A comprehensive look at the psychoneuroimmunoendocrinology of spinal cord injury and its progression: mechanisms and clinical opportunities

Spinal cord injury(SCI)is a devastating and disabling medical condition generally caused by a traumatic event(primary injury).This initial trauma is accompanied by a set of biological mechanisms directed to ameliorate neural damage but also exacerbate initial damage(secondary injury).The alterations that occur in the spinal cord have not only local but also systemic consequences and virtually all organs and tissues of the body incur important changes after SCI,explaining the progression and detrimental consequences related to this condition.Psychoneuroimmunoendocrinology(PNIE)is a growing area of research aiming to integrate and explore the interactions among the different systems that compose the human organism,considering the mind and the body as a whole.The initial traumatic event and the consequent neurological disruption trigger immune,endocrine,and multisystem dysfunction,which in turn affect the patient's psyche and well-being.In the present review,we will explore the most important local and systemic consequences of SCI from a PNIE perspective,defining the changes occurring in each system and how all these mechanisms are interconnected.Finally,potential clinical approaches derived from this knowledge will also be collectively presented with the aim to develop integrative therapies to maximize the clinical management of these patients.

Viral-mediated gene therapy for spinal cord injury(SCI) from a translational neuroanatomical perspective

Repairing spinal cord injury（SCI）is one of the most challenging endeavours currently faced by neuroscientists.One promising therapeutic avenue to reverse this once considered permanent condition is gene therapy,however progress has been hampered by the anatomica intricacy of the spinal cord itself as well as by the sheer complexity of the molecular cascades of events that take place in the injured cord.

The future of bone marrow stromal cell transplantation for the treatment of spinal cord injury

Bone marrow stromal cell （BMSC） transplantation therapy is a promising approach for treating spinal cord injury （SCI）, based on a number of experimental and clinical reports （Wright et al., 2011）. BMSCs are a source of neuroregenerative somatic stem cells that are without the potential for tumorigenicity. Although clinical studies of autologous BMSC transplantation have been reported in Asia （fiang et al., 2013; Yoon et al., 2007）, in Japan, it is currently an uncommon procedure and highly controversial as well. This perspective paper provides an overview of the clinical effectiveness of BMSC trans- 191antation and a proposal to enhance its use as a viable therapy.

Facilitating transparency in spinal cord injury studies using data standards and ontologies

Progress in developing robust therapies for spinal cord injury （SCI）, trau- matic brain injury （TBI） and peripheral nerve injury has been slow. A great deal has been learned over the past 30 years regarding both the intrinsic factors and the environmental factors that regulate axon growth, but this large body of information has not yet resulted in clinically available thera- peutics. This therapeutic bottleneck has many root causes, but a consensus is emerging that one contributing factor is a lack of standards for experi- mental design and reporting. The absence of reporting standards, and even of commonly accepted definitions of key words, also make data mining and bioinformatics analysis of neural plasticity and regeneration difficult, if not impossible. This short review will consider relevant background and poten- tial solutions to this problem in the axon regeneration domain.

Role of chondroitin sulfate proteoglycan signaling in regulating neuroinflammation following spinal cord injury

Spinal cord injury （SCI） elicits a robust inflammatory response that is a hallmark of the secondary injury mechanisms. Neuroinflammation is orchestrated initially by the response of resident astrocytes and microglia to injury, which subsequently facilitates the recruitment of peripheral immune cells into the SCI lesion （Orr and Gensel, 2018）. This inflammatory response contributes to cell death and tissue degeneration through the production of pro-inflammatory cytokines and chemokines, free radicals and proteolytic enzymes. However, neuroinflammatory cells also play beneficial regulatory role in repair mechanisms after SCI by adopting a reparative and wound healing phenotype （Orr and Gensel, 2018; Tran et al., 2018）. Hence, understanding the underlying mechanisms by which immune cells are reg- ulated within the microenvironment of injury would aid in harnessing the reparative potential of inflammation following SCI.

Glial cell line-derived neurotrophic factor as a treatment after spinal cord injury

Spinal cord injury（SCI）is a devastating trauma that currently affects 54 people out of every million,which is approximately 270,000people in the United States（National Spinal Cord Injury Statistical Center,2013）.The effects of such an injury can cause a loss of both motor and sensory function below the injury site,normally leaving the patient unable to care for themselves entirely and relying on family and friends to provide personal care.Currently there are no.

