Translational Neurosurgery

Overall goal

The objective of the program is to combat Traumatic Brain Injury (TBI), a major global public health problem. The strategy is to provide translational results for exploration in the Neuro-ICU ultimately resulting in novel principles for neuroprotection, neurorepair and rehabilitation. The program is closely related to the Center of Excellence – Neurotrauma (www.neurotrauma.se) at the Uppsala University Hospital.
Uppsala Brain Injury Center (UBIC) – The neurotrauma research is organised as a translational research network with focus on TBI research. The basic objective of this multidisciplinary endeavour is to study TBI with a broad spectrum of competencies ranging from molecule to man, i.e. from molecular genetics, cellculture systems, animals models, TBI patients in the Neuro-ICU to rehabilitation and follow-up (read more at UBIC´s web page).

Methods

The Division of Neurosurgery provides a well established animal modelling facility, one of the major research platforms within the UBIC. To simulate the high degree of complexity of human TBI pathophysiology (e.g. focal contusions, epidural, subdural and intraparechymal hemorrhages, diffuse axonal injury and mixed forms) a battery of animal models with different mechanical impact properties is required. We have established two focal contusion models of TBI (the Controlled Cortical Contusion Model and the Controlled Cortical Impact Model) and one mixed model (the Fluid Percussion Injury Model) for rodents. We are currently setting up a diffuse axonal injury model in the mouse for use in transgenic animals. All the models are widely used internationally facilitating comparison of data between research groups.
A few years back a long term strategy was adopted to establish a battery of methods for evaluation of the functional outcome of animals following TBI. Behavioural outcome measures are considered increasingly important in studies of neuroprotective drug effects, other therapeutic interventions and neurorepair strategies. This effort is being done in close collaboration with Prof Bengt Meyerson, BMC. The following methods have thus far been set up: the Morris Water Maze, the Rotarod and the Concentric Square Field Method.

Main lines of research

The main conceptual lines of research within the UBIC comprise molecular studies of secondary brain injury mechanisms with focus on oxidative stress, inflammation, diffuse axonal injury, endogenous brain repair and plasticity, and neurorepair.
Interventional studies are ongoing with the following directions:
- Neuroprotection: studies on neuroprotective drug candidates to block important identified secondary injury mechanisms such as oxidative stress and injurious components of the inflammatory response (e.g. T cell trafficking) to reduce the total amount of brain damage or specific components (e.g. diffuse axonal injury).
- Endogenous repair: studies on strategies to enhance axonal regeneration and placticity following TBI.
- Neurorepair: studies on stem cell transplantation strategies to replace injured/dead brain cells and to promote endogenous stem cell repair.

Significance

The basic science part of UBIC and the animal modelling platform will provide important novel knowledge on the secondary injury mechanisms following TBI and generate new concepts of intervention for neuroprotection and neurorepair that can be translated to the Neuro-ICU setting with the ultimate goal of improving the outcomes for human vitims of TBI.
 

Neuroregeneration and Plasticity (Niklas Marklund)


Background

The adult, human brain has an extremely limited capacity for recovery following injury or stroke. For instance, following a severe traumatic brain injury (TBI) numerous brain regions are immediately damaged with large areas of neuronal and glial cell death. Unfortunately, lost neuronal cells are not replaced to a significant degree after TBI. Also, the processes of nerve cells (the axons) are also damaged and in the injured central nervous system (CNS), axons cannot regenerate in part due to inhibitors present in myelin. Damage to myelin surrounding the axons could alter signal conduction after brain injury although has only rarely been evaluated, to date.
In the early phase after a severe brain injury and during neurointensive care, patients are frequently unconscious with marked motor deficits. In view of the inability for recovery after brain injury, it is surprising that many patients recover to some extent. In fact, at several months post-injury many of these patients are able to walk, talk and at least partly function in everyday life. Since TBI patients still frequently suffer from reduced memory and motor function, personality changes and a markedly reduced quality of life this recovery process is clearly not sufficient and needs to be improved. Beyond doubt, high age is associated with a very poor prognosis after TBI, likely due to poor capacity for recovery and regeneration. The process of brain recovery is named plasticity, defined e.g. as the capacity of the brain to reorganise itself in response to an injury/damage where uninjured brain regions or fiber tracts can respond to the loss of other regions to take over the lost functions. The role for plasticity and in particular the lack of plasticity in the adult or aged CNS in TBI is to a large extent unknown.

Aims

The overall aim is to develop new treatment options for patients with severe TBI which is urgently needed. There is a need for increased understanding of the factors promoting the (limited) recovery after TBI and the factors inhibiting attempts for axon repair and regeneration.

Methods

We use clinically-relevant rodent models of TBI and extensive behavioral outcome measures are used evaluating memory/cognition and motor function. To detect attempts to form new connections, sprouting, we use tract-tracing and brain mapping techniques in young adult as well as aged animals. These studies will evaluate how, where and when the plasticity occurs after brain injury. Modern immunohistochemical and imaging techniques are used. Pharmacological tools are used to promote recovery targeting inhibitors in myelin. Knockout mice are also used, deficient in important factors responsible for the lack of recovery post-injury. Characterization of axonal death and the role for demyelination and oligodendrocyte death and/or proliferation in important brain areas is also a key component of the projects. Analysis of biopsies from human brain after TBI is possible and modern neurointensive care and neuroradiological techniques evaluate the role for axonal injury in patients.

Significance

The concept of “brain repair”, i.e. the understanding and enhancement of the naturally occurring recovery mechanisms, is promising when trying to improve the outcome of brain trauma patients. If factors present in myelin could be inhibited, improved recovery is also expected. These studies are a novel approach to the devastating clinical consequences occurring after a traumatic brain injury.
 

In Vivo Brain Injury Modelling (Fredrik Clausen)


Traumatisk hjärnskada (THS) kan ske på många olika sätt, trafikolyckor, fall eller annat våld mot skallen som leder till att hjärnan skadas. Den primära skadan kan verka enkel, men det leder till kaskader av komplexa processer.

De mest studerade kaskaderna är glutamat-toxicitet, störd jonhomeostas, fri radikalbildning och aktivering av immunsvaret. Dessa processer bidrar med så mycket som hälften av den slutliga skadan efter THS. Min forskning är fokuserad på just hur immunsystemet aktiveras efter THS och hur fri radikalbildning i samband med det kan påverka skadeprocessen.

För att kunna återskapa de mest komplicerade förhållandena som finns i den skadade hjärnan är man tvungen att använda djurmodeller. Detta gäller bl.a. hur hjärnans celler och blodkärl interagerar med immunsystemet efter skada, något som förstås är väldigt svårt att återskapa i cellkultur. I vår verksamhet har vi modeller för att återskapa både diffus och fokal skada i gnagare. Vi har även tillgång till flera beteendetester för att studera funktionen hos djuren.

Contact

bild på Lars Hillered

Group leader:

Prof Lars Hillered

E-mail: lars.hillered@neuro.uu.se