Autonomic reinnervation and functional regeneration in autologous transplanted submandibular glands in patients with severe keratoconjunctivitis sicca

Autologous submandibular gland（SMG） transplantation has been proved to ameliorate the discomforts in patients with severe keratoconjunctivitis sicca. The transplanted glands underwent a hypofunctional period and then restored secretion spontaneously.This study aims to investigate whether autonomic nerves reinnervate the grafts and contribute to the functional recovery, and further determine the origin of these nerves. Parts of the transplanted SMGs were collected from the epiphora patients, and a rabbit SMG transplantation model was established to fulfill the serial observation on the transplanted glands with time. The results showed that autonomic nerves distributed in the transplanted SMGs and parasympathetic ganglionic cells were observed in the stroma of the glands. Low-dense and unevenly distributed cholinergic axons, severe acinar atrophy and fibrosis were visible in the patients＇ glands 4–6 months post-transplantation, whereas the cholinergic axon density and acinar area were increased with time. The acinar area or the secretory flow rate of the transplanted glands was statistically correlated with the cholinergic axon density in the rabbit model, respectively. Meanwhile, large cholinergic nerve trunks were found to locate in the temporal fascia lower to the gland, and sympathetic plexus concomitant with the arteries was observed both in the adjacent fascia and in the stroma of the glands. In summary, the transplanted SMGs are reinnervated by autonomic nerves and the cholinergic nerves play a role in the morphological and functional restoration of the glands. Moreover, these autonomic nerves might originate from the auriculotemporal nerve and the sympathetic plexus around the supplying arteries.

Functional regeneration of the brain:white matter matters

In the human brain, white matter makes up about 50% of the brain volume and consumes 43.8% of the brain＇s total energy budget for resting potential maintenance （Harris and Attwell, 2012）. Composed of primarily myelinated axons, the white matter is the ＂highways and subways of the brain＂ connecting one region to another and trafficking in and out of the grey matter. In the myelinated nerve fibers, layers of myelin sheaths wrap around each axon to provide protection and insulation to the axon and to allow rapid conduction of action potentials. Myelin establishment and maintenance is considered a crucial requirement for fully functional con- nections between neurons in the central nerve system （CNS）.

Evidence of cortical reorganization of language networks after stroke with subacute Broca's aphasia:a blood oxygenation level dependent-functional magnetic resonance imaging study

Aphasia is an acquired language disorder that is a common consequence of stroke.The pathogenesis of the disease is not fully understood,and as a result,current treatment options are not satisfactory.Here,we used blood oxygenation level-dependent functional magnetic resonance imaging to evaluate the activation of bilateral cortices in patients with Broca＇s aphasia 1 to 3 months after stroke.Our results showed that language expression was associated with multiple brain regions in which the right hemisphere participated in the generation of language.The activation areas in the left hemisphere of aphasia patients were significantly smaller compared with those in healthy adults.The activation frequency,volumes,and intensity in the regions related to language,such as the left inferior frontal gyrus（Broca＇s area）,the left superior temporal gyrus,and the right inferior frontal gyrus（the mirror region of Broca＇s area）,were lower in patients compared with healthy adults.In contrast,activation in the right superior temporal gyrus,the bilateral superior parietal lobule,and the left inferior temporal gyrus was stronger in patients compared with healthy controls.These results suggest that the right inferior frontal gyrus plays a role in the recovery of language function in the subacute stage of stroke-related aphasia by increasing the engagement of related brain areas.

The potential of neural transplantation for brain repair and regeneration following traumatic brain injury

Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent development in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury.

Fine motor skill training enhances functional plasticity of the corticospinal tract after spinal cord injury

Following central nervous system injury, axonal sprouts form distal to the injury site and extend into the denervated area, reconstructing neural circuits through neural plasticity. How to facilitate this plasticity has become the key to the success of central nervous system repair. It remains controversial whether fine motor skill training contributes to the recovery of neurological function after spinal cord injury. Therefore, we established a rat model of unilateral corticospinal tract injury using a pyramidal tract cutting method. Horizontal ladder crawling and food ball grasping training procedures were conducted 2 weeks before injury and 3 days after injury. The neurological function of rat forelimbs was assessed at 1, 2, 3, 4, and 6 weeks after injury. Axon growth was observed with biotinylated dextran amine anterograde tracing in the healthy corticospinal tract of the denervated area at different time periods. Our results demonstrate that compared with untrained rats, functional recovery was better in the forelimbs and forepaws of trained rats. The number of axons and the expression of growth associated protein 43 were increased at the injury site 3 weeks after corticospinal tract injury. These findings confirm that fine motor skill training promotes central nervous system plasticity in spinal cord injury rats.

