Altered Functional Connectivity in the Motor and Prefrontal Cortex for Children With Down's Syndrome: An fNIRS Study.

Children with Down's syndrome (DS) might exhibit disrupted brain functional connectivity in the motor and prefrontal cortex. To inspect the alterations in brain activation and functional connectivity for children with DS, the functional near-infrared spectroscopy (fNIRS) method was applied to examine the brain activation difference in the motor and prefrontal cortex between the DS and typically developing (TD) groups during a fine motor task. In addition, small-world analysis based on graph theory was also carried out to characterize the topological organization of functional brain networks. Interestingly, behavior data demonstrated that the DS group showed significantly long reaction time and low accuracy as compared to the TD group (p < 0.05). More importantly, significantly reduced brain activations in the frontopolar area, the pre-motor, and the supplementary motor cortex (p < 0.05) were identified in the DS group compared with the TD group. Meanwhile, significantly high global efficiency (E g ) and short average path length (L p ) were also detected for the DS group. This pilot study illustrated that the disrupted connectivity of frontopolar area, pre-motor, and supplementary motor cortex might be one of the core mechanisms associated with motor and cognitive impairments for children with DS. Therefore, the combination of the fNIRS technique with functional network analysis may pave a new avenue for improving our understanding of the neural mechanisms of DS.

Promoting nerve regeneration in a neurotmesis rat model using poly(DL-lactide-ε-caprolactone) membranes and mesenchymal stem cells from the Wharton's jelly: in vitro and in vivo analysis.

In peripheral nerves MSCs can modulate Wallerian degeneration and the overall regenerative response by acting through paracrine mechanisms directly on regenerating axons or upon the nerve-supporting Schwann cells. In the present study, the effect of human MSCs from Wharton's jelly (HMSCs), differentiated into neuroglial-like cells associated to poly (DL-lactide-ε-caprolactone) membrane, on nerve regeneration, was evaluated in the neurotmesis injury rat sciatic nerve model. Results in vitro showed successful differentiation of HMSCs into neuroglial-like cells, characterized by expression of specific neuroglial markers confirmed by immunocytochemistry and by RT-PCR and qPCR targeting specific genes expressed. In vivo testing evaluated during the healing period of 20 weeks, showed no evident positive effect of HMSCs or neuroglial-like cell enrichment at the sciatic nerve repair site on most of the functional and nerve morphometric predictors of nerve regeneration although the nociception function was almost normal. EPT on the other hand, recovered significantly better after HMSCs enriched membrane employment, to values of residual functional impairment compared to other treated groups. When the neurotmesis injury can be surgically reconstructed with an end-to-end suture or by grafting, the addition of a PLC membrane associated with HMSCs seems to bring significant advantage, especially concerning the motor function recovery.

The cadence and water temperature effect on physiological responses during water cycling.

The aim of the study was to compare the maximal physiological responses during three protocols: maximal test on land cycle ergometer, maximal test on water cycling in an indoor pool at 27 °C (WC27) and at 31 °C (WC31). Moreover, the submaximal physiological responses were compared according cycling cadences and water temperatures during the water protocols. Ten young men were included and performed the protocols in separate days. Blood lactate (BL) concentration, heart rate (HR), oxygen uptake (VO2), ventilation (VE) and thermal comfort (TC) were collected during the exercise. The maximal HR and VO2 showed no significant differences between the protocols: HRmax: 189 ± 7 (Land), 188 ± 14 (WC27), 185 ± 9 bpm (WC31) and VO2max: 4.2 ± 0.4 (Land), 4.1 ± 0.5 (WC27) and 4.3 ± 0.5 l min(-1) (WC31). However, the maximal BL demonstrated significant lower values during the water protocols compared to the land protocol (p=0.018). All the submaximal physiological responses showed significant differences between the cadences (60, 70, 80 and 90 rpm). The effect of water temperature was significant for TC response (p=0.001) showing higher values at 31 °C than 27 °C (TCW27: 7 ± 1 and TCW31:9 ± 1). In conclusion, higher physiological responses were showed by increasing the cadence by 10 rpm and the subjects were more comfortable when cycling in the lower water temperature.

Role of physical exercise for improving posttraumatic nerve regeneration.

