Primate Spinal Cord Injury Research Articles

Transplantation of human neural stem cells for spinal cord injury in primates

Recent studies have shown that delayed transplantation of neural stem/progenitor cells (NSPCs) into the injured spinal cord can promote functional recovery in adult rats. Preclinical studies using nonhuman primates, however, are necessary before NSPCs can be used in clinical trials to treat human patients with spinal cord injury (SCI). Cervical contusion SCIs were induced in 10 adult common marmosets using a stereotaxic device. Nine days after injury, in vitro-expanded human NSPCs were transplanted into the spinal cord of five randomly selected animals, and the other sham-operated control animals received culture medium alone. Motor functions were evaluated through measurements of bar grip power and spontaneous motor activity, and temporal changes in the intramedullary signals were monitored by magnetic resonance imaging. Eight weeks after transplantation, all animals were sacrificed. Histologic analysis revealed that the grafted human NSPCs survived and differentiated into neurons, astrocytes, and oligodendrocytes, and that the cavities were smaller than those in sham-operated control animals. The bar grip power and the spontaneous motor activity of the transplanted animals were significantly higher than those of sham-operated control animals. These findings show that NSPC transplantation was effective for SCI in primates and suggest that human NSPC transplantation could be a feasible treatment for human SCI.

Functional recovery by grafted human neural stem cells after spinal cord injury in primates

Functional recovery by grafted human neural stem cells after spinal cord injury in primates

Spontaneous and augmented growth of axons in the primate spinal cord: effects of local injury and nerve growth factor-secreting cell grafts.

Little is known about molecular and cellular responses to spinal cord injury in primates. In this study, the normal milieu of the primate spinal cord was disturbed by multiple needle penetrations and cell injections in the mid-thoracic spinal cord; subsequent effects on local axons and expression of extracellular matrix (ECM) molecules were examined, together with effects of cellular delivery of nerve growth factor (NGF) to the injured region. Four adult rhesus monkeys each received injections of two grafts of autologous fibroblasts genetically modified to secrete human NGF, and, in control injection sites, two separate grafts of autologous fibroblasts transduced to express the reporter gene, beta-galactosidase. Three months later, Schwann cells extensively infiltrated the region of localized injury and penetrated both NGF and control fibroblast grafts. Marked upregulation of several ECM molecules occurred, including chondroitin and heparan sulfate proteoglycans and type IV collagen, in or adjacent to all injection sites. Schwann cells were an apparent source of some ECM expression. Spinal cord sensory axons and putative coerulospinal axons extended into both graft types, but they penetrated NGF grafts to a significantly greater extent. Many of these axons expressed the cell adhesion molecule L1. Thus, extensive cellular and molecular changes occur at sites of localized primate spinal cord injury and grafting, attributable in part to migrating Schwann cells, and are accompanied by spontaneous axonal plasticity. These molecular and cellular events closely resemble those observed in the rodent spinal cord after injury. Furthermore, as in rodent studies, cellular delivery of a trophic factor significantly augments axonal plasticity in the primate spinal cord.

Allodynia and hyperalgesia within dermatomes caudal to a spinal cord injury in primates and rodents

Publisher Summary This chapter discusses allodynia and hyperalgesia within dermatomes caudal to a spinal cord injury in primates and rodents. Persistent pain of central nervous system origin is a common consequence of spinal cord injury and is highly refractory to treatment. In order to understand mechanisms and develop treatments for this condition, an effective laboratory animal model is needed. Clinical observations indicate that interruption of the spinothalamic tract is a prerequisite for development of deafferentation zone pain referred to segments well below the site of spinal cord injury. Therefore, a series of studies has evaluated nociceptive responses of monkeys and rats before and after an anterolateral spinal lesion. Attention to the variability of responses to a wide range of stimulus intensities across testing sessions has shown that contralateral sensitivity oscillates from nearly analgesic to allodynic. All animals cycled between these states of hyper- or hypo-sensitivity. Information from animal model and observations of human beings indicate that superficial lesions of lateral spinal cord white matter that do not extend into the gray matter produce an enduring contralateral hypoalgesia, with minimal allodynia and/or central pain.

The reorganization of somatosensory and motor cortex after peripheral nerve or spinal cord injury in primates

The reorganization of somatosensory and motor cortex after peripheral nerve or spinal cord injury in primates

Nonpyramidal motor activation produced by stimulation of the cerebellum, direct or transcranial: a cerebellar evoked potential.

