Disentangling motor planning and motor execution in unmedicated de novo Parkinson's disease patients: An fMRI study.

Many studies have used functional magnetic resonance imaging to unravel the neuronal underpinnings of motor system abnormalities in Parkinson's disease, indicating functional inhibition at the level of basal ganglia-thalamo-cortical motor networks. The study aim was to extend the characterization of functional motor changes in Parkinson's Disease by dissociating between two phases of action (i.e. motor planning and motor execution) during an automated unilateral finger movement sequence with the left and right hand, separately. In essence, we wished to identify neuronal dysfunction and potential neuronal compensation before (planning) and during (execution) automated sequential motor behavior in unmedicated early stage Parkinson's Disease patients. Twenty-two Parkinson's Disease patients (14 males; 53 ±â€¯11 years; Hoehn and Yahr score 1.4 ±â€¯0.6; UPDRS (part 3) motor score 16 ±â€¯6) and 22 healthy controls (14 males; 49 ±â€¯12 years) performed a pre-learnt four finger sequence (index, ring, middle and little finger, in order), either self-initiated (FREE) or externally triggered (REACT), within an 8-second time window. Findings were most pronounced during FREE with the clinically most affected side, where motor execution revealed significant underactivity of contralateral primary motor cortex, contralateral posterior putamen (sensorimotor territory), ipsilateral anterior cerebellum / cerebellar vermis, along with underactivity in supplementary motor area (based on ROI analyses only), corroborating previous findings in Parkinson's Disease. During motor planning, Parkinson's Disease patients showed a significant relative overactivity in dorsolateral prefrontal cortex (DLPFC), suggesting a compensatory overactivity. To a variable extent this relative overactivity in the DLPFC went along with a relative overactivity in the precuneus and the ipsilateral anterior cerebellum/cerebellar vermis Our study illustrates that a refined view of disturbances in motor function and compensatory processes can be gained from experimental designs that try to dissociate motor planning from motor execution, emphasizing that compensatory mechanisms are triggered in Parkinson's Disease when voluntary movements are conceptualized for action.

Management of Barrett esophagus: a practical guide for clinicians based on the BADCAT and BoB CAT recommendations.

We undertook two of the largest evidence-based reviews in clinical medicine to assess the rationale for the management of gastroesophageal reflux disease, Barrett esophagus (BE), dysplasia, and early invasive esophageal adenocarcinoma. These reviews involved over 150 world experts in 4 continents, and over 20 000 papers were assessed. Quality assessment of the publications was made using Grading of Recommendations Assessment, Development and Evaluation, and of over 240 questions formulated, we were able to answer 30% with an agreement of at least 80%. We agreed on a unique global definition of BE meaning that the presence both of hiatus hernia endoscopically and of intestinal metaplasia histologically should be noted. In addition, we devised an escalation and deescalation pathway for the management of esophagitis, metaplasia, dysplasia, and adenocarcinoma sequence. Endoscopic resection (ER) is recommended for visible mucosal lesions. Moreover, we endorsed the early use of ablation therapy for persistent dysplasia of any degree. In this regard, ER may be both diagnostic and therapeutic and may be sufficient even in early mucosal lesions (T1m). In conclusion, fewer people should be surveyed but those that do will require more detailed mapping and endoscopic interventions than currently. In addition, patients accumulating other potentially life-threaten-ing comorbidities should be offered cessation of surveillance. In the future, chemoprevention may be the game-changing solution but results from large randomized trials, including AspECT and BOSS, are awaited.

Abnormal movement preparation in task-specific focal hand dystonia.

Electrophysiological and behavioral studies in primary dystonia suggest abnormalities during movement preparation, but this crucial phase preceding movement onset has not yet been studied specifically with functional magnetic resonance imaging (fMRI). To identify abnormalities in brain activation during movement preparation, we used event-related fMRI to analyze behaviorally unimpaired sequential finger movements in 18 patients with task-specific focal hand dystonia (FHD) and 18 healthy subjects. Patients and controls executed self-initiated or externally cued prelearnt four-digit sequential movements using either right or left hands. In FHD patients, motor performance of the sequential finger task was not associated with task-related dystonic posturing and their activation levels during motor execution were highly comparable with controls. On the other hand reduced activation was observed during movement preparation in the FHD patients in left premotor cortex / precentral gyrus for all conditions, and for self-initiation additionally in supplementary motor area, left mid-insula and anterior putamen, independent of effector side. Findings argue for abnormalities of early stages of motor control in FHD, manifesting during movement preparation. Since deficits map to regions involved in the coding of motor programs, we propose that task-specific dystonia is characterized by abnormalities during recruitment of motor programs: these do not manifest at the behavioral level during simple automated movements, however, errors in motor programs of complex movements established by extensive practice (a core feature of FHD), trigger the inappropriate movement patterns observed in task-specific dystonia.