Despite the great regenerative ability of the peripheral nervous system (PNS), traumatic peripheral nerve damage often causes severe chronic disability. Rehabilitation following PNS trauma usually employs therapeutic exercise in an attempt to reanimate the target organs and stimulate functional recovery. Over the past years, important neurobiological determinants of PNS regeneration and successful end-organ reinnervation were unveiled. Such knowledge provides cues for designing novel strategies for treating and rehabilitating traumatic PNS damage. Physical exercise, by means of treadmill or wheel running, is neuroprotective and neuroregenerative. Research conducted on rodents demonstrates that endurance exercise modulates several of the cellular and molecular responses to peripheral nerve injury and by doing so it stimulates nerve regeneration and functional recovery following experimental PNS injury. Treadmill running increases the number of regenerating neurons, the rate of axonal growth, and the extent of muscle reinnervation following peripheral nerve injury. Furthermore, treadmill running has the ability to increase the release of neurotrophins and growth factors in the spinal cord, the injured nerve, and reinnervating muscles. Treadmill running also seems to prevent the development of neuropathic pain and allodynia as a result of peripheral nerve damage. In addition, physical exercise, even if performed for a short period of time, exerts positive conditioning effects in neuroregeneration capacity, improving the acute response to peripheral nerve insults. Some of these effects can also be obtained with passive exercise or manual stimulation. In humans, however, evidence demonstrating a positive effect of exercise on nerve regeneration is at best poor.

A moderate dose of caffeine ingestion does not change energy expenditure but decreases sleep time in physically active males: a double-blind randomized controlled trial.

Research on the effect of caffeine on energy expenditure (EE), physical activity (PA), and total sleep time (TST) during free-living conditions using objective measures is scarce. We aimed to determine the impact of a moderate dose of caffeine on TST, resting EE (REE), physical activity EE (PAEE), total EE (TEE), and daily time spent in sedentary, light, moderate, and vigorous intensity activities in a 4-day period and the acute effects on heart rate (HR) and EE in physically active males. Using a double-blind crossover trial (ClinicalTrials.gov ID: NCT01477294) with two conditions (4 days each with 3-day washout) randomly ordered as caffeine (5 mg/kg of body mass/day) and placebo (maltodextrin) administered twice per day (2.5 mg/kg), 30 nonsmoker males, low-caffeine users (<100 mg/day), aged 20-39, were followed. Body composition was assessed by dual-energy X-ray absorptiometry. PA was assessed by accelerometry, while a combined HR and movement sensor estimated EE and HR on the second hour after the first administration dose. REE was assessed by indirect calorimetry, and PAEE was calculated as [TEE - (REE + 0.1TEE)]. TST and daily food records were obtained. Repeated measures ANOVA and ANCOVA were used. After a 4-day period, adjusting for fat-free mass, PAEE, and REE, TST was reduced (p = 0.022) under caffeine intake, while no differences were found between conditions for REE, PAEE, TEE, and PA patterns. Also, no acute effects on HR and EE were found between conditions. Though a large individual variability was observed, our findings revealed no acute or long-term effects of caffeine on EE and PA but decreased TST during free-living conditions in healthy males.

The sensitivity of two-dimensional hindlimb joint kinematics analysis in assessing functional recovery in rats after sciatic nerve crush.

Walking analysis in the rat is increasingly used to assess functional recovery after peripheral nerve injury. Here we assess the sensitivity and specificity of hindlimb joint kinematics measures during the rat gait early after sciatic nerve crush injury (DEN), after twelve weeks of recovery (REINN) and in sham-operated controls (Sham) using discriminant analysis. The analysis addressed gait spatiotemporal variables and hip, knee and ankle angle and angular velocity measures during the entire walking cycle. In DEN animals, changes affected all studied joints plus spatiotemporal parameters of gait. Both the spatiotemporal and ankle kinematics parameters recovered to normality within twelve weeks. At this time point, some hip and knee kinematics values were still abnormal when compared to sham controls. Discriminant models based on hip, knee and ankle kinematics displayed maximal sensitivity to identify DEN animals. However, the discriminant models based on spatiotemporal and ankle kinematics data showed a poor performance when assigning animals to the REINN and Sham groups. Models using hip and knee kinematics during walking showed the best sensitivity to recognize the reinnervated animals. The model construed on the basis of hip joint kinematics was the one combining highest sensitivity with robustness and high specificity. It is concluded that ankle joint kinematics fails in detecting minor functional deficits after long term recovery from sciatic nerve crush and extending the kinematic analysis during walking to the hip and knee joints improves the sensitivity of this functional test.

