacy.

Activation of frontoparietal cortices during memorized triple-step sequences of saccadic eye movements: an fMRI study

To determine the cortical areas controlling memory‐guided sequences of saccadic eye movements, we performed functional magnetic resonance imaging (fMRI) in six healthy adults. Subjects had to perform a memorized sequence of three saccades in darkness, after a triple‐step stimulus of successively flashed laser targets. To assess the differential contribution of saccadic subfunctions, we applied several control conditions, such as central fixation with or without triple‐step visual stimulation, self‐paced saccades in darkness, visually guided saccades and single memory‐guided saccades. Triple‐step saccades strongly activated the regions of the frontal eye fields, the adjacent ventral premotor cortex, the supplementary eye fields, the anterior cingulate cortex and several posterior parietal foci in the superior parietal lobule, the precuneus, and the middle and posterior portion of the intraparietal sulcus, the probable location of the human parietal eye field. Comparison with the control conditions showed that the right intraparietal sulcus and parts of the frontal and supplementary eye fields are more involved in the execution of triple‐step saccades than in the other saccade tasks. In accordance with evidence from clinical lesion studies, we propose that the supplementary eye field essentially controls the triggering of memorized saccadic sequences, whereas activation near the middle portion of the right intraparietal sulcus appears to reflect the necessary spatial computations, including the use of extraretinal information (efference copy) about a saccadic eye displacement for updating the spatial representation of the second or third target of the triple‐step sequence.

Cell Entry of Arginine-rich Peptides Is Independent of Endocytosis *□

Arginine-rich peptides are a subclass of cell-penetrating peptides that are taken up by living cells and can be detected freely diffusing inside the cytoplasm and nucleoplasm. This phenomenon has been attributed to either an endocytic mode of uptake and a subsequent release from vesicles or to direct membrane penetration (transduction). To distinguish between both possibilities, we have blocked endocytic pathways suggested to be involved in uptake of cell-penetrating peptides. We have then monitored by confocal microscopy the uptake and distribution of the cell-penetrating transactivator of transcription (TAT) peptide into living mammalian cells over time. To prevent side effects of chemical inhibitors, we used genetically engineered cells as well as different temperature. We found that a knockdown of clathrin-mediated endocytosis and a knock-out of caveolin-mediated endocytosis did not affect the ability of TAT to enter cells. In addition, the TAT peptide showed the same intracellular distribution throughout the cytoplasm and nucleus as in control cells. Even incubation of cells at 4 °C did not abrogate TAT uptake nor change its intracellular distribution. We therefore conclude that this distribution results from TAT peptide that directly penetrated (transduced) the plasma membrane. The formation of nonselective pores is unlikely, because simultaneously added fluorophores were not taken up together with the TAT peptide. In summary, although the frequency and kinetics of TAT transduction varied between cell types, it was independent of endocytosis.

Somatotopy in the human motor cortex hand area. A high-resolution functional MRI study.

Fine‐scale somatotopic encoding in brain areas devoted to sensorimotor processing has recently been questioned by functional neuroimaging studies which suggested its absence within the hand area of the human primary motor cortex. We re‐examined this issue by addressing somatotopy both in terms of functional segregation and of cortical response preference using oxygenation‐sensitive magnetic resonance imaging at high spatial resolution. In a first step, spatial representations of self‐paced isolated finger movements were mapped by using motor rest as a control state. A subsequent experimental design studied the predominance of individual finger movements by using contrasting finger movements as the control task. While the first approach confirmed previous reports of extensive overlap in spatial representations, the second approach revealed foci of differential activation which displayed an orderly mediolateral progression in accordance with the classical cortical motor homunculus. We conclude that somatotopy within the hand area of the primary motor cortex does not present as qualitative functional segregation but as quantitative predominance of certain movement or digit representation embedded in an overall joint hand area.

Different extraretinal neuronal mechanisms of smooth pursuit eye movements in schizophrenia: An fMRI study.

Smooth pursuit eye movements (SPEM) are necessary to follow slowly moving targets while maintaining foveal fixation. In about 50% of schizophrenic patients SPEM velocity is reduced. In this study we were interested in identifying the cortical mechanisms associated with extraretinal processing of SPEM in schizophrenic patients. During condition A, patients and healthy subjects had to pursue a constantly visible target (10 degrees /s). During condition B the target was blanked out for 1000 ms while subjects were instructed to continue SPEM. Eye movement data were assessed during scanning sessions by a limbus tracker. During condition A, reduced SPEM velocity in patients was associated with reduced activation of the right ventral premotor cortex and increased activation of the left dorsolateral prefrontal cortex, the right thalamus and the Crus II of the left cerebellar hemisphere. During condition B, SPEM velocity was reduced to a similar extent in both groups. While in patients a decrease in activation was observed in the right cerebellar area VIIIA, the activation of the right anterior cingulate, the right superior temporal cortex, and the bilateral frontal eye fields was increased. The results implicate that schizophrenic patients employ different strategies during SPEM both with and without target blanking than healthy subjects. These strategies predominantly involve extraretinal mechanisms.

