2007 Medical Student Research Program

Thermal injury is characterized by increased microvascular permeability, which causes massive fluid volume requirements during resuscitation. Peripheral tissue thermal injury often causes systemic reactions, such as fever, hyperalgesia, anorexia, and increased permeability of the blood-brain-barrier (BBB). Since thermal injury remains one of the leading causes of childhood death in the United States (one million children are injured and 3,000 children die each year as a result of burn trauma, according to the Children's burn Awareness Program, Chicago), and since generalized encephalopathy is the most common neurologic complication of thermal injury in children occurring with a 14% incidence, research on the effect of peripheral thermal injury on cerebrovascular integrity is essential.

The two specific aims of our current studies are 1) to evaluate injurious effect of peripheral thermal injury on BBB integrity; 2) to investigate inflammatory mechanisms underlying BBB dysfunction. These studies could provide important new information on the mechanistic tissues in thermal injury on the central nervous system in the rat model. The results may lead to development of effective therapies on thermal injury beyond the level that current treatments achieve.

Barone M, Jimenez DF, Huxley VH, Yang XY. (1997) Morphologic Analysis of the Cerebral Microcirculation after Thermal Injury and the Response to Fluid Resuscitation. Acta Neurochirurgica Supplements. 70:267-268

Barone M, Jimenez DF, Huxley VH, Yang XY. (1997) Cerebral Vascular Response to Hypertonic Fluid Resuscitation in Thermal Injury. Acta Neurochirurgica Supplements. 70:254-256

Barone M, Jimenez DF, Huxley VH, Yang XY. (2000) In Vivo Visualization of Cerebral Microcirculation in Systemic Thermal Injury. Journal of Burn Care & Rehabilitation. 21:20-25

Jimenez DF, Barone CM, Tigno T Yang XF, Clapper A. (1997) The Effects of Methylmethacrylate's Hyperthermic Polymerization on Cerebral Vascular Permeability. Acta Neurochirurgica Supplements. 70:265-266

Berger J, Sprague SM, Wu Y, Davis WW, Barone CM, Jimenez DF, Ding Y(2005) Blood Brain Barrier Dysfunction after Peripheral Thermal Injury Is Associated with Early Expression of Matrix Metalloproteinase (MMP) in Rat

Berger J, Sprague SM, Wu Y, Mrizek M., Davis WW, Barone CM, Jimenez FD, Ding Y (2005) Peripheral Thermal Injury Causes Brain Inflammation Which is Modulated by Cytokines

Reyes Jr. R, Wu YM, Lai Q, Mrizek M, Berger J, Jimenez DF, Barone CM, Ding Y. (2006). Early Inflammatory Rresponse in Rat Brain after Peripheral Thermal Injury. Neuroscience Letters. 407 (1):11-5.

Ding YH, Mrizek M, Lai Q, Wu Y, Li J, Davis W, Ding Y. (2006 Exercise Preconditioning Inhibit Expressions of TNF- α Receptors in Stroke. Current Neurovascular Res. 3 (4):263-71.

Swann K, Berger J, Sprague S, Wu Y, Davis W, Jimenez DF, Barone CM, Ding Y. (2007) Peripheral Thermal Injury Causes Early Blood Brain Barrier Dysfunction Associated with Expression of Matrix Metalloproteinase (MMP) in Rat. Brain Res. 1129: 26-33

Berger J, Sprague S, Wu Y, Davis W, Jimenez DF, Barone CM, Ding Y. (2007) Peripheral Thermal Injury Causes Early Blood Brain Barrier Dysfunction Associated with Expression of Matrix Metalloproteinase (MMP) in Rat. Neurological Res. (in press)

Clinically, there are no effective therapeutic tools for amelioration of cerebral ischemia/reperfusion caused by stroke. It has been emphasized that ischemia/reperfusion injury is initiated by a series of events occurring at the blood-vascular-parenchymal interface, leading to inflammatory injury, disruption of endothelial integrity, and neuron death. B rain cooling is a remarkable neuroprotectant in stroke therapy if applied soon after onset of ischemia. Due to management difficulties, hypothermic induction by surface cooling in current clinical settings is vastly limited. Results from our recent studies indicate that highly localized intra-arterial “flushing” of the ischemic territory prior to reperfusion significantly reduces brain injury in experimental stroke. The mechanisms of neuroprotection conferred by hypothermia or vascular infusion are thought to be multifunctional. This leads to a new hypothesis that local intraarterial cold hypertonic solution infusion, concurrent with regional cerebral hypothermia in ischemic areas prior to reperfusion, synergistically minimizes brain injury. This may provide the ultimate neuroprotective “cocktail” that limits inflammation and neurovascular disruption during reperfusion. In our laboratory, we define the therapeutic and systematic optimization of a combined infusion and cooling procedure in our stroke model by evaluating long-term motor deficits, brain infarct volume, as well as cerebral and pulmonary edema. W e also elucidate protective mechanisms of the novel model that targets the brains vascular-parenchymal interface by reducing inflammatory mediators, endothelial activation of nuclear factor kappa-B, leukocyte infiltration, matrix metalloproteinase expression, and blood-brain barrier disruption.