There is a need to monitor the functional status of the motor pathways well enough to predict the state of that function during operations and in injured or diseased patients. We previously reported that a motor evoked potential (MEP) can be produced by direct or transcranial stimulation of the motor cortex in both cats and humans. This signal descends through both the dorsolateral and ventral spinal cord and is primarily localized in the pyramidal tracts, producing a peripheral nerve signal and an electromyogram (EMG) response. It is more sensitive to injury than the somatosensory evoked potential (SEP). We report here that one can stimulate the cerebellar cortex, either directly or transcranially, and produce a descending signal in the spinal cord that has different characteristics from the MEP. The cerebellar evoked potential (CEP), located in the dorsolateral and the ventral cord, has an earlier latency and a faster conduction velocity than the MEP. It is predominantly ipsilateral with some contralateral components and also produces EMG responses. In the peripheral nerves, the CEP often produces a pattern of several waves that is different from the one or two predominant contralateral waves of the MEP. The CEP is not diminished by pyramidotomy. It arises from two sites on the cerebellar cortex, medial and lateral. The pathways activated may be the vestibulospinal, rubrospinal, reticulospinal, and fastigiospinal systems. This test seems to offer a monitor of selected motor pathways in the spinal cord largely separate from and complementary to the MEP. The ventral pathways activated probably include those demonstrated to be most essential to basic ambulation after spinal cord injury in primates. Also of importance, one type of evoked potential can facilitate another, which provides additional diagnostic tests. The CEP should be of investigative and clinical value.

Nonpyramidal motor activation produced by stimulation of the cerebellum, direct or transcranial

There is a need to monitor the functional status of the motor pathways well enough to predict the state of that function during operations and in injured or diseased patients. We previously reported that a motor evoked potential (MEP) can be produced by direct or transcranial stimulation of the motor cortex in both cats and humans. This signal descends through both the dorsolateral and ventral spinal cord and is primarily localized in the pyramidal tracts, producing a peripheral nerve signal and an electromyogram (EMG) response. It is more sensitive to injury than the somatosensory evoked potential (SEP). We report here that one can stimulate the cerebellar cortex, either directly or transcranially, and produce a descending signal in the spinal cord that has different characteristics from the MEP. The cerebellar evoked potential (CEP), located in the dorsolateral and the ventral cord, has an earlier latency and a faster conduction velocity than the MEP. It is predominantly ipsilateral with some contralateral components and also produces EMG responses. In the peripheral nerves, the CEP often produces a pattern of several waves that is different from the one or two predominant contralateral waves of the MEP. The CEP is not diminished by pyramidotomy. It arises from two sites on the cerebellar cortex, medial and lateral. The pathways activated may be the vestibulospinal, rubrospinal, reticulospinal, and fastigiospinal systems. This test seems to offer a monitor of selected motor pathways in the spinal cord largely separate from and complementary to the MEP. The ventral pathways activated probably incude those demonstrated to be most essential to basic ambulation after spinal cord injury in primates. Also of importance, one type of evoked potential can facilitate another, which provides additional diagnostic tests. The CEP should be of investigative and clinical value. (Neurosurgery 19:163-176, 1986)

Studies of the treatment and pathophysiology of acute spinal cord injury in primates.

Studies of the treatment and pathophysiology of acute spinal cord injury in primates.

Ischemia in primate spinal cord injury.

✓ Lactate accumulation in spinal cord tissue following trauma was determined to ascertain the role and magnitude of ischemia. High thoracic and low thoracic laminectomies were performed on each of nine rhesus monkeys. The lower exposed cord was traumatized with a calibrated blow of 300 gm cm. The upper exposed cord served as a nontraumatized control. At time intervals of 1.5 min to 48 hrs after trauma, both cord segments were removed and assayed for lactic acid. Lactate in nontraumatized segments averaged 3.64 mM/kg tissue, with a range of 2.20 to 4.95. Lactate in traumatized segments removed in from 1.5 min to 12 hrs from six monkeys averaged 5.50 mM/kg tissue, with a range of 4.32 to 6.46. Lactate in traumatized segments from three monkeys 18 to 40 hrs after trauma averaged 4.07 mM/kg, with a range of 3.20 to 5.18. This finding supports the concept that ischemia plays a role early in the traumatic process in spinal cord injury.

Study of functional recovery produced by delayed localized cooling after spinal cord injury in primates.

N SPITE of the sophisticated advances in modern surgical therapy, the present day management of spinal cord trauma generally remains unsatisfactory. 6,~,:3 Current methods used in the treatment of spinal cord trauma consist of immobilization with skeletal traction, surgical decompression with or without incision of dural coverings, and immediate or delayed bony fusion to provide stabilization. Controversy even exists as to the merits of conservative treatment versus surgical decompression. s,'~,1'-1:~,1~,~7,:~~ Even among those favoring early laminectomy in patients displaying sensory-motor paralysis associated with a spinal fluid block, there is no unanimity of opinion whether the dura should be opened or left intact. In reviewing other approaches to the problem of spinal cord injury, we were impressed with some of the work relating to the protective effect of cold on brain. It has been shown that hypothermia will decrease the cerebral metabolic demand, reduce brain volume, bring about a reduction in the inflammatory response to brain injury, and allow the brain to tolerate extended periods of circulatory arrest? 4,1a-2u24,~'~,~'J,33 It has also been demonstrated that total body cooling to 30~ will protect the spinal cord of the dog during occlusion of the thoracic aorta? 5,16 Because of the accessibility of the injured segment of the spinal cord during surgical laminectomy, an attempt has been made to assess the practical advantages of direct