Effects of collagen membranes enriched with in vitro-differentiated N1E-115 cells on rat sciatic nerve regeneration after end-to-end repair.

Peripheral nerves possess the capacity of self-regeneration after traumatic injury but the extent of regeneration is often poor and may benefit from exogenous factors that enhance growth. The use of cellular systems is a rational approach for delivering neurotrophic factors at the nerve lesion site, and in the present study we investigated the effects of enwrapping the site of end-to-end rat sciatic nerve repair with an equine type III collagen membrane enriched or not with N1E-115 pre-differentiated neural cells. After neurotmesis, the sciatic nerve was repaired by end-to-end suture (End-to-End group), end-to-end suture enwrapped with an equine collagen type III membrane (End-to-EndMemb group); and end-to-end suture enwrapped with an equine collagen type III membrane previously covered with neural cells pre-differentiated in vitro from N1E-115 cells (End-to-EndMembCell group). Along the postoperative, motor and sensory functional recovery was evaluated using extensor postural thrust (EPT), withdrawal reflex latency (WRL) and ankle kinematics. After 20 weeks animals were sacrificed and the repaired sciatic nerves were processed for histological and stereological analysis. Results showed that enwrapment of the rapair site with a collagen membrane, with or without neural cell enrichment, did not lead to any significant improvement in most of functional and stereological predictors of nerve regeneration that we have assessed, with the exception of EPT which recovered significantly better after neural cell enriched membrane employment. It can thus be concluded that this particular type of nerve tissue engineering approach has very limited effects on nerve regeneration after sciatic end-to-end nerve reconstruction in the rat.

Use of chitosan scaffolds for repairing rat sciatic nerve defects.

Neurotmesis must be surgically treated by direct end-to-end suture of the two nerve stumps or by a nerve graft harvested from elsewhere in the body in case of tissue loss. To avoid secondary damage due to harvesting of the nerve graft, a tube-guide can be used to bridge the nerve gap. Previously, our group developed and tested hybrid chitosan membranes for peripheral nerve tubulization and showed that freeze-dried chitosan type III membranes were particularly effective for improving peripheral nerve functional recovery after axonotmesis. Chitosan type III membranes have about 110 microm pores and about 90% of porosity, due to the employment of freeze-drying technique. The present study aimed to verify if chitosan type III membranes can be successfully used also for improving peripheral nerve functional recovery after neurotmesis of the rat sciatic nerve. Sasco Sprague-Dawley adult rats were divided into 6 groups: Group 1: end-to-end neurorrhaphy enwrapped by chitosan membrane type III (End-to-EndChitll); Group 2: 10mm-nerve gap bridged by an autologous nerve graft enwrapped by chitosan membrane type III (Graf180degreeChitIII); Group 3: 10 mm-nerve gap bridged by chitosan type III tube-guides (GapChitIII); These 3 experimental groups were compared with 3 control groups, respectively: Group 4: 10 mm-nerve gap bridged by an autologous nerve graft (Graft180degree); Group 5: 10 mm-nerve gap bridged by PLGA 90:10 tube-guides (PLGA); Group 6: end-to-end neurorrhaphy alone (End-to-End). Motor and sensory functional recovery were evaluated throughout a healing period of 20 weeks using extensor postural thrust (EPT), withdrawal reflex latency (WRL) and ankle kinematics. Regenerated nerves withdrawn at the end of the experiment were analysed histologically. Results showed that nerve regeneration was successful in all experimental and control groups and that chitosan type III tubulization induced a significantly better nerve regeneration and functional recovery in comparison to PLGA tubulization control. Further investigation is needed to explore the mechanisms at the basis of the positive effects of chitosan type III on axonal regeneration.

Use of PLGA 90:10 scaffolds enriched with in vitro-differentiated neural cells for repairing rat sciatic nerve defects.