Results from these studies will provide fundamental information on the establishment of a novel therapeutic procedure in stroke beyond the levels achieved by current therapy. Intravascular cold infusion into the ischemic region, which combines recanalization of the occluded middle cerebral artery (mechanically or thrombolytically) and administration of neuroprotective drugs, may improve outcome in stroke patients.

Ding, Y., Yao , B., Yang, D-Z, Park, H., McAllister J.P., Diaz, FG. (2002) Pre-reperfusion Flushing of Ischemic Territory: A Therapeutic Study on Ischemia-reperfusion Injury in Stroked Rats Using Histological and Behavioral Assessments. Journal of Neurosurgery . 96:310-319.

Ding, Y., Li, J., Phillis J.W. Rafols J.A., Diaz, FG. (2002) Pre-reperfusion Flushing into Ischemic Territory Reduces Inflammatory Injury in Rat with Transient Middle Cerebral Artery Occlusion. Stroke . 33: (10) 2492-2498.

Ding Y., Young C, Li C, Luan X, McAllister JP, II, Clark J, Diaz FG (2003) Reduced Inflammatory Mediator expression by Pre-reperfusion Infusion into Ischemic Territory : A real-time Polymerase Chain Reaction Analysis.Neurosci.Lett. 353: 173-176.

Ding YH; Li J, Rafols, JA, Ding, Y. (2004) Reduced Brain Edema and Matrix Metalloproteinase (MMP) Expression By Pre-reperfusion Infusion into Ischemic Territory in Rat. Neuroscience Letters. 372: 35-39.

Ding, Y., Li, J., Luan XD., Lai Q., McAllister J.P., Phillis, J.W., Guthikonda, M., Diaz, FG (2004) Neuroprotection of Regional Brain Cooling and Local Saline Infusion into Ischemic Territory in Rats with Transient Middle Cerebral Artery Occlusion. Neurosurgery . 54 (4):956-965.

Luan XD, Li J, McAllister JP, II, Clark J, Diaz FG, Fessler RD. , Ding Y. (2004) Regional Brain Cooling Induced by Local Saline Infusion into Ischemic Territory Reduces Brain Inflammation in Stroke. Acta Neuropathologica. 107:227-234.

Li J, Luan X, Clark J, Rafols JA, McAllister JP, II, Diaz, FG. Ding Y. (2004) Regional Brain Cooling Induced by Local Saline Infusion into Ischemic Territory Produced A Long-term Neuroprotection in Ischemic Rats Using a Behavioral Assessment. Neurological Res 26:677-683.

Ding, Y, Li, J., Lai Q., Azam, S., Rafols, JA., Diaz, FG. (2002) Functional Improvement After Motor Training Is Correlated with Synaptic Plasticity in Rat Thalamus. Neurological Research . 24:(12) 829-836.

Ding, Y, Li, J., Clark J., Diaz F.G., Rafols, JA. (2003) Synaptic Plasticity in Thalamic Nuclei Enhanced by Motor Skill Training in Rat with Transient Middle Cerebral Artery Occlusion. Neurological Research . 23:(2) 189-194.

Ding, Y, Li, J., Luan, XD, Lai Q., Rafols, JA, Diaz, FG (2004) Motor Balance and Coordination Training Enhances Functional Outcome in Rat with Transient Middle Cerebral Artery Occlusion. Neuroscience . 123: 667-674.

Ding, Y, Li, J., Luan XD, Rafols JA, Phillis, JW, Diaz, FG (2004) Exercise Pre-conditioning Reduces Brain Damage in Ischemic Rats That May be Associated with Regional Angiogenesis and Cellular Overexpression of Neurotrophin. Neuroscience 124: 583-591.

Li J, Luan X, Clark J, Rafols JA, Ding Y. (2004) Neuroprotection against transient cerebral ischemia by exercise pre-conditioning in rats. Neurological Res 26 (6):404-408.

