The spectrum of traumatic brain injuries ranges from mild concussions that are treated in the emergency room, to severe head injuries that require acute critical and neurosurgical care. Improved critical and advanced radiological and neurosurgical techniques have led to decreases in mortality rates over the past two decades. However, survivors of brain injuries suffer long-term behavioral problems such as learning deficits, memory dysfunction, psychological and emotional disturbances – functional aspects that affect the quality of life and currently have no therapies. The economic costs of traumatic brain injuries, which include hospitalization, health care and lost work hours, is estimated at almost $35 billion. This problem has become particularly relevant in the past decade, with the Iraq war veterans returning home having suffered blast-related concussions, injuries that are poorly understood. It is estimated that several thousand soldiers have suffered head injuries since March 2003.

The damage observed after TBI comprises both primary disruption of neural tissue related to the impact, and secondary mechanisms that develop over the weeks to months after the traumatic event. The spectrum of pathologies observed after TBI include focal contusions in the grey matter and diffuse injuries to axons in the white matter. It has been suggested that these pathologies are a consequence of the biomechanics of the impact, i.e., focal injuries occur due to contact forces to the head, while diffuse injuries are a result of non-contact, rotational forces to the brain. While aspects of focal pathology can be superimposed on diffuse brain injury (and vice versa), it is our belief that significant differences exist between the pathobiology of these two types of injuries that warrant the separate evaluation of mechanisms of damage in the cell body (soma) and the axon. Secondary mechanisms of neural damage are initiated immediately after impact and result in a number of cascades that affect both the neural tissue and the vasculature. In response to the impact, the brain becomes edematous leading to increases in intracranial pressure and subsequent neuronal death, which may be an underlying cause for the neurologic impairment. In turn, injured neurons are faced with imbalances in ionic homeostasis, over-activation of excitatory amino acid receptors, increases in intracellular calcium, increased free radical generation, and mitochondrial dysfunction that may underlie the eventual death of injured neurons. Concomitant with neuronal death and damage, axons are also subjected to mechanical forces that lead to traumatic axonal injury. Injury to axons is characterized by focal accumulations of cytoskeletal proteins resulting in a swollen phenotype in the acute post-traumatic period. Over time these swollen axons undergo complete axotomy (Wallerian degeneration), a process that is associated with death of oligodendrocytes.

Our studies of traumatic brain injury (TBI) have led to the following accomplishments:

• Documenting programmed cell death after brain injury in rats and in humans
• Demonstrating that strategies aimed at reducing the extent of programmed cell death can attenuate cognitive and motor deficits
• Development of injury-specific and clinically-relevant animal models of TBI (concussive to repetitive to severe brain injuries)
• Identification of specific intracellular pathways that underlie grey matter injuries (neuronal death) and white matter injuries (axonal damage)

The ongoing research efforts, funded in part by the National Institutes of Health and the Division of Veterans' Affairs, are aimed at addressing the feasibility of cellular and pharmacologic strategies to attenuate and reverse TBI pathology. The focus of the research in this group of investigators extend from the basic cell biology of neuronal death and axonal injury to inhibition of seizure induction to the behavioral and rehabilitative strategies (including neuro-robotics and prosthetic use) that may be applied in the chronic post-traumatic phase. The mission of the Raghupathi laboratory is to develop pharmacological treatment and behaviorally therapeutic strategies to, respectively, reduce acute post-traumatic neural damage and augment behavioral recovery in the chronic phase. Our research efforts offer some unique capabilities such as comparisons of acute and chronic pharmacologic treatments in multiple models of TBI, in both mice and rats, and, combination treatment strategies that encompass acute pharmacologic treatments with chronic phase behavioral modifications and/or stem cell transplants.