Real-time and wearable functional electrical stimulation system for volitional hand motor function control using the electromyography bridge method

Voluntary participation of hemiplegic patients is crucial for functional electrical stimulation therapy.A wearable functional electrical stimulation system has been proposed for real-time volitional hand motor function control using the electromyography bridge method.Through a series of novel design concepts,including the integration of a detecting circuit and an analog-to-digital converter,a miniaturized functional electrical stimulation circuit technique,a low-power super-regeneration chip for wireless receiving,and two wearable armbands,a prototype system has been established with reduced size,power,and overall cost.Based on wrist joint torque reproduction and classification experiments performed on six healthy subjects,the optimized surface electromyography thresholds and trained logistic regression classifier parameters were statistically chosen to establish wrist and hand motion control with high accuracy.Test results showed that wrist flexion/extension,hand grasp,and finger extension could be reproduced with high accuracy and low latency.This system can build a bridge of information transmission between healthy limbs and paralyzed limbs,effectively improve voluntary participation of hemiplegic patients,and elevate efficiency of rehabilitation training.

Femoral nerve regeneration and its accuracy under different injury mechanisms

Surgical accuracy has greatly improved with the advent of microsurgical techniques. However, complete functional recovery after peripheral nerve injury has not been achieved to date. The mechanisms hindering accurate regeneration of damaged axons after peripheral nerve injury are in urgent need of exploration. The present study was designed to explore the mechanisms of peripheral nerve regeneration after different types of injury. Femoral nerves of rats were injured by crushing or freezing. At 2, 3, 6, and 12 weeks after injury, axons were retrogradely labeled using 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate（Dil） and True Blue, and motor and sensory axons that had regenerated at the site of injury were counted. The number and percentage of Dil-labeled neurons in the anterior horn of the spinal cord increased over time. No significant differences were found in the number of labeled neurons between the freeze and crush injury groups at any time point. Our results confirmed that the accuracy of peripheral nerve regeneration increased with time, after both crush and freeze injury, and indicated that axonal regeneration accuracy was still satisfactory after freezing, despite the prolonged damage.

Connectivity differences between adult male and female patients with attention deficit hyperactivity disorder according to resting-state functional MRI

Attention deficit hyperactivity disorder（ADHD） is a pervasive psychiatric disorder that affects both children and adults. Adult male and female patients with ADHD are differentially affected, but few studies have explored the differences. The purpose of this study was to quantify differences between adult male and female patients with ADHD based on neuroimaging and connectivity analysis. Resting-state functional magnetic resonance imaging scans were obtained and preprocessed in 82 patients. Group-wise differences between male and female patients were quantified using degree centrality for different brain regions. The medial-, middle-, and inferior-frontal gyrus, superior parietal lobule, precuneus, supramarginal gyrus, superior- and middle-temporal gyrus, middle occipital gyrus, and cuneus were identified as regions with significant group-wise differences. The identified regions were correlated with clinical scores reflecting depression and anxiety and significant correlations were found. Adult ADHD patients exhibit different levels of depression and anxiety depending on sex, and our study provides insight into how changes in brain circuitry might differentially impact male and female ADHD patients.

