BackgroundThe biological process underlying axonal myelination is complex and often prone to injury and disease. The ratio of the inner axonal diameter to the total outer diameter or g-ratio is widely utilized as a functional and structural index of optimal axonal myelination. Based on the speed of fiber conduction, Rushton was the first to derive a theoretical estimate of the optimal g-ratio of 0.6 [1]. This theoretical limit nicely explains the experimental data for myelinated axons obtained for some peripheral fibers but appears significantly lower than that found for CNS fibers. This is, however, hardly surprising given that in the CNS, axonal myelination must achieve multiple goals including reducing conduction delays, promoting conduction fidelity, lowering energy costs, and saving space.Methodology/Principal FindingsIn this study we explore the notion that a balanced set-point can be achieved at a functional level as the micro-structure of individual axons becomes optimized, particularly for the central system where axons tend to be smaller and their myelin sheath thinner. We used an intuitive yet novel theoretical approach based on the fundamental biophysical properties describing axonal structure and function to show that an optimal g-ratio can be defined for the central nervous system (≈0.77). Furthermore, by reducing the influence of volume constraints on structural design by about 40%, this approach can also predict the g-ratio observed in some peripheral fibers (≈0.6).Conclusions/SignificanceThese results support the notion of optimization theory in nervous system design and construction and may also help explain why the central and peripheral systems have evolved different g-ratios as a result of volume constraints.

Purpose: Skp2 plays a critical role in cell cycle progression, especially at the G 1 -S transition, putatively through its control of several cell cycle regulator proteins. The Skp2 gene is located on a region of chromosome 5p that is commonly overrepresented in lung cancer. The present study aimed to evaluate Skp2 abnormalities and their prognostic value in non-small cell lung cancer (NSCLC).Experimental Design: In total 16 NSCLC cell lines and 163 primary tumors were included in studies to measure Skp2 relative gene copy number, mRNA abundance, and protein level. The tumors were also evaluated for p27 protein expression level and ras mutation. These values were correlated with the clinical and pathological features of the patients.Results: Skp2 relative gene copy number aberrations were found in 88 and 65% of NSCLC cell lines and primary tumors, respectively. Overrepresentation was especially common among squamous cell carcinoma (74%). Both gene copy overrepresentation (13%) and loss (35%) were found in adenocarcinoma. Skp2 relative gene copy number was significantly correlated with mRNA and protein levels, but none of these were correlated with p27 protein levels. Neither high Skp2 protein expression nor ras mutation was prognostically significant. In NSCLCs with ras mutation, however, high Skp2 protein expression was a significant independent poor prognostic marker.Conclusion: There appears to be a synergistic interaction between high Skp2 protein expression and ras mutation with negative impact on the survival of NSCLC patients.

Two recent epidemiological investigations in children exposed to valproic acid (VPA) treatment in utero have reported a significant risk associated with neurodevelopmental disorders and autism spectrum disorder (ASD) in particular. Parallel to this work, there is a growing body of animal research literature using VPA as an animal model of ASD. In this focused review we first summarize the epidemiological evidence linking VPA to ASD and then comment on two important neurobiological findings linking VPA to ASD clinicopathology, namely, accelerated or early brain overgrowth and hyperexcitable networks. Improving our understanding of how the drug VPA can alter early development of neurological systems will ultimately improve our understanding of ASD.

Antidromic cortical excitation has been implicated as a contributing mechanism for high-frequency deep brain stimulation (DBS). Here, we examined the reliability of antidromic responses of type 2 corticofugal fibres in rat over a stimulation frequency range compatible to the DBS used in humans. We activated antidromically individual layer V neurones by stimulating their two subcortical axonal branches. We found that antidromic cortical excitation is not as reliable as generally assumed. Whereas the fast conducting branches of a type 2 axon in the highly myelinated brainstem region follow high-frequency stimulation, the slower conducting fibres in the poorly myelinated thalamic region function as low-pass filters. These fibres fail to transmit consecutive antidromic spikes at the beginning of high-frequency stimulation, but are able to maintain a steady low-frequency (6-12 Hz) spike output during the stimulation. In addition, antidromic responses evoked from both branches are rarely present in cortical neurones with a more hyperpolarized membrane potential. Our data indicate that axon-mediated antidromic excitation in the cortex is strongly influenced by the myelo-architecture of the stimulation site and the excitability of individual cortical neurones.