Ding YH; Li J, Rafols, JA, Clark JC; McAllister II JP, Diaz, F. G.; Guthikonda, M., Ding, Y. (2004) Exercise-induced angiogenic factors and reduction in ischemia/reperfusion injury. Current Neurovascular Res 1 (5): 411-420.

Ding Y, Ding YH, Young C, Luan X, Li J, Rafols JA, Phillis JW, Clark JC. (2005) Exercise pre-conditioning reduces inflammatory injury in ischemic rats during reperfusion. Acta Neuropathologica. 109:237-246.

Li J, Ding YH, Rafols JA, Lai Q, McAllister JP II , Ding Y-C (2005) . Increased Astrocyte Proliferation in Rats After Running Exercise. Neurosci.Lett. 386(3):160-4.

Ding YH, Li J, Rafols, JA, Clark JC, Guthinkonda, M, Ding Y-C. Angiogenesis and Expression of Angiogenic Factors in Aging Rats after Exercise.

Ding YH, Li J, Rafols JA, Clark JC, Guthinkonda, M, Ding Y. (2006) Angiogenesis and Expression of Angiogenic Factors in Aging Rats after Exercise. Current Neurovascular Res. 3 (1):15-23.

Ding YH, Mrizek M, Lai Q, Wu Y, Li J, Davis W, Ding Y. (2006) Exercise Preconditioning Inhibit Expressions of TNF- α Receptors in Stroke. Current Neurovascular Res. 3 (4):263-71.

Increasing evidence has revealed that exercise produces endogenous protection in focal cerebral ischemia through a variety of mechanisms. However, whether exercise preconditioning promotes protection in stroke by enhancing the integrity of the neurovascular unit (a construct consisting of microvascular endothelium, astroglia, neurons, and the extracellular matrix) has never been investigated.

We first determine if exercise enhances brain microvascular integrity against ischemia/reperfusion injury by maintaining blood brain barrier (BBB) function and proper structural relations of endothelium, astrocyte, and intervening basal lamina in the neurovascular unit, leading to functional recovery after stroke. We investigate if the reduction in ischemic injury is caused by endothelial and astrocytic integrin upregulation after exercise preconditioning. Finally, we elucidate causal roles of tumor necrosis factor-alpha (TNF-alpha) induced during exercise in mediating integrin expression as well as BBB function and behavioral outcome. Identification of the TNF-alpha-integrin mechanism in exercise-induced neuroprotection would help establish an efficacious approach for stroke treatment beyond levels achieved by current studies. Insights gained by this investigation are also likely to refine evolving concepts of the neurovascular unit.

Ding YH, Rafols, JA, Li J, Denise A. Bessert, Ding Y. (2005) Exercise Pre-conditioning Strengthens Brain Microvascular Integrity in A Rat Stroke Model. Neurological Res.

Ding YH, Rafols, JA, Li J, Denise A. Bessert, Ding Y. (2005) Upregulation of Tumor Necrosis Factor- a and Integrins After Exercise Pre-conditioning Enhances Cerebrovascular Integrity in Ischemic Rats.

Ding Y, Clark JC (2006) Cerebrovascular Injury in Stroke. Neurological Res. 28 (1):3-10.

Ding YH, Rafols HA, Li J, McAllister JP II, Guthinkonda M, Ding Y. (2006) Neuroprotective Effect of Exercise Pre-conditioning on Brain Integrity After Experimental Stroke in Rats. Neurological Res. 28 (2):184-9.

Ding YH, Li J, Rafols JA, Clark JC, Ding Y. (2006) Upregulation of Tumor Necrosis Factor-α and Integrins After Exercise Pre-conditioning Enhances Cerebrovascular Integrity in Ischemic Rats. Acta Neuropathologica. 112 (1):74- 84.

Davis W, Mahale S, Ding Y. (2007) Exercise Ameliorates BBB Dysfunction in Stroke by Enhancing Basal Lamina. Neurological Res. (in press).

Mechanisms and Treatment of Hydrocephalus

Neurotolerance to chronic ischemia during hydrocephalus. The objective of this project is to investigate neurotolerance during chronic ischemia in hydrocephalus. The hypothesis was tested by comparing the death of cortical and hippocampal neuron during global ischemia, with death of neuron in hydrocephalic animals subjected to a severe, acute episode of cerebral ischemia. Effect of expression of growth-associated protein ( GAP -43) on neuronal tolerance is investigated.