Aligned carbon nanotube containing scaffolds for neural tissue regeneration

Neuropathologies include the deterioration and damage of the nervous system,especially neurons present in the brain,spinal cord and peripheral nervous system.Damage or alternations in neurons makes their structure and functionality abnormal.Every year over 90,000 people get affected by neurodegenerative diseases in the USA.Among all the neurological pathologies,

Gait improvement after treadmill training in ischemic stroke survivors A critical review of functional MRI studies

Stroke survivors often present with abnormal gait, movement training can improve the walking performance post-stroke, and functional MRI can objectively evaluate the brain functions before and after movement training. This paper analyzes the functional MRI changes in patients with ischemic stroke after treadmill training with voluntary and passive ankle dorsiflexion. Functional MRI showed that there are some changes in some regions of patients with ischemic stroke including primary sensorimotor cortex, supplementary motor area and cingulate motor area after treadmill training. These findings suggest that treadmill training likely improves ischemic stroke patients＇ lower limb functions and gait performance and promotes stroke recovery by changing patients＇ brain plasticity; meanwhile, the novel treadmill training methods can better training effects.

Age-related connectivity differences between attention deficit and hyperactivity disorder patients and typically developing subjects：a resting-state functional MRI study

Attention deficit and hyperactivity disorder（ADHD） is a disorder characterized by behavioral symptoms including hyperactivity/impulsivity among children,adolescents,and adults.These ADHD related symptoms are influenced by the complex interaction of brain networks which were under explored.We explored age-related brain network differences between ADHD patients and typically developing（TD） subjects using resting state f MRI（rs-f MRI） for three age groups of children,adolescents,and adults.We collected rs-f MRI data from 184 individuals（27 ADHD children and 31 TD children;32 ADHD adolescents and 32 TD adolescents;and 31 ADHD adults and 31 TD adults）.The Brainnetome Atlas was used to define nodes in the network analysis.We compared three age groups of ADHD and TD subjects to identify the distinct regions that could explain age-related brain network differences based on degree centrality,a well-known measure of nodal centrality.The left middle temporal gyrus showed significant interaction effects between disease status（i.e.,ADHD or TD） and age（i.e.,child,adolescent,or adult）（P 0.001）.Additional regions were identified at a relaxed threshold（P 0.05）.Many of the identified regions（the left inferior frontal gyrus,the left middle temporal gyrus,and the left insular gyrus） were related to cognitive function.The results of our study suggest that aberrant development in cognitive brain regions might be associated with age-related brain network changes in ADHD patients.These findings contribute to better understand how brain function influences the symptoms of ADHD.

L4-to-L4 nerve root transfer for hindlimb hemiplegia after hypertensive intracerebral hemorrhage

There is no effective treatment for hemiplegia after hypertensive intracerebral hemorrhage.Considering that the branches of L4 nerve roots in the lumbar plexus root control the movement of the lower extremity anterior and posterior muscles,we investigated a potential method of nerve repair using the L4 nerve roots.Rat models of hindlimb hemiplegia after a hypertensive intracerebral hemorrhage were established by injecting autogenous blood into the posterior limb of internal capsule.The L4 nerve root on the healthy side of model rats was transferred and then anastomosed with the L4 nerve root on the affected side to drive the extensor and flexor muscles of the hindlimbs.We investigated whether this method can restore the flexible movement of the hindlimbs of paralyzed rats after hypertensive intracerebral hemorrhage.In a beam-walking test and ladder rung walking task,model rats exhibited an initial high number of slips,but improved in accuracy on the paretic side over time.At 17 weeks after surgery,rats gained approximately 58.2%accuracy from baseline performance and performed ankle motions on the paretic side.At 9 weeks after surgery,a retrograde tracing test showed a large number of fluoro-gold-labeled motoneurons in the left anterior horn of the spinal cord that supports the L4-to-L4 nerve roots.In addition,histological and ultramicrostructural findings showed axon regeneration of motoneurons in the anterior horn of the spinal cord.Electromyography and paw print analysis showed that denervated hindlimb muscles regained reliable innervation and walking coordination improved.These findings suggest that the L4-to-L4 nerve root transfer method for the treatment of hindlimb hemiplegia after hypertensive intracerebral hemorrhage can improve the locomotion of hindlimb major joints,particularly of the distal ankle.Findings from study support that the L4-to-L4 nerve root transfer method can effectively repair the hindlimb hemiplegia after hypertensive intracerebral hemorrhage.All animal experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Nanjing Medical University(No.IACUC-1906009)in June 2019.

