Beng Ti Ang

F3/Contactin Acts as a Functional Ligand for Notch during Oligodendrocyte Maturation

Axon-derived molecules are temporally and spatially required as positive or negative signals to coordinate oligodendrocyte differentiation. Increasing evidence suggests that, in addition to the inhibitory Jagged1/Notch1 signaling cascade, other pathways act via Notch to mediate oligodendrocyte differentiation. The GPI-linked neural cell recognition molecule F3/contactin is clustered during development at the paranodal region, a vital site for axoglial interaction. Here, we show that F3/contactin acts as a functional ligand of Notch. This trans-extracellular interaction triggers gamma-secretase-dependent nuclear translocation of the Notch intracellular domain. F3/Notch signaling promotes oligodendrocyte precursor cell differentiation and upregulates the myelin-related protein MAG in OLN-93 cells. This can be blocked by dominant negative Notch1, Notch2, and two Deltex1 mutants lacking the RING-H2 finger motif, but not by dominant-negative RBP-J or Hes1 antisense oligonucleotides. Expression of constitutively active Notch1 or Notch2 does not upregulate MAG. Thus, F3/contactin specifically initiates a Notch/Deltex1 signaling pathway that promotes oligodendrocyte maturation and myelination.

A Large Clinical Study on the Ability of Stroke Patients to Use an EEG-Based Motor Imagery Brain-Computer Interface

Brain-computer interface (BCI) technology has the prospects of helping stroke survivors by enabling the interaction with their environment through brain signals rather than through muscles, and restoring motor function by inducing activity-dependent brain plasticity. This paper presents a clinical study on the extent of detectable brain signals from a large population of stroke patients in using EEG-based motor imagery BCI. EEG data were collected from 54 stroke patients whereby finger tapping and motor imagery of the stroke-affected hand were performed by 8 and 46 patients, respectively. EEG data from 11 patients who gave further consent to perform motor imagery were also collected for second calibration and third independent test sessions conducted on separate days. Off-line accuracies of classifying the two classes of EEG from finger tapping or motor imagery of the stroke-affected hand versus the EEG from background rest were then assessed and compared to 16 healthy subjects. The mean off-line accuracy of detecting motor imagery by the 46 patients (μ=0.74) was significantly lower than finger tapping by 8 patients (μ=0.87, p=0.008), but not significantly lower than motor imagery by healthy subjects (μ=0.78, p=0.23). Six stroke patients performed motor imagery at chance level, and no correlation was found between the accuracies of detecting motor imagery and their motor impairment in terms of Fugl-Meyer Assessment (p=0.29). The off-line accuracies of the 11 patients in the second session (μ=0.76) were not significantly different from the first session (μ=0.72, p=0.16), or from the on-line accuracies of the third independent test session (μ=0.82, p=0.14). Hence this study showed that the majority of stroke patients could use EEG-based motor imagery BCI.

Resting state changes in functional connectivity correlate with movement recovery for BCI and robot-assisted upper-extremity training after stroke.

Background. Robot-assisted training may improve motor function in some hemiparetic patients after stroke, but no physiological predictor of rehabilitation progress is reliable. Resting state functional magnetic resonance imaging (RS-fMRI) may serve as a method to assess and predict changes in the motor network. Objective. The authors examined the effects of upper-extremity robot-assisted rehabilitation (MANUS) versus an electroencephalography-based brain computer interface setup with motor imagery (MI EEG-BCI) and compared pretreatment and posttreatment RS-fMRI. Methods. In all, 9 adults with upper-extremity paresis were trained for 4 weeks with a MANUS shoulder-elbow robotic rehabilitation paradigm. In 3 participants, robot-assisted movement began if no voluntary movement was initiated within 2 s. In 6 participants, MI-BCI–based movement was initiated if motor imagery was detected. RS-fMRI and Fugl-Meyer (FM) upper-extremity motor score were assessed before and after training. Results. The individual gain in FM scores over 12 weeks could be predicted from functional connectivity changes (FCCs) based on the pre-post differences in RS-fMRI measurements. Both the FM gain and FCC were numerically higher in the MI-BCI group. Increases in FC of the supplementary motor area, the contralesional and ipsilesional motor cortex, and parts of the visuospatial system with mostly association cortex regions and the cerebellum correlated with individual upper-extremity function improvement. Conclusion. FCC may predict the steepness of individual motor gains. Future training could therefore focus on directly inducing these beneficial increases in FC. Evaluation of the treatment groups suggests that MI is a potential facilitator of such neuroplasticity.