Poly(lactic-co-glycolic acid) (PLGA) nerve tube guides, made of a novel proportion (90:10) of the two polymers, poly(L-lactide): poly(glycolide) and covered with a neural cell line differentiated in vitro, were tested in vivo for promoting nerve regeneration across a 10-mm gap of the rat sciatic nerve. Before in vivo testing, the PLGA 90:10 tubes were tested in vitro for water uptake and mass loss and compared with collagen sheets. The water uptake of the PLGA tubes was lower, and the mass loss was more rapid and higher than those of the collagen sheets when immersed in phosphate-buffered saline (PBS) solution. The pH values of immersing PBS did not change after soaking the collagen sheets and showed to be around 7.4. On the other hand, the pH values of PBS after soaking PLGA tubes decreased gradually during 10 days reaching values around 3.5. For the in vivo testing, 22 Sasco Sprague adult rats were divided into four groups--group 1: gap not reconstructed; group 2: gap reconstructed using an autologous nerve graft; group 3: gap reconstructed with PLGA 90:10 tube guides; group 4: gap reconstructed with PLGA 90:10 tube guides covered with neural cells differentiated in vitro. Motor and sensory functional recovery was evaluated throughout a healing period of 20 weeks using sciatic functional index, static sciatic index, extensor postural thrust, withdrawal reflex latency, and ankle kinematics. Stereological analysis was carried out on regenerated nerve fibers. Both motor and sensory functions improved significantly in the three experimental nerve repair groups, although the rate and extent of recovery was significantly higher in the group where the gap was reconstructed using the autologous graft. The presence of neural cells covering the inside of the PLGA tube guides did not make any difference in the functional recovery. By contrast, morphometric analysis showed that the introduction of N1E-115 cells inside PLGA 90:10 tube guides led to a significant lower number and size of regenerated nerve fibers, suggesting thus that this approach is not adequate for promoting peripheral nerve repair. Further studies are warranted to assess the role of other cellular systems as a foreseeable therapeutic strategy in peripheral nerve regeneration.

PLGA 90/10 and caprolactone biodegradable nerve guides for the reconstruction of the rat sciatic nerve.

The purpose of this study was to test in vivo two different nerve guides for promoting nerve regeneration across a 10-mm gap of the rat sciatic nerve: 1) one made of PLGA in a novel proportion (90:10) of the two polymers poly(L-lactide):poly(glycolide); 2) another made of (DL-lactide-epsilon-caprolactone) copolyester (Neurolac) tube, by comparing its healing efficacy with that of the more traditional methods of end-to-end nerve suture and autologous graft. Motor and sensory functional recovery were assessed throughout the healing period of 20 weeks, and the repaired nerves were processed for morphological and histomorphometrical analysis. Both motor and sensory functions improved significantly in all experimental nerve repaired groups. At the end of the 20-week follow-up, the end-to-end group showed better recovery of motor function when compared with the groups treated with guiding tubes. However, at this time point, the level of motor function in the Neurolac(R) and PLGA groups was similar to the one of the graft group. Nociception function also recovered faster in the end-to-end group compared with the Neurolac(R) and PLGA groups, and in this case, recovery was also delayed in the graft group. At the end of follow-up, nociception was similar in all experimental groups. Morphological and histomorphometrical analysis showed that axon regeneration occurred in both PLGA and Neurolac(R) experimental groups, with no significant differences in the total number of regenerated fibers, but disclosed a different pattern of degradation of the two types of tubes with larger biodegradation of PLGA material by the end of 20 weeks. These results suggest that both types of biomaterials are a good substrate for preparing tubular nerve guides, and their different pattern of degradation does not seem to influence the degree of nerve regeneration.

Evaluation of two biodegradable nerve guides for the reconstruction of the rat sciatic nerve.

The purpose of this study was to test in vivo two different nerve guides, one of PLGA made of a novel proportion (90:10) of the two polymers, Poly(L-lactide):Poly(glycolide), with (DL-lactide-epsilon-caprolactone) copolyester (Neurolac) tube, in promoting nerve regeneration across a 10 mm-gap of the rat sciatic nerve. Finally, end-to-end coaptation was performed. Motor and sensory functional recovery was assessed throughout the healing period of 20 weeks and the repaired nerves were processed for morphological analysis. Both motor and sensory functions improved significantly in all experimental nerve repair groups, although the rate and extent of recovery was significantly higher in the end-to-end group. No significant differences were detected in the comparison between the two types of tubes. Compatible with results of functional tests, morphological analysis showed that axon regeneration occurred in both PLGA and Neurolac experimental groups but disclosed a different pattern of degradation of the two types of tubes with larger biodegradation of PLGA material by the end of 20 weeks. These results suggest that both types of biomaterial are a good substrate for preparing tubular nerve guides and the different pattern of degradation does not seem to influence the degree of nerve regeneration.