Biomaterials reinforced MSCs transplantation for spinal cord injury repair

Due to the complex pathophysiological mechanism, spinal cord injury (SCI) has become one of the most intractable central nervous system (CNS) diseases to therapy. Stem cell transplantation, mesenchymal stem cells (MSCs) particularly, appeals to more and more attention along with the encouraging therapeutic results for the functional regeneration of SCI. However, traditional cell transplantation strategies have some limitations, including the unsatisfying survival rate of MSCs and their random diffusion from the injection site to ambient tissues. The application of biomaterials in tissue engineering provides a new horizon. Biomaterials can not only confine MSCs in the injured lesions with higher cell viability, but also promote their therapeutic efficacy. This review summarizes the strategies and advantages of biomaterials reinforced MSCs transplantation to treat SCI in recent years,which are clarified in the light of various therapeutic effects in pathophysiological aspects of SCI.

Umbilical cord-derived mesenchymal stem cell transplantation combined with hyperbaric oxygen treatment for repair of traumatic brain injury

Transplantation of umbilical cord-derived mesenchymal stem cells（UC-MSCs） for repair of traumatic brain injury has been used in the clinic. Hyperbaric oxygen（HBO） treatment has long been widely used as an adjunctive therapy for treating traumatic brain injury. UC-MSC transplantation combined with HBO treatment is expected to yield better therapeutic effects on traumatic brain injury. In this study, we established rat models of severe traumatic brain injury by pressurized fluid（2.5–3.0 atm impact force）. The injured rats were then administered UC-MSC transplantation via the tail vein in combination with HBO treatment. Compared with monotherapy, aquaporin 4 expression decreased in the injured rat brain, but growth-associated protein-43 expression, calaxon-like structures, and CM-Dil-positive cell number increased. Following combination therapy, however, rat cognitive and neurological function significantly improved. UC-MSC transplantation combined with HBO therapyfor repair of traumatic brain injury shows better therapeutic effects than monotherapy and significantly promotes recovery of neurological functions.

Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 m L/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test（indicating an improved ability to maintain body position）, prolonged tail-flick latency and foot-licking time（indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds）, and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

Does a combined intervention program of repetitive transcranial magnetic stimulation and intensive occupational therapy affect cognitive function in patients with post-stroke upper limb hemiparesis?

Low-frequency repetitive transcranial magnetic stimulation（LF-r TMS） to the contralesional hemisphere and intensive occupational therapy（i OT） have been shown to contribute to a significant improvement in upper limb hemiparesis in patients with chronic stroke. However, the effect of the combined intervention program of LF-r TMS and i OT on cognitive function is unknown. We retrospectively investigated whether the combined treatment influence patient＇s Trail-Making Test part B（TMT-B） performance, which is a group of easy and inexpensive neuropsychological tests that evaluate several cognitive functions. Twenty-five patients received 11 sessions of LF-r TMS to the contralesional hemisphere and 2 sessions of i OT per day over 15 successive days. Patients with right- and left-sided hemiparesis demonstrated significant improvements in upper limb motor function following the combined intervention program. Only patients with right-sided hemiparesis exhibited improved TMT-B performance following the combined intervention program, and there was a significant negative correlation between Fugl-Meyer Assessment scale total score change and TMT-B performance. The results indicate the possibility that LF-r TMS to the contralesional hemisphere combined with i OT improves the upper limb motor function and cognitive function of patients with right-sided hemiparesis. However, further studies are necessary to elucidate the mechanism of improved cognitive function.

Neuroprotection against vascular dementia after acupuncture combined with donepezil hydrochloride：P300 event related potential

Acupuncture can be used to treat various nervous system diseases.Here,168 vascular dementia patients were orally administered donepezil hydrochloride alone（5 mg/day,once a day for 56 days）,or combined with acupuncture at Shenting（DU24）,Tianzhu（BL10）,Sishencong（Extra）,Yintang（Extra）,Renzhong（DU26）,Neiguan（PC6）,Shenmen（HT7）,Fengchi（GB20）,Wangu（GB12） and Baihui（DU20）（once a day for 56 days）.Compared with donepezil hydrochloride alone,P300 event related potential latency was shorter with an increased amplitude in patients treated with donepezil hydrochloride and acupuncture.Mini-Mental State Examination score was also higher.Moreover,these differences in P300 latency were identified within different infarcted regions in patients treated with donepezil hydrochloride and acupuncture.These findings indicate that acupuncture combined with donepezil hydrochloride noticeably improves cognitive function in patients with vascular dementia,and exerts neuroprotective effects against vascular dementia.