We currently use models of focal or diffuse brain trauma in rodents, and have the capability to expand any of these injuries to poly-trauma, particularly focused on controlled hemorrhage and/or controlled hypoxia. Behavioral measures used in the group include (see list of publications): Cognitive function using the Morris water maze, the T-maze and the conditioned fear response test; motor function using the Schallert cylinder test of limb placement and the Feeney beam walk test. In addition, standard outcome measures include measurement of compound action potentials in the corpus callosum using ex vivo preparations of uninjured and injured coronal brain slices. Histological techniques include gross alterations using Nissl-Luxol Fast Blue stained sections followed by quantification of lesions; microscopic evidence of cell survival using unbiased stereology with the optical fractionator; stereologic approaches to counting double-labeled axonal profiles with confocal microscopy; optical imaging in live animals; cryoplane microscopy for imaging from the micro- to the macro-scale. We use a combination of in vivo and in vitro models of mechanical injury to delineate cellular mechanisms leading to neuronal and glial death and dysfunction. Using rodent models of focal or diffuse brain trauma (including repetitive injury), we ask fundamental questions whether inhibiting neural injury phenotypes (apoptosis, necrosis, axonal injury) will lead to better functional recovery. The working hypothesis in this project is that the choice of an appropriate treatment paradigm for head-injured patients will depend on the severity of the injury.

Funded Projects

• Mild TBI and Catecholamine systems, a collaboration with Barry Waterhouse, PhD, funded by the New Jersey Department of Health
• Bridging Alliances to Infuse Neuroscience at The Lincoln University (BRAIN-LU), a collaboration with Karen Baskerville, PhD, funded by the National Science Foundation
• Mechanisms and treatment strategies to counter addiction susceptibility post TBI, a collaboration with Temple University funded by the PA Department of Health
• Corticotropin-releasing factor mediates behavioral disturbances following adolescent mild traumatic brain injury, a collaboration with Jessica Barson, PhD, funded by the PA Department of Health

Lab Personnel

• Laura (Krafjack) Giacometti, PhD candidate (Neuroscience)
  "Sex-specific effects of mild TBI in the adolescent rat"
• Dana Lengel, PhD candidate (Neuroscience)
  "Treatment strategies to limit HPA axis dysfunction following pediatric TBI"
• Lauren Plyler, MS candidate (Neuroscience)
  "Mechanisms and treatment for post-traumatic headache following mild TBI in the mouse"
• Avery Runyan, MS candidate (Neuroscience)
  "Social recognition memory and sociability deficits following mild TBI"
• Mohibur Shah Rahman, MS candidate (Medical Science)
  "Exercise as a therapy for repetitive mild TBI"

Collaborators

• Jimmy Huh, MD, Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia
• Jessica Barson, PhD, Department of Neurobiology and Anatomy, Drexel University College of Medicine
• Rodrigo España, PhD, Department of Neurobiology and Anatomy, Drexel University College of Medicine
• Servio Ramirez, PhD, Department of Pathology and Lab Medicine, Temple University
• Barry Waterhouse, PhD, Department of Cell Biology and Neuroscience, Rowan University
• Karen Baskerville, PhD, Department of Biology, Lincoln University

• Why women are more at risk from concussion
  BBC (January 31, 2020)
• Men and women aren't equal when it comes to concussion
  MedicalXPress (December 6, 2019)
• The Unexplored Brain: Nearly 100 Uncharted Areas Revealed
  Live Science (July 20, 2016)
• Ramesh Raghupathi on animal models of traumatic brain injury
  Neurology Central (February 17, 2016)
• Mouse study offers clues to brain’s response to concussions
  Science News (February 5, 2016)
• From Cities To Suburbs | Traumatic Brain Injuries | Cutting Crime
  Georgia Public Broadcasting, On Second Thought (January 2016)
• On concussions, separate hype from science
  Philly.com (January 6, 2016)
• NFL team hires health clinic led by man who sold sham concussion prevention product – report
  RT America (December 22, 2015)

Recent Peer-reviewed Publications

"Age-at-injury effects of microglial activation following traumatic brain injury: implications for treatment strategies"
Raghupathi R. and Huh J.W.
Neural Regen. Res. 12:741-42, 2017.