BackgroundAutism is a behaviourally defined neurodevelopmental disorder with unknown etiology. Recent studies in autistic children consistently point to neuropathological and functional abnormalities in the temporal association cortex (TeA) and its associated structures. It has been proposed that the trajectory of postnatal development in these regions may undergo accelerated maturational alterations that predominantly affect sensory recognition and social interaction. Indeed, the temporal association regions that are important for sensory recognition and social interaction are one of the last regions to mature suggesting a potential vulnerability to early maturation. However, direct evaluation of the emerging hypothesis that an altered time course of early postnatal development can lead to an ASD phenotype remains lacking.ResultsWe used electrophysiological, histological, and behavioural techniques to investigate if the known neuronal maturational promoter valproate, similar to that in culture systems, can influence the normal developmental trajectory of TeA in vivo. Brain sections obtained from postnatal rat pups treated with VPA in vivo revealed that almost 40% of cortical cells in TeA prematurely exhibited adult-like intrinsic electrophysiological properties and that this was often associated with gross cortical hypertrophy and a reduced predisposition for social play behaviour.ConclusionsThe co-manifestation of these functional, structural and behavioural features suggests that alteration of the developmental time course in certain high-order cortical networks may play an important role in the neurophysiological basis of autism.

People with Parkinson's disease (PD) can exhibit disabling gait symptoms such as freezing of gait especially when distracted by a secondary task. Quantitative measurement method of this type of cognitive-motor abnormality, however, remains poorly developed. Here we examined whether stepping-in-place (SIP) with a concurrent mental task (e.g., subtraction) can be used as a simple method for evaluating cognitive-motor deficits in PD. We used a 4th generation iPod Touch sensor system to capture hip flexion data and obtain step height (SH) measurements (z axis). The accuracy of the method was compared to and validated by kinematic video analysis software. We found a general trend of reduced SH for PD subjects relative to controls under all conditions. However, the SH of PD freezers was significantly worse than PD non-freezers and controls during concurrent serial 7 subtraction and SIP tasking. During serial 7 subtraction, SH was significantly associated with whether or not a PD patient was a self-reported freezer even when controlling for disease severity. Given that this SIP-based dual-task paradigm is not limited by space requirements and can be quantified using a mobile tracking device that delivers specifically designed auditory task instructions, the method reported here may be used to standardize clinical assessment of cognitive-motor deficits under a variety of dual-task conditions in PD.

Background:Deficits in motor movement automaticity in Parkinson's disease (PD), especially during multitasking, are early and consistent hallmarks of cognitive function decline, which increases fall risk and reduces quality of life. This study aimed to test the feasibility and potential efficacy of a wearable sensor-enabled technological platform designed for an in-home music-contingent stepping-in-place (SIP) training program to improve step automaticity during dual-tasking (DT).Methods:This was a 4-week prospective intervention pilot study. The intervention uses a sensor system and algorithm that runs off the iPod Touch which calculates step height (SH) in real-time. These measurements were then used to trigger auditory (treatment group, music; control group, radio podcast) playback in real-time through wireless headphones upon maintenance of repeated large amplitude stepping. With small steps or shuffling, auditory playback stops, thus allowing participants to use anticipatory motor control to regain positive feedback. Eleven participants were recruited from an ongoing trial (Trial Number: ISRCTN06023392). Fear of falling (FES-I), general cognitive functioning (MoCA), self-reported freezing of gait (FOG-Q), and DT step automaticity were evaluated.Results:While we found no significant effect of training on FES-I, MoCA, or FOG-Q, we did observe a significant group (music vs podcast) by training interaction in DT step automaticity (P<0.01).Conclusion:Wearable device technology can be used to enable musically-contingent SIP training to increase motor automaticity for people living with PD. The training approach described here can be implemented at home to meet the growing demand for self-management of symptoms by patients.

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