Genetically modified human umbilical cord blood cells as a promising strategy for treatment of spinal cord injury

Spinal cord injury （SCI） continues to be a pressing health and social problem. The injury leads to neuronal and glial cell death accompanied by degeneration of nerve fibers. There are currently no particularly effective treatments. SCI causes profound disabil- ity of people affected and has attracted increased attention in the international field of neuroregeneration. For the past two decades, much hope has been placed in cell therapies for the restoration of both structure and function of the injured spinal cord. Embryonic and neural stem cells, olfactory ensheathing cells, microglia-like cells, Schwann cells, mesenchymal stem cells.

Relay strategies combined with axon regeneration: a promising approach to restore spinal cord injury

For decades, numerous investigations have only focused on axon regeneration to restore function after traumatic spinal cord injury （SCI）, as interrupted neuronal pathways have to be reconnected for sensorimotor and autonomic recovery to occur. Experimental approaches have ranged from drug delivery and cell transplantation to genetic manipulations. Certainly, it would be an extraordinary achievement for injured axons to regenerate over long distances, to form synapses with target neurons, and to result in dramatic functional improvement. However, these efforts have been rewarded with limited success to date suggesting that axon regeneration alone may be insufficient to repair compromised functions.

Micromechanical adaptation as a treatment for spinal cord injury

Spinal cord injury: Thus far injury of the spinal cord is incurable and, in the majority of cases, a devastating and life-changing event. The worldwide incidence rate of spinal cord injury (SCI) ranges from 250,000 to 900,000 (www.who.int, 2013;Kumar et al., 2018) new cases per year. SCI outcome includes the damage of axons, demyelination of axons, loss of signal transduction, and consequential long-lasting motor and sensory deficits. Additionally, the non-use of muscles can lead to atrophy and joint contractures, thereby further reducing the possibility of recovery. Depending on the spinal level and the severity of the injury, the extent of the damage can vary and spontaneous recovery is possible to varying degrees.

Neural prostheses for restoring functions lost after spinal cord injury

Spinal cord injury（SCI）is a debilitating condition that affects more than 2.5 million individuals worldwide（Thuret et al.,2006）.In addition to its devastating effects on the individual,this disease is a heavy burden to the society in terms of health care costs, which are estimated in billions of dollars annually in most developed countries （Cadotte and Fehlings, 2011）.

Interactions of primary insult biomechanics and secondary cascades in spinal cord injury： implications for therapy

The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.

Commentary on:“Facilitating transparency in spinal cord injury studies using data standards and ontologies”

Commentary Most would agree that providing comprehensive detail in scientific reporting is critical for the development of mean- ingful therapies and treatments for diseases. Such stellar practices 1） allow for reproduction of experiments to con- firm results, 2） promote thorough analyses of data, and 3） foster the incremental advancement of valid approaches. Unfortunately, most would also agree we have far to go to reach this vital goal （Hackam and Redelmeier, 2006; Prinz et al., 2011; Baker et al., 2014）.

Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain

Spinal cord injury （SCI） currently ranks second after mental retarda- tion among neurological disorders in terms of cost to society. Pain is a debilitating consequence of SCI related to the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes of surviving tissues （Yezierski, 2005; D＇Angelo et al., 2013）.

Reducing intrathecal pressure after traumatic spinal cord injury: a potential clinical target to promote tissue survival

Spinal cord injury （SCI） is an unexpected event that is both devastating and debilitating, resulting in not just motor and sensory loss, but also autonomic dysfunction of the bladder, bowel and sexual organs. Currently, there are no treatments available to improve outcome follow- ing SCI, leaving individuals with permanent and lifelong physical disability. Worldwide it is estimated that more than 500,000 people sustain a SCI each year, with average lifetime cost of paraplegia and quadriplegia estimated at $5 million and $9.5 million respectively. We therefore urgently need effective therapies to improve quality of life following SCI, and this requires a greater understanding of how cell and axonal injury develops after the traumatic event.

“Bad regenerators” die after spinal cord injury:insights from lampreys

In mammalian species, including humans, spinal cord in- jury （SCI） leads to permanent disability. A major cause of disability after SCI is the failure of axotomized descending axons to regenerate across the trauma zone and to reconnect to they appropriate targets distal to the site of injury. Cur- renfly, major research efforts are devoted to find new ways of promoting the regrowth of damaged descending axons. However, activation of axonal regrowth will depend on the survival of the axotomized descending brain neurons.