An fMRI study on the acute effects of exercise on pain processing in trained athletes.

Endurance exercise is known to promote sustained antinociceptive effects, and there is evidence that the reduction of pain perception mediated by exercise is driven by central opioidergic neurotransmission. To directly investigate the involved brain areas and the underlying neural mechanisms in humans, thermal heat-pain challenges were applied to 20 athletes during 4 separate functional magnetic resonance imaging (fMRI) scans, i.e., before and after 2 hours of running (exercise condition) and walking (control condition), respectively. Imaging revealed a reproducible pattern of distributed pain-related activation in all 4 conditions, including the mesial and lateral pain systems, and the periaqueductal gray (PAG) as a key region of the descending antinociceptive pathway. At the behavioral level, running as compared with walking decreased affective pain ratings. The influence of exercise on pain-related activation was reflected in a significant time × treatment interaction in the PAG, along with similar trends in the pregenual anterior cingulate cortex and the middle insular cortex, where pain-induced activation levels were elevated after walking, but decreased or unchanged after running. Our findings indicate that enhanced reactive recruitment of endogenous antinociceptive mechanisms after aversive repeated pain exposure is attenuated by exercise. The fact that running, but not walking, reproducibly elevated ß-endorphin levels in plasma indicates involvement of the opioidergic system in exercise. This may argue for an elevated opioidergic tone in the brain of athletes, mediating antinociceptive mechanisms. Our findings provide the first evidence using functional imaging to support the role of endurance exercise in pain modulation.

Cell death as a regulator of cerebellar histogenesis and compartmentation.

Programmed cell death is essential for the homeostasis of tissues and organs. During the development of the central nervous system, programmed cell death is highly regulated and restricted to distinct developmental time points of histogenesis. In this review, we will summarize recent data on the temporal and spatial distribution of programmed Purkinje cell death within the cerebellar cortex. We point out that programmed cell death within distinct regions of the developing cerebellar cortex differs by type and its cellular consequences. We submit the concept that local Purkinje cell death is important for late compartmentation of the cerebellar cortex and its wiring. To support this hypothesis, we provide new data obtained from a cerebellar mutant with prolonged expression of Engrailed-2 specifically in cerebellar Purkinje cells which shows increased local physiological cell death and concomitant changes in the pattern of afferent innervation.

Advocating neuroimaging studies of transmitter release in human physical exercise challenges studies.

This perspective attempts to outline the emerging role of positron emission tomography (PET) ligand activation studies in human exercise research. By focusing on the endorphinergic system and its acclaimed role for exercise-induced antinociception and mood enhancement, we like to emphasize the unique potential of ligand PET applied to human athletes for uncovering the neurochemistry of exercise-induced psychophysiological phenomena. Compared with conventional approaches, in particular quantification of plasma beta-endorphin levels under exercise challenges, which are reviewed in this article, studying opioidergic effects directly in the central nervous system (CNS) with PET and relating opioidergic binding changes to neuropsychological assessments, provides a more refined and promising experimental strategy. Although a vast literature dating back to the 1980s of the last century has been able to reproducibly demonstrate peripheral increases of beta-endorphin levels after various exercise challenges, so far, these studies have failed to establish robust links between peripheral beta-endorphin levels and centrally mediated behavioral effects, ie, modulation of mood and/or pain perception. As the quantitative relation between endorphins in the peripheral blood and the CNS remains unknown, the question arises, to what extent conventional blood-based methods can inform researchers about central neurotransmitter effects. As previous studies using receptor blocking approaches have also revealed equivocal results regarding exercise effects on pain and mood processing, it is expected that PET and other functional neuroimaging applications in athletes may in future help uncover some of the hitherto unknown links between neurotransmission and psychophysiological effects related to physical exercise.

Physiological purkinje cell death is spatiotemporally organized in the developing mouse cerebellum.

Physiological cell death is crucial for matching defined cellular populations within the central nervous system. Whereas the time course of developmental cell death in the central nervous system is well analyzed, information about its precise spatial patterning is scarce. Yet, the latter one is needed to appraise its contribution to circuit formation and refinement. Here, we document that during normal cerebellar development, dying Purkinje cells were highly localized within the vermal midline and in a lobule specific, parasagittal pattern along the whole mediolateral axis. In addition, single hot spots of cell death localized to the caudal declive and ventral lobule IX within the posterolateral fissure. These hot spots of dying Purkinje cells partly overlapped with gaps within the Purkinje cell layer which supports the classification of different gaps based on histological and molecular criteria, i.e., midline gap, patchy gaps, and raphes. Areas characterized by a high incidence of Purkinje cell death and gaps colocalize with known molecular and functional boundaries within the cerebellar cortex. Physiological cell death can thus be considered to serve as an important regulator of cerebellar histogenesis.