Impaired motor learning after traumatic brain injury , such as hydrocephalus, in human. In order to elucidate motor learning behavior in children with chronic brain injury, a novel computerized rhythmic sequential test is used to compare the motor skill acquisition and retention in two different age groups of children with and without hydrocephalus. To elucidate pathophysiological mechanisms associated with cognitive motor disorders in hydrocephalus, we determine motor activation produced by stimulation of motor cortex with Motor Evoked Potential (MEP) Equipment (MAGSTIM), and impairment in motor learning and memory formation. We also determine if a combination of part-practice and variable-practice method benefits motor-skill learning for the children with hydrocephalus .

Recent Publications in Peer-reviewed Journals

Eskandari R, McAllister JP II, Miller JM, Ding Y, Ham SD, Shearer DM, Way JS (2004) Effects of hydrocephalus and ventriculoperitoneal shunting on afferent and efferent connections of the feline sensorimotor cortex. Journal of Neurosurgery-Pediatrics-2 101:196-210.

Ding, Y, Lai, Q., McAllister J.P., Canady, A.I. (2001) Impaired motor learning in children with hydrocephalus. Pediatric Neurosurgery . 34:182-189.

Ding, Y, McAllister J.P., Yao , B., Yan, N., Canady, A.I. (2001) Neuron tolerance during hydrocephalus. Neuroscience. 106:659-667.

Ding, Y, McAllister J.P., Yao , B., Yan, N., Canady, A.I. (2001) Axonal Damage Associated with Enlargement of Ventricles during Hydrocephalus: A Silver Impregnation Study. Neurological Research. 23: 581-587.

Impaired Motor Learning and Diffuse Axonal Damage in Traumatic Brain Injury

Cognitive-motor functioning or motor skill learning is impaired in humans following traumatic brain injury. A more complete understanding of the mechanisms involved in the disorders is essential for any effective rehabilitation. The specific goals of this study are to examine motor learning disorders, and their relationship to pathological changes in adult rats with closed head injury. Motor learning deficits can be determined by comparing the ability to complete a series of complex motor learning tasks with simple motor activity. In our previous study, extent of neuronal damage was determined using silver impregnation. At all post-injury time points (day 1 to day 14), statistically significant deficits were observed in parallel bar traversing, foot placing, ladder climbing, and rope climbing. Performance improved with time, but never reached control levels. In contrast, no deficits were found in simple motor activity tested with beam balance and runway traverse. Histologically, axonal degeneration was widely distributed in several brain areas that relate to motor learning, including the white matter of sensorimotor cortex, corpus callosum, striatum, thalamus, and cerebellum. Additionally, severely damaged axons were observed in the primary visual pathway, including the optic chiasm, optic tract, lateral geniculate nuclei, and superior colliculus.

Recent Publications in Peer-reviewed Journals

Ding, Y-C, Yao , B., Lai, Q., McAllister J.P. (2001) Impaired motor learning and diffuse axonal damage in motor and visual systems of the rat following traumatic brain injury. Neurological Research , Special issue on Neurotrauma. 23:193-202.

Other Projects

Recent Publications in Peer-reviewed Journals

Ding, Y , Yang, D-Z, Lai, Q., Li, J. Diaz, FG. (2001) Long Term Neuroprotective Effect of Inhibiting Poly ( ADP -Ribose) Polymerase in Rats with Middle Cerebral Artery Occlusion Using A Behavioral Assessment. Brain Research . 915: 210-217.

Ding, Y , Yang, D-Z, Lai, Q., Li, J., Diaz, FG. (2002) Impaired Motor Activity and Motor Learning Function in Rat with Middle Cerebral Artery Occlusion. Behavioural Brain Research . 132:29-36.

Shostak, Y., Ding, Y , Mavity-Hudson, J, and Casagrande, V.A. (2002) Cortical synaptic arrangement of the third visual pathway in three primate species: Macaca mulatta, Saimiri sciureus and Aotus trivirgatus . Journal of Neuroscience. 22:2885-2893.

Shostak, Y., Ding, Y, and Casagrande, V.A. (2003) Neurochemical Comparison of Synaptic Arrangement of Parvocellular (P), Magnocellular (M), and Koniocellular (K) geniculate Pathways in Owl Monkey ( Aotus trivirgatus ) visual cortex (V1). Journal of Comparative Neurology . 456:12-28.

Dujovny M., Ding YH, Ding Y, Agner C, Perez-Arjona E. (2004) Current concepts on the expression of neurotrophins in the greater omentum. Neurological Res. 26 (4):226-229.

Wei G, Ji XM, Bai H, Ding Y (2006) Stroke Research in China. Neurological Res. 28 (1):11-5.

Casagrande VA, Yazart F, Jones KD, Ding Y. (2007) The morphology of Koniocellular Axon Pathway in the Macaque Monkey. Cerebral Cortex (in press).