High-intensity, unilateral resistance training of a non-paretic muscle group increases active range of motion in a severely paretic upper extremity muscle group after stroke

Limited rehabilitation strategies are available for movement restoration when paresis is too severe following stroke. Previous research has shown that high-intensity resistance training of one muscle group enhances strength of the homologous, contralateral muscle group in neurologically-intact adults. How this cross education phenomenon might be exploited to moderate severe weakness in an upper extremity muscle group after stroke is not well understood. The primary aim of this study was to examine adaptations in force-generating capacity of severely paretic wrist extensors resulting from high-intensity, dynamic contractions of the non-paretic wrist extensors. A secondary, exploratory aim was to probe neural adaptations in a subset of participants from each sample using a single-pulse, transcranial magnetic stimulation protocol. Separate samples of neurologically-intact controls (n=7) and individuals > 4 months post stroke (n=6) underwent 16 sessions of training. Following training, one-repetition maximum of the untrained wrist extensors in the control group and active range of motion of the untrained, paretic wrist extensors in the stroke group were significantly increased. No changes in corticospinal excitability, intracortical inhibition or interhemispheric inhibition were observed in control participants. Both stroke participants who underwent TMS testing, however, exhibited increased voluntary muscle activation following the intervention. In addition, motor-evoked potentials that were unobtainable prior to the intervention were readily elicited afterwards in a stroke participant. Results of this study demonstrate that high-intensity resistance training of a non-paretic upper extremity muscle group can enhance voluntary muscle activation and force-generating capacity of a severely paretic muscle group after stroke. There is also preliminary evidence that corticospinal adaptations may accompany these gains

Distinct interactions between fronto-parietal and default mode networks in impaired consciousness

Existing evidence suggests that the default-mode network (DMN) and fronto-pariatal network (FPN) play an important role in altered states of consciousness. However, the brain mechanisms underlying impaired consciousness and the specific network interactions involved are not well understood. We studied the topological properties of brain functional networks using resting-state functional MRI data acquired from 18 patients (11 vegetative state/unresponsive wakefulness syndrome, VS/UWS, and 7 minimally conscious state, MCS) and compared these properties with those of healthy controls. We identified that the topological properties in DMN and FPN are anti-correlated which comes, in part, from the contribution of interactions between dorsolateral prefrontal cortex of the FPN and precuneus of the DMN. Notably, altered nodal connectivity strength was distance-dependent, with most disruptions appearing in long-distance connections within the FPN but in short-distance connections within the DMN. A multivariate pattern-classification analysis revealed that combination of topological patterns between the FPN and DMN could predict conscious state more effectively than connectivity within either network. Taken together, our results imply distinct interactions between the FPN and DMN, which may mediate conscious state

Motor Sequence Learning Is Associated With Hippocampal Subfield Volume in Humans With Medial Temporal Lobe Epilepsy

Objectives: Medial temporal lobe epilepsy (mTLE) is characterized by decreased hippocampal volume, which results in motor memory consolidation impairments. However, the extent to which motor memory acquisition are affected in humans with mTLE remains poorly understood. We therefore examined the extent to which learning of a motor tapping sequence task is affected by mTLE.Methods: MRI volumetric analysis was performed using a T1-weighted three-dimensional gradient echo sequence in 15 patients with right mTLE and 15 control subjects. Subjects trained on a motor sequence tapping task with the left hand in right mTLE and non-dominant hand in neurologically-intact controls.Results: The number of correct sequences performed by the mTLE patient group increased after training, albeit to a lesser extent than the control group. Although hippocampal subfield volume was reduced in mTLE relative to controls, no differences were observed in the volumes of other brain areas including thalamus, caudate, putamen and amygdala. Correlations between hippocampal subfield volumes and the change in pre- to post-training performance indicated that the volume of hippocampal subfield CA2–3 was associated with motor sequence learning in patients with mTLE.Significance: These results provide evidence that individuals with mTLE exhibit learning on a motor sequence task. Learning is linked to the volume of hippocampal subfield CA2–3, supporting a role of the hippocampus in motor memory acquisition.Highlights-Humans with mTLE exhibit learning on a motor tapping sequence task but not to the same extent as neurologically-intact controls.-Hippocampal subfield volumes are significantly reduced after mTLE. Surrounding brain area volumes do not show abnormalities.-Hippocampal subfield CA2–3 volume is associated with motor sequence learning in humans with mTLE

Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination

In vertebrates, homologous recombinational repair (HRR) requires RAD51 and five RAD51 paralogs (XRCC2, XRCC3, RAD51B, RAD51C and RAD51D) that all contain conserved Walker A and B ATPase motifs. In human RAD51D we examined the requirement for these motifs in interactions with XRCC2 and RAD51C, and for survival of cells in response to DNA interstrand crosslinks (ICLs). Ectopic expression of wild-type human RAD51D or mutants having a non-functional A or B motif was used to test for complementation of a rad51d knockout hamster CHO cell line. Although A-motif mutants complement very efficiently, B-motif mutants do not. Consistent with these results, experiments using the yeast two- and three-hybrid systems show that the interactions between RAD51D and its XRCC2 and RAD51C partners also require a functional RAD51D B motif, but not motif A. Similarly, hamster Xrcc2 is unable to bind to the non-complementing human RAD51D B-motif mutants in co-immunoprecipitation assays. We conclude that a functional Walker B motif, but not A motif, is necessary for RAD51D's interactions with other paralogs and for efficient HRR. We present a model in which ATPase sites are formed in a bipartite manner between RAD51D and other RAD51 paralogs

Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis

Fanconi anemia (FA) is a chromosomal instability disorder in which DNA-damage processing defects are reported for translesion synthesis (TLS), non-homologous end joining (NHEJ) and homologous recombination (HR; both increased and decreased). To reconcile these diverse findings, we compared spontaneous mutagenesis in FA and HR mutants of hamster CHO cells. In the fancg mutant we find a reduced mutation rate accompanied by an increased proportion of deletions within the hprt gene. Moreover, in fancg cells gene amplification at the CAD and dhfr loci is elevated, another manifestation of inappropriate processing of damage during DNA replication. In contrast, the rad51d HR mutant has a greatly elevated rate of hprt mutations, >85% of which are deletions. Our analysis supports the concept that HR faithfully restores broken replication forks, whereas the FA pathway acts more globally to ensure chromosome stability by promoting efficient end joining of replication-derived breaks, as well as TLS and HR

An LES Turbulent Inflow Generator using A Recycling and Rescaling Method

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The present paper describes a recycling and rescaling method for generating turbulent inflow conditions for Large Eddy Simulation. The method is first validated by simulating a turbulent boundary layer and a turbulent mixing layer. It is demonstrated that, with input specification of mean velocities and turbulence rms levels (normal stresses) only, it can produce realistic and self-consistent turbulence structures. Comparison of shear stress and integral length scale indicates the success of the method in generating turbulent 1-point and 2-point correlations not specified in the input data. With the turbulent inlet conditions generated by this method, the growth rate of the turbulent boundary/mixing layer is properly predicted. Furthermore, the method can be used for the more complex inlet boundary flow types commonly found in industrial applications, which is demonstrated by generating non-equilibrium turbulent inflow and spanwise inhomogeneous inflow. As a final illustration of the benefits brought by this approach, a droplet-laden mixing layer is simulated. The dispersion of droplets in the near-field immediately downstream of the splitter plate trailing edge where the turbulent mixing layer begins is accurately reproduced due to the realistic turbulent structures captured by the recycling/rescaling method

Acute intermittent hypoxia enhances corticospinal synaptic plasticity in humans

Acute intermittent hypoxia (AIH) enhances voluntary motor output in humans with central nervous system damage. The neural mechanisms contributing to these beneficial effects are unknown. We examined corticospinal function by evaluating motor evoked potentials (MEPs) elicited by cortical and subcortical stimulation of corticospinal axons and the activity in intracortical circuits in a finger muscle before and after 30 min of AIH or sham AIH. We found that the amplitude of cortically and subcortically elicited MEPs increased for 75 min after AIH but not sham AIH while intracortical activity remained unchanged. To examine further these subcortical effects, we assessed spike-timing dependent plasticity (STDP) targeting spinal synapses and the excitability of spinal motoneurons. Notably, AIH increased STDP outcomes while spinal motoneuron excitability remained unchanged. Our results provide the first evidence that AIH changes corticospinal function in humans, likely by altering corticospinal-motoneuronal synaptic transmission. AIH may represent a novel noninvasive approach for inducing spinal plasticity in humans

Spike-timing-dependent plasticity in lower-limb motoneurons after human spinal cord injury

Recovery of lower-limb function after spinal cord injury (SCI) likely depends on transmission in the corticospinal pathway. Here, we examined whether paired corticospinal-motoneuronal stimulation (PCMS) changes transmission at spinal synapses of lower-limb motoneurons in humans with chronic incomplete SCI and aged-matched controls. We used 200 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the leg representation of the motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the tibialis anterior (TA) muscle 2 ms before antidromic potentials evoked in motoneurons by electrical stimulation of the common peroneal nerve (PCMS+) or when antidromic potentials arrived 15 or 28 ms before corticospinal volleys (PCMS-) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the TA muscle before and after each stimulation protocol. After PCMS+, the size of MEPs elicited by TMS and electrical stimulation increased for up to 30 min in control and SCI participants. Notably, this was accompanied by increases in TA electromyographic activity and ankle dorsiflexion force in both groups, suggesting that this plasticity has functional implications. After PCMS-, MEPs elicited by TMS and electrical stimulation were suppressed if afferent input from the common peroneal nerve reduced TA MEP size during paired stimulation in both groups. In conclusion, PCMS elicits spike-timing-dependent changes at spinal synapses of lower-limb motoneurons in humans and has potential to improve lower-limb motor output following SCI. Approaches that aim to enhance corticospinal transmission to lower-limb muscles following spinal cord injury (SCI) are needed. We demonstrate that paired corticomotoneuronal stimulation (PCMS) can enhance plasticity at spinal synapses of lower-limb motoneurons in humans with and without SCI. We propose that PCMS has potential for improving motor output in leg muscles in individuals with damage to the corticospinal tract