Functional magnetic resonance imaging of the sensorimotor system in preterm infants.

OBJECTIVE: Preterm birth at <32 weeks' gestational age has a specific predilection for periventricular white matter injury. Early prediction of concomitant motor sequelae is a fundamental clinical issue. Recently, functional MRI was introduced as a noninvasive method for investigating the functional integrity of the neonatal brain. We aimed at implementing a unilateral passive forearm extension/flexion functional MRI paradigm in a routine clinical MRI setup to allow noninvasive mapping of the sensorimotor system in preterm infants and to relate the functional data to structural and behavioral data. PATIENTS AND METHODS: Eight patients (median gestational age: 26.5 weeks; median birth weight: 885 g) were included. The functional MRI was performed at term-equivalent age (median: 39 weeks' postconceptional age) under chloral hydrate (50 mg/kg) sedation. In 5 of 8 patients, functional MRI data acquisition was successful. This resulted in 10 functional data sets (5 for passive stimulation of each forearm). RESULTS: Unilateral stimulation was associated with mainly bilateral activation of the primary sensorimotor cortex (n = 7 of 10 data sets), the prevailing hemodynamic response being a negative blood oxygenation level-dependent signal. Positive blood oxygenation level-dependent response or failure to activate the sensorimotor cortex (n = 3 of 10 data sets) were seen in those patients with aberrant structural/behavioral indices. CONCLUSIONS: Our data show the feasibility of passive unilateral sensorimotor stimulation during neonatal clinical MRI protocols. The bilateral activation pattern observed at this age is compatible with a bilaterally distributed sensorimotor system. Our data validate initial accounts for a raised incidence of negative blood oxygenation level-dependent responses in the primary sensorimotor cortex at this developmental stage. The negative blood oxygenation level-dependent response is likely to reflect a reduction of the oxy/deoxy-hemoglobin ratio during a maturational stage characterized by rapid formation of synapses, yet ineffective processing. Positive blood oxygenation level-dependent responses or failure to activate the sensorimotor cortex may be an early indicator of abnormal development and will have to be followed up carefully.

Engrailed-2 regulates genes related to vesicle formation and transport in cerebellar Purkinje cells.

Engrailed transcription factors regulate survival, cell fate decisions and axon pathfinding in central neurons. En-2 can also attenuate Purkinje cell (PC) maturation. Here, we use array analysis to scrutinize gene expression in developing PCs overexpressing Engrailed-2 (L7En-2). The majority (70%) of regulated genes was found down-regulated in L7En-2 cerebella, consistent with the known repressive function of Engrailed-2. Differential gene expression, verified by in situ hybridization or Western blotting, was particularly evident during the first postnatal week, when L7En-2 PCs display conspicuous deficits in dendritogenesis. Functional classification revealed clusters of genes linked to vesicle formation and transport. Consistently, Golgi stacks located at the axonal pole of wild type PC somata were rarely detected in L7En-2 PCs. In addition, long continuous stretches of endoplasmic reticulum typically found around the axonal pole of wild type PCs were less frequently observed in transgenic cells. Engrailed-2 might therefore orchestrate PC survival and process formation as a regulator of subcellular organization.

Hyaluronan is organized into fiber-like structures along migratory pathways in the developing mouse cerebellum.

Hyaluronan is a free glycosaminoglycan which is abundant in the extracellular matrix of the developing brain. Although not covalently linked to any protein it can act as a backbone molecule forming aggregates with chondroitin sulfate proteoglycans of the lectican family and link proteins. Using neurocan-GFP as a direct histochemical probe we analyzed the distribution and organization of hyaluronan in the developing mouse cerebellum, and related its fine structure to cell types of specified developmental stages. We observed a high affinity of this probe to fiber-like structures in the prospective white matter which are preferentially oriented parallel to the cerebellar cortex during postnatal development suggesting a specially organized form of hyaluronan. In other layers of the cerebellar cortex, the hyaluronan organization seemed to be more diffuse. During the second postnatal week, the overall staining intensity of hyaluronan in the white matter declined but fiber-like structures were still present at the adult stage. This type of hyaluronan organization is different from perineuronal nets e.g. found in deep cerebellar nuclei. Double staining experiments with cell type specific markers indicated that these fiber-like structures are predominantly situated in regions where motile cells such as Pax2-positive inhibitory interneuron precursors and MBP-positive oligodendroglial cells are located. In contrast, more stationary cells such as mature granule cells and Purkinje cells are associated with lower levels of hyaluronan in their environment. Thus, hyaluronan-rich fibers are concentrated at sites where specific neural precursor cell types migrate, and the anisotropic orientation of these fibers suggests that they may support guided neural migration during brain development.