Gonadotropin-inhibitory hormone is a hypothalamic peptide that provides a molecular switch between reproduction and feeding

Objective: Gonadotropin-inhibitory hormone (GnIH)-3 is a neuropeptide that plays a major role in the regulation of reproduction and feeding in mammals. Materials and Methods: We measured endocrine and behavioural parameters of reproduction in sheep, and sexual behaviour in sheep, mice and cynomolgus monkeys. In addition, GnIH gene expression (in situ hybridization) was examined in ewes, and effects of GnIH-3 on food intake and energy expenditure were measured in various species. GnIH-3 was infused (i.v.) into ewes after an i.m. injection of estradiol benzoate to determine whether the peptide blocks the surge in luteinizing hormone (LH) secretion. Results: GnIH gene expression was reduced in the preovulatory period in ewes. Infusion (i.v.) of GnIH-3 blocked the estrogen-induced LH surge (in ewes). Intracerebroventricular infusion had no effect on female or male sexual behaviour in each of the three species, but increased food intake. There were no effects on energy expenditure in sheep or rats. GnIH increased fos protein (immunohistochemistry) was seen in orexigenic neurons (in sheep and rats), but also in anorexigenic neurons (in sheep). Conclusions: GnIH-3 reduces reproductive hormone levels and increases food intake in mammals without reducing energy expenditure. There is minimal effect on reproductive behaviour. The dual effect on reproduction and feeding suggests that GnIH-3 provides a molecular switch between these two functions. Blockade of the positive feedback effect of estrogen with parenteral infusion indicates that this peptide may have utility as a blocker of reproductive function in mammals.

A clinical study of motor imagery-based brain-computer interface for upper limb robotic rehabilitation

Non-invasive EEG-based motor imagery brain-computer interface (MI-BCI) holds promise to effectively restore motor control to stroke survivors. This clinical study investigates the effects of MI-BCI for upper limb robotic rehabilitation compared to standard robotic rehabilitation. The subjects are hemiparetic stroke patients with mean age of 50.2 and baseline Fugl-Meyer (FM) score 29.7 (out of 66, higher = 3D better) randomly assigned to each group respectively (N = 3D8 and 10). Each subject underwent 12 sessions of 1-hour rehabilitation for 4 weeks. Significant gains in FM scores were observed in both groups at post-rehabilitation (4.9, p = 3D0.001) and 2-month post-rehabilitation (4.9, p = 3D0.002). The experimental group yielded higher 2-month post-rehabilitation gain than the control (6.0 versus 4.0) but no significance was found (p = 3D0.475). However, among subjects with positive gain (N = 3D6 and 7), the initial difference of 2.8 between the two groups was increased to a significant 6.5 (p = 3D0.019) after adjustment for age and gender. Hence this study provides evidence that BCI-driven robotic rehabilitation is effective in restoring motor control for stroke.

Cerebral oxygenation, vascular reactivity, and neurochemistry following decompressive craniectomy for severe traumatic brain injury

OBJECT This study addresses the changes in brain oxygenation, cerebrovascular reactivity, and cerebral neurochemistry in patients following decompressive craniectomy for the control of elevated intracranial pressure (ICP) after severe traumatic brain injury (TBI). METHODS Sixteen consecutive patients with isolated TBI and elevated ICP, who were refractory to maximal medical therapy, underwent decompressive craniectomy over a 1-year period. Thirteen patients were male and 3 were female. The mean age of the patients was 38 years and the median Glasgow Coma Scale score on admission was 5. RESULTS Six months following TBI, 11 patients had a poor outcome (Group 1, Glasgow Outcome Scale [GOS] Score 1-3), whereas the remaining 5 patients had a favorable outcome (Group 2, GOS Score 4 or 5). Decompressive craniectomy resulted in a significant reduction (p < 0.001) in the mean ICP and cerebrovascular pressure reactivity index to autoregulatory values (< 0.3) in both groups of patients. There was a significant improvement in brain tissue oxygenation (PbtO(2)) in Group 2 patients from 3 to 17 mm Hg and an 85% reduction in episodes of cerebral ischemia. In addition, the durations of abnormal PbtO(2) and biochemical indices were significantly reduced in Group 2 patients after decompressive craniectomy, but there was no improvement in the biochemical indices in Group 1 patients despite surgery. CONCLUSIONS Decompressive craniectomy, when used appropriately in protocol-driven intensive care regimens for the treatment of recalcitrant elevated ICP, is associated with a return of abnormal metabolic parameters to normal values in patients with eventually favorable outcomes.

Nogo‐A at CNS paranodes is a ligand of Caspr: possible regulation of K+ channel localization

We report Nogo‐A as an oligodendroglial component congregating and interacting with the Caspr–F3 complex at paranodes. However, its receptor Nogo‐66 receptor (NgR) does not segregate to specific axonal domains. CHO cells cotransfected with Caspr and F3, but not with F3 alone, bound specifically to substrates coated with Nogo‐66 peptide and GST–Nogo‐66. Binding persisted even after phosphatidylinositol‐ specific phospholipase C (PI‐PLC) removal of GPI‐linked F3 from the cell surface, suggesting a direct interaction between Nogo‐66 and Caspr. Both Nogo‐A and Caspr co‐immunoprecipitated with Kv1.1 and Kv1.2, and the developmental expression pattern of both paralleled compared with Kv1.1, implicating a transient interaction between Nogo‐A–Caspr and K+ channels at early stages of myelination. In pathological models that display paranodal junctional defects (EAE rats, and Shiverer and CGT−/− mice), distances between the paired labeling of K+ channels were shortened significantly and their localization shifted toward paranodes, while paranodal Nogo‐A congregation was markedly reduced. Our results demonstrate that Nogo‐A interacts in trans with axonal Caspr at CNS paranodes, an interaction that may have a role in modulating axon–glial junction architecture and possibly K+‐channel localization during development.