"Factors affecting increased risk for substance use disorders following traumatic brain injury: What we can learn from animal models"
Merkel S.F., Cannella L.A., Razmpour R., Lutton E., Raghupathi R., Rawls S.M. and Ramirez S.H.
Neurosci. Biobehav. Rev. 77:209–218, 2017.

"Strong correlation of genome-wide expression after traumatic brain injury in vitro and in vivo implicates a role for SORLA"
Lamprecht M.R., Elkin B.S., Kesavabhotla K., Crary J.F., Hammers J.L., Huh J.W., Raghupathi R. and Morrison B. 3rd
J Neurotrauma. 34:97-108, 2017.

"Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat"
Hanlon L.A., Raghupathi R. and Huh J.W.
Exp. Neurol. 290:1-14, 2017.

"Minocycline Transiently Reduces Microglia/Macrophage Activation But Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat"
Hanlon L.A., Huh J.W. and Raghupathi R.
J. Neuropathol. Exp. Neurol. 75:214-226, 2016.

"Neuroprotective effects of the glutamate transporter activator, MS-153, following traumatic brain injury in the adult rat"
Fontana A.C., Fox D.P., Zoubroulis A., Mortensen O.V. and Raghupathi R.
J. Neurotrauma 33:1073-1083, 2016.

"Spinal Cord Concussion: Studying the Risks of Repetitive Injury"
Fischer I., Haas C., Raghupathi R., and Jin Y.
Neural Regen. Res. 11:58-60, 2016.

"Combination Therapies for Traumatic Brain Injury: Retrospective Considerations"
Margulies S., Anderson G., Atif F., Badaut J., Clark R., Empey P., Guseva M., Hoane M., Huh J., Pauly J., Raghupathi R., Scheff S., Stein D., Tang H. and Hicks R.
J. Neurotrauma 33:101-112, 2016.

"Genetics and Pathology of Chronic Traumatic Encephalopathy"
Krafjack L.L. and Raghupathi R.
Curr. Genet. Med. Reports 3:191-195, 2015.

"Cathepsin L mediates the degradation of novel APP C-terminal fragments"
Wang H., Sang N., Zhang C., Raghupathi R., Tanzi R.E. and Saunders A.
Biochem. 54:2806-2816, 2015.

"Experimental traumatic brain injury alters ethanol consumption and sensitivity"
Lowing J.L., Susick L.L, Caruso J.P., Provenzano A.M., Raghupathi R. and Conti A.C.
J Neurotrauma. 31:1700-1710, 2014.

Reviews and Book Chapters

"Calpain as a therapeutic target for traumatic brain injury"
Saatman KE, Creed J and Raghupathi R
Neurotherapeutics 7:31-42, 2010.

"New concepts in treatment of pediatric traumatic brain injury"
Huh JW and Raghupathi R
Anesthesiol. Clin. 27:213-40, 2009.

"Neurointensive care for traumatic brain injury in children"
Su F, Huh JW, Raghupathi R
http://www.emedicine.com/ped/topic3082.htm, updated July 2009.

"Shaken Baby Syndrome"
Martin HA, Woodson A, Christian CW, Helfaer MA, Raghupathi R, Huh JW, in Critical Care Nursing Clinics of North America, Thompson HJ and Alexy EM, Eds., 18:279-286, 2006.

"Cell death mechanisms following traumatic brain injury"
Raghupathi R
Brain Pathol. 14:215-222, 2004.

"Apoptosis and DNA Damage in Head Trauma"
Raghupathi R
Head Trauma: Basic, Preclinical and Clinical Aspects. John Wiley & Sons, Inc., NY: 239-255, 2001.

"Drugs in the Management of Acute TBI"
Raghupathi R, McIntosh TK
Physical Medicine and Rehabilitation Clinics of North America 8:629-649, 1997.

Patents

Patent No. US 6,326,146: O'Dell DM, Raghupathi R, McIntosh TK, Crino P, Eberwine J
Method of determining multiple mRNAs in dying cells. 2001.