Tetraspanin-5 (Tm4sf9) mRNA expression parallels neuronal maturation in the cerebellum of normal and L7En-2 transgenic mice.

Tetraspanin-5 (Tspan-5) mRNA was recently shown to be strongly expressed within the central nervous system. In order to address Tspan-5 function during nervous system development, we performed a detailed expression analysis in the postnatal FVB/N mouse cerebellum using in situ hybridizations. Tspan-5 mRNA was expressed within cerebellar Purkinje cells (PCs) throughout postnatal development. The expression level, however, changed significantly with ongoing development. At the day of birth (P0), Tspan-5 mRNA was expressed at very low levels in PCs. At this time, PCs of the FVB/N strain are postmitotic and bear axons, but no dendrites. At P7, Tspan-5 mRNA expression was visible in all PCs, but was more prominent in those of the posterior lobules as compared to those of the anterior lobules. After P7, high levels of Tspan-5 mRNA were seen in all PCs, which is when PCs elaborate and maintain their typical dendritic tree. This demonstrates that the level of Tspan-5 mRNA is related to the developmental status of PCs. Consistently, expression of Tspan-5 mRNA was specifically reduced in PCs of L7En-2 animals, which display a delay in PC maturation during postnatal cerebellar development. In addition, whereas no Tspan-5 mRNA signal could be detected in the proliferating granule cell layer, low levels could be found in postmitotic, premigratory granule cells and high levels in settled and differentiated granule cells. Thus, the level of Tspan-5 mRNA expression correlates very well with the differentiation status of particular neurons. The level of Tspan-5 expression might therefore be important for distinct phases of neuronal maturation.

Characterization of the neuronal marker NeuN as a multiply phosphorylated antigen with discrete subcellular localization.

NeuN (neuronal nuclei) is an antigen used widely in research and diagnostics to identify postmitotic neurons. The present study aims at an initial understanding of the molecular nature and functional significance of this as yet ill-defined antigen. Using isoelectric focusing, both the 46- and 48-kDa isoforms of NeuN can be separated in multiple spots spanning a pH range of 8-10.5, suggesting that they might be phosphorylated. Enzymatic dephosphorylation abolishes NeuN immunoreactivity, confirming that NeuN is indeed a phosphoprotein, and establishing that binding of the defining antibody depends on its state of phosphorylation. Combined biochemical and immunohistochemical analysis show that both the 46- and the 48-kDa NeuN isoforms can be localized to the cell nucleus as well as in the neuronal cytoplasm. Their relative concentration in these compartments is distinct, however, with the 48-kDa isoform being the predominant isoform in the cytoplasm. Within the nucleus, NeuN is found preferentially in areas of low chromatin density and virtually excluded from areas containing densely packed DNA. The present identification of multiple differentially phosphorylated isoforms of NeuN, together with recent reports on the dependence of NeuN immunoreactivity levels on a variety of physiologic or pathologic signals, suggests a previously unappreciated level of complexity in the regulation of this enigmatic, neuron-specific antigen.

Engrailed-2 negatively regulates the onset of perinatal Purkinje cell differentiation.

The transcription factor Engrailed-2 is expressed in cerebellar Purkinje cells (PCs) throughout embryonic development but is downregulated in PCs after birth. Since the onset of PC differentiation coincides with this change of gene expression, we asked whether downregulation of Engrailed-2 is necessary for proper timing of PC differentiation. To investigate this, we used an L7En-2 transgenic mouse model in which Engrailed-2 expression in PCs is maintained beyond the day of birth. In these L7En-2 mice the onset of parvalbumin expression was delayed in all PCs by about 3 days; the spatial expression pattern, however, remained comparable to wildtype cerebella. Furthermore, parvalbumin expression resembled the known pattern of normal PC maturation, suggesting a direct link between parvalbumin expression and PC differentiation. Consistent with a delay of PC differentiation, we found that PCs of L7En-2 cerebella displayed a reduced tendency to align in the typical monolayer. The average size of L7En-2 PCs was reduced and the dendritic arbor developed more slowly than in wildtype PCs. In contrast, major morphological features of PCs were comparable in L7En-2 and wildtype cerebella after postnatal day 11. In addition, we observed a transient reduction of PC survival in organotypic slice cultures of L7En-2 cerebella in comparison with wildtype slice cultures. Since PC survival parallels PC differentiation in vitro, we propose that the observed delay in PC differentiation upon Engrailed-2 overexpression is an intrinsic property of Engrailed-2 activity, and that downregulation of Engrailed-2 in wildtype PCs around the day of birth is critical for the timing of distinct steps of PC differentiation.