Optic nerve regeneration in polyglycolic acid-chitosan conduits coated with recombinant L1-Fc.

Autografts have been extensively studied to facilitate optic nerve (ON) regeneration in animal experiments, but the clinical application of this approach to aid autoregeneration has not yet been attempted. This study aims to explore the guided regeneration by an artificial polyglycolic acid–chitosan conduit coated with recombinant L1-Fc. Consistent with previous studies; in vitro assay showed that both chitosan, a natural biomaterial, and the neural cell adhesion molecule L1-Fc enhanced neurite outgrowth. Rat optic nerve transection was used as an in vivo model. The implanted PGA-chitosan conduit was progressively degraded and absorbed, accompanied by significant axonal regeneration as revealed by immunohistochemistry, anterograde and retrograde tracing. The polyglycolic acid–chitosan conduit coated with L1-Fc showed more effective to promote axonal regeneration and remyelination. Taken together, our observations demonstrated that the L1-Fc coated PGA–chitosan conduits provided a compatible and supportive canal to guild the injured nerve regeneration and remyelination.

Protein phosphatase 2A regulates self-renewal of Drosophila neural stem cells.

Drosophila larval brain neural stem cells, also known as neuroblasts, divide asymmetrically to generate a self-renewing neuroblast and a ganglion mother cell (GMC) that divides terminally to produce two differentiated neurons or glia. Failure of asymmetric cell division can result in hyperproliferation of neuroblasts, a phenotype resembling brain tumors. Here we have identified Drosophila Protein phosphatase 2A (PP2A) as a brain tumor-suppressor that can inhibit self-renewal of neuroblasts. Supernumerary larval brain neuroblasts are generated at the expense of differentiated neurons in PP2A mutants. Neuroblast overgrowth was observed in both dorsomedial (DM)/posterior Asense-negative (PAN) neuroblast lineages and non-DM neuroblast lineages. The PP2A heterotrimeric complex, composed of the catalytic subunit (Mts), scaffold subunit (PP2A-29B) and a B-regulatory subunit (Tws), is required for the asymmetric cell division of neuroblasts. The PP2A complex regulates asymmetric localization of Numb, Pon and Atypical protein kinase C, as well as proper mitotic spindle orientation. Interestingly, PP2A and Polo kinase enhance Numb and Pon phosphorylation. PP2A, like Polo, acts to prevent excess neuroblast self-renewal primarily by regulating asymmetric localization and activation of Numb. Reduction of PP2A function in larval brains or S2 cells causes a marked decrease in Polo transcript and protein abundance. Overexpression of Polo or Numb significantly suppresses neuroblast overgrowth in PP2A mutants, suggesting that PP2A inhibits excess neuroblast self-renewal in the Polo/Numb pathway.

Characterization of cerebrovascular reactivity after craniectomy for acute brain injury.

Analysis of slow waves in arterial blood pressure (ABP) and intracranial pressure (ICP) has been used as an index to describe cerebrovascular pressure-reactivity. It has been previously demonstrated that the pressure-reactivity index (PRx) can be used to reflect global cerebrovascular reactivity with changes in ABP. A positive PRx signifies a positive association between ABP and ICP, indicating a non-reactive vascular bed, while a negative PRx is reflective of intact cerebral autoregulation, where ABP waves provoke inversely correlated waves in ICP. To date, there has been no characterization of pressure-reactivity following decompressive craniectomy. In this prospective observational study, 33 patients who underwent surgery for acute brain injury with mass lesions for which the bone flap was left out were studied. The PRx was calculated as a moving correlation coefficient between 30 consecutive samples of values of ICP and ABP averaged for a period of 10 s. The time profiles of mean PRx values at 6-hourly intervals were analysed and compared with that in seven patients treated by medical therapy alone. The initial mean PRx 6 h after surgery was positive, indicative of disturbed pressure-reactivity. With time, PRx trended towards a more negative value, suggestive of an improving cerebrovascular autoregulatory reserve. The mean PRx 24 h after surgery was 0.28 (±0.26), while the mean PRx 72 h after surgery was 0.15 (±0.25) (p = 0.012). In contrast, the mean PRx in patients that were not decompressed did not change significantly with time (p = 0.357). Surgery in acute brain injury for which the bone flap is left out in anticipation of raised intracranial pressure in the postoperative period leads to an improved PRx as compared with controls. Craniectomy in this situation may have a contribution to the restoration of disturbed cerebrovascular pressure-reactivity.