Senegenin inhibits neuronal apoptosis after spinal cord contusion injury

Senegenin has been shown to inhibit neuronal apoptosis,thereby exerting a neuroprotective effect.In the present study,we established a rat model of spinal cord contusion injury using the modified Allen＇s method.Three hours after injury,senegenin（30 mg/g） was injected into the tail vein for 3 consecutive days.Senegenin reduced the size of syringomyelic cavities,and it substantially reduced the number of apoptotic cells in the spinal cord.At the site of injury,Bax and Caspase-3 m RNA and protein levels were decreased by senegenin,while Bcl-2 m RNA and protein levels were increased.Nerve fiber density was increased in the spinal cord proximal to the brain,and hindlimb motor function and electrophysiological properties of rat hindlimb were improved.Taken together,our results suggest that senegenin exerts a neuroprotective effect by suppressing neuronal apoptosis at the site of spinal cord injury.

Bone marrow mesenchymal stem cells transplantation promotes the release of endogenous erythropoietin after ischemic stroke

This study investigated whether bone marrow mesenchymal stem cell（BMSC） transplantation protected ischemic cerebral injury by stimulating endogenous erythropoietin. The model of ischemic stroke was established in rats through transient middle cerebral artery occlusion. Twenty-four hours later, 1 × 106 human BMSCs（h BMSCs） were injected into the tail vein. Fourteen days later, we found that h BMSCs promoted the release of endogenous erythropoietin in the ischemic region of rats. Simultaneously, 3 μg/d soluble erythropoietin receptor（s EPOR） was injected into the lateral ventricle, and on the next 13 consecutive days. s EPOR blocked the release of endogenous erythropoietin. The neurogenesis in the subventricular zone was less in the h BMSCs ＋ s EPOR group than in the h BMSCs ＋ heat-denatured s EPOR group. The adhesive-removal test result and the modified Neurological Severity Scores（m NSS） were lower in the h BMSCs ＋ s EPOR group than in the heat-denatured s EPOR group. The adhesive-removal test result and m NSS were similar between the h BMSCs ＋ heat-denatured s EPOR group and the h BMSCs ＋ s EPOR group. These findings confirm that BMSCs contribute to neurogenesis and improve neurological function by promoting the release of endogenous erythropoietin following ischemic stroke.

Nischarin-siRNA delivered by polyethyleniminealginate nanoparticles accelerates motor function recovery after spinal cord injury

A previous study by our group found that inhibition of nischarin promotes neurite outgrowth and neuronal regeneration in Neuro-2 a cells and primary cortical neurons.In recent years,more and more studies have shown that nanomaterials have good prospects in treatment of spinal cord injury.We proposed that small interfering RNA targeting nischarin（Nis-si RNA） delivered by polyethyleneimine-alginate（PEIALG） nanoparticles promoted motor function recovery in rats with spinal cord injury.Direct microinjection of 5 μL PEI-ALG/Nis-si RNA into the spinal cord lesion area of spinal cord injury rats was performed.From day 7 after surgery,Basso,Beattie and Bresnahan score was significantly higher in rats from the PEI-ALG/Nis-si RNA group compared with the spinal cord injury group and PEI-ALG/Control-si RNA group.On day 21 after injection,hematoxylin-eosin staining showed that the necrotic area was reduced in the PEI-ALG/Nis-si RNA group.Immunohistochemistry and western blot assay results confirmed successful inhibition of nischarin expression and increased protein expression of growth-associated protein-43 in the PEI-ALG/Nis-si RNA group.These findings suggest that a complex of PEI-ALG nanoparticles and Nis-si RNA effectively suppresses nischarin expression,induces expression of growth-associated protein-43,and accelerates motor function recovery after spinal cord injury.