15 Years of Evolution of Non-Invasive EEG-Based Methods for Restoring Hand &Arm Function with Motor Neuroprosthetics in Individuals with High Spinal Cord Injury: A Review of Graz BCI Research

Patients who suffer from a high spinal cord injury have severe motor disabilities in the lower as well as in the upper extremities. Thus they rely on the help of other people in everyday life. Restoring the function of the upper limbs, especially the grasp function can help them to gain some independence. Using EEG-based neuroprosthetics is a way to help tetraplegic people restore different grasp types as well as moving the arm and the elbow. In this work an overview of non-invasive EEG-based methods for restoring the hand and arm function with the use of neuroprosthetics in individuals with high spinal cord injury is given. Since the Graz BCI group is leading in this area of non-invasive research mainly, the work of this group is represented.

Reorganization of spinal neural circuitry and functional recovery after spinal cord injury

The ability of the adult central nervous system to reorganize its circuits over time is the key to understand the functional improvement in subjects with spinal cord injury （SCI）. Adaptive changes within spared neuronal circuits may occur at cortical, brainstem, or spinal cord level, both above and below a spinal lesion （Bareyre et al., 2004）. At each level the reorganization is a very dynamic process, and its degree is highly variable, depending on several factors, including the age of the subject when SCI has occurred and the rehabilitative therapy. The use of electrophysiological techniques to assess these functional changes in neural networks is of great interest, because invasive methodologies as employed in preclinical models can obviously not be used in clinical studies.

New perspectives for investigating respiratory failure induced by cervical spinal cord injury

Traumatic cervical spinal cord injury （SCI）, with an annual incidence of 12,000 new cases in USA （NSCISC 2013）, causes devastating locomotor and respiratory paralysis and unfortunately compromises the human patient＇s lifespan. The severity of the injury depends on the degree and the extent of the initial trauma. In fact, respiratory failure is the leading cause of mortality following upper cervical SCI. However, 80% of the injuries are incomplete, allowing some modest spontaneous recovery. To date, no effective treatment is available in order to restore the loss of function.

A comprehensive study of long-term skeletal changes after spinal cord injury in adult rats

Spinal cord injury（SCI）-induced bone loss represents the most severe osteoporosis with no effective treatment.Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To mimic chronic SCI in human patients, we performed a comprehensive analysis of long-term structural and mechanical changes in axial and appendicular bones in adult rats after SCI. In this experiment, 4-month-old Fischer 344 male rats received a clinically relevant T13 contusion injury. Sixteen weeks later, sublesional femurs, tibiae,and L4 vertebrae, supralesional humeri, and blood were collected from these rats and additional non-surgery rats for micro-computed tomography（m CT）, micro-finite element, histology, and serum biochemical analyses.At trabecular sites, extreme losses of bone structure and mechanical competence were detected in the metaphysis of sublesional long bones after SCI, while the subchondral part of the same bones showed much milder damage. Marked reductions in bone mass and strength were also observed in sublesional L4 vertebrae but not in supralesional humeri. At cortical sites, SCI induced structural and strength damage in both sub- and supralesional long bones. These changes were accompanied by diminished osteoblast number and activity and increased osteoclast number and activity. Taken together, our study revealed site-specific effects of SCI on bone and demonstrated sustained inhibition of bone formation and elevation of bone resorption at the chronic stage of SCI.

Autophagy in degenerating axons following spinal cord injury: evidence for autophagosome biogenesis in retraction bulbs

Macroautophagy （here autophagy） is a catabolic mechanism responsible for the degradation of bulk cytoplasm, long-lived proteins and organeUes. During autophagy, the cargos are engulfed by double-membrane structures named phagophores, which expand to form the autophagosomes. Subsequently, these autophagosomes fuse with lysosomes, in which the cytoplasmic cargos are degraded. Autophagy is a constitutive pro- cess, which plays an important role in cellular homeostasis. In primary neurons autophagosome formation occurs continuously and preferentially at the distal end of axons. On the other hand, autophagy is increased by different stresses, and its dysregulation or excessive induction may lead to detrimental effects. Many neurological disorders have been associated with alterations in the autophagic pathway and an increase in autophagy during axonal degeneration was described.