Equine arteritis virus is delivered to an acidic compartment of host cells via clathrin-dependent endocytosis.

Abstract Equine arteritis virus (EAV) is an enveloped, positive-stranded RNA virus belonging to the family Arteriviridae. Infection by EAV requires the release of the viral genome by fusion with the respective target membrane of the host cell. We have investigated the entry pathway of EAV into Baby Hamster Kindey cells (BHK). Infection of cells assessed by the plaque reduction assay was strongly inhibited by substances which interfere with clathrin-dependent endocytosis and by lysosomotropic compounds. Furthermore, infection of BHK cells was suppressed when clathrin-dependent endocytosis was inhibited by expression of antisense RNA of the clathrin-heavy chain before infection. These results strongly suggest that EAV is taken up via clathrin-dependent endocytosis and is delivered to acidic endosomal compartments.

Modulation of cerebellar activation by predictive and non-predictive sequential finger movements.

We investigated the modulation of cerebellar activation by predictive and non-predictive sequential finger movements. It is hypothesized that the prediction of desired movement sequences and adaptation to new movement parameters is mediated by the cerebellum. Using functional MRI at 1.5T, seven normal subjects performed sequential finger to thumb opposition movements, either in predictive (repeatedly 2,3,4,5) or non-predictive (randomized) fashion at a constant frequency of 1 Hz. Performance and error rates were monitored by simultaneous recording of the finger movements. Predictive sequential finger opposition movements activated a cerebellar network including the lobuli IV–VI ipsilateral to the movements, the contralateral lobuli IV–VI, the vermis, and lobuli VIIB–VIII ipsilaterally. Non-predictive compared to predictive finger opposition movements activated a broader area within the ipsi- and contralateral anterior cerebellum, lobuli IV–VI, the vermis, and the ipsilateral lobuli VIIB–VIII. Additional activation foci were found in the contralateral lobuli VIIA and VIIB–VIII. Our study demonstrates a modulated information processing within the cerebellar network dependent on the predictability of movement sequences.

Activation of the Cerebellum by Sensory Finger Stimulation and by Finger Opposition Movements; A Functional Magnetic Resonance Imaging Study

Activation of the ipsilateral anterior lobe of the cerebellum by means of hand movements by humans is a well‐known phenomenon, but the cerebellar encoding of sensory information has not been well established. The authors delineated the representation of sensory stimulation of fingers in the anterior lobe of the cerebellum using functional magnetic resonance imaging sensitized to changes in blood oxygenation and compared these areas to the regions activated by means of finger opposition movements. Activation was determined by means of pixel‐bypixel correlation of the signal intensity time course with a reference waveform equivalent to the stimulus protocol. All subjects showed significant activation of the anterior lobe of the cerebellum, mainly located in the ipsilateral Larsell lobules IV‐V and less consistent in the vermis in relation to sensory finger stimulation. Among some subjects the authors also found activation in the anterior lobe on the contralateral side. The finger movements activated regions that overlapped with the areas activated by sensory finger stimulation but showing a larger and more intense activation pattern.

Bestimmung und Visualisierung von aktivierten Hirnregionen aus fMRT-Daten

Mit der funktionellen Magnetresonanztomographie fMRT kann neuronale Aktivierung des menschlichen Gehirns erfast werden. Zu deren Visualisierung ist die Klassifikation aktivierter und nicht-aktivierter Voxel anhand der. gemessenen zeitlichen Signalverlaufe erforderlich. Hierzu werden verschiedene Merkmalsextraktions- und Segmentierungsverfahren systematisch untersucht, anhand von Simulationsdaten optimiert und schlieslich auf klinische Daten angewendet.

Probabilistische Relaxation zur Segmentierung aktivierter Hirnregionen in fMRT-Daten

Mit der funktionellen Magnetresonanztomographie fMRT kann neuronale Aktivierung des menschlichen Gehirns mit guter zeitlicher und hoher raumlicher Auflosung dargestellt werden. Die Klassifikation aktivierter und nicht-aktivierter Voxel anhand der gemessenen Signalverlaufe erfolgt in dem hier beschriebenen Ansatz in zwei Stufen. Zunachst wird aus den Signalverlaufen mit verteilungsfreien statistischen Verfahren ein Parameterbild berechnet. Anschliesend wird dieses segmentiert, wozu erstmalig der Ansatz der probabilistischen Relaxation erfolgreich verwendet und etablierten Verfahren gegenubergestellt wird. Die Evaluation der Verfahren erfolgt anhand von simulierten und klinischen Daten.