Periodic Reporting for period 3 - NEUROPRECISE (Precision medicine in traumatic brain injury using individual neurosteroid response)
Reporting period: 2022-03-01 to 2023-08-31
Traumatic brain injury (TBI) is very common and affects 1.8 million Europeans seeking medical help each year. TBI is a major challenge for healthcare providers and poses an enormous economic burden. For decades, TBI has been characterized by severity of symptoms for diagnosis, prognosis, and therapy. However, this classification system is limited since it does not allow to predict long-term outcome after TBI. This state of affairs thus hinders the advancement of TBI research and the development of therapies. The field is thus in dire need of a novel understanding and classification of the individual’s response to brain injury and, most importantly, a fresh perspective on potential targets for effective treatment and prevention of long-term impairment.
My main hypothesis is that brain injury leads to a neurosteroid response with inter-individual variability and that this response is associated with the trajectory of recovery. I further hypothesize, that the most vulnerable patient cohorts, such as adolescent girls, show distinct patterns of neurosteroid response associated with an increased risk for persistent symptoms.
NEUROPRECISE proposes a longitudinal cohort study 1) to characterize neurosteroid response with respect to age and sex in children and adolescents with TBI, 2) to evaluate the association of the neuroimaging derived individual injury profile with neurosteroid response, and 3) to explore individual differences in neurosteroid response as a potential target for acute therapy and prevention of chronic symptoms with respect to age and sex in a rodent model.
NEUROPRECISE will overcome a critical barrier towards the treatment of TBI by establishing a novel, biological-driven way to stratify TBI patients based on inter-individual differences in the response to TBI. By exploring the individual neurosteroid response as potential therapeutic target, NEUROPRECISE will bring the power of precision medicine to neurotrauma research.
My main hypothesis is that brain injury leads to a neurosteroid response with inter-individual variability and that this response is associated with the trajectory of recovery. I further hypothesize, that the most vulnerable patient cohorts, such as adolescent girls, show distinct patterns of neurosteroid response associated with an increased risk for persistent symptoms.
NEUROPRECISE proposes a longitudinal cohort study 1) to characterize neurosteroid response with respect to age and sex in children and adolescents with TBI, 2) to evaluate the association of the neuroimaging derived individual injury profile with neurosteroid response, and 3) to explore individual differences in neurosteroid response as a potential target for acute therapy and prevention of chronic symptoms with respect to age and sex in a rodent model.
NEUROPRECISE will overcome a critical barrier towards the treatment of TBI by establishing a novel, biological-driven way to stratify TBI patients based on inter-individual differences in the response to TBI. By exploring the individual neurosteroid response as potential therapeutic target, NEUROPRECISE will bring the power of precision medicine to neurotrauma research.
Since the beginning of the project, each of the three WPs has made significant progress despite the severe challenges imposed by the pandemic. In the following, work performed as well as achievements related to each WP are listed:
WP1: The major achievement since the beginning of the project has been to setup the clinical infrastructure necessary to conduct the human study within NEUROPRECISE. In collaboration with the Dr. von Hauner’s Children’s Hospital, we founded the Concussion Clinic for children and adolescents that experience a mild traumatic brain injury in the Munich area. This infrastructure of clinical care at the highest level of medical excellence did not exist before. The Concussion Clinic is now led by an experienced pediatric neurologist, Dr. Michaela Bonfert, who is also study physician of NEUROPRECISE. We developed an interdisciplinary clinical pathway and organizational algorithm to be able to screen all incoming patients for inclusion and exclusion criteria. Further, we reached out to two Munich-based hospitals as well as to 15 large local pediatric practices, provided information material on mTBI in children and adolescents with the intention to receive transferred patients from these centers. The concussion Clinic now screens patients 5 days a week and is setup to clinically evaluate every eligible patient on the same day.
WP2: Setting up the newly installed MRI scanner dedicated to brain research in the building next door has been the major effort. As one of four managing directors, the PI Dr. Inga Koerte, is shaping excellence in research within this new neuroimaging core unit NICUM (Neuroimaging-Core-Unit-Munich: https://www.mcn.uni-muenchen.de/aktuelles/nicum/index.html). Originally, NICUM was supposed to provide personnel to perform the MRI in this study. However, due to financial constraints, NICUM no longer plans to offer this service. Therefore, the PI Dr. Koerte, developed a training curriculum for research assistants to be trained as MRI operators. The NEUROPRECISE team not only managed to train 8 MRI operators in a short period of time, secured additional funding to pay for these research assistants but most importantly serves as a hall mark for performing research studies within NICUM.
WP3: The animal project began in June 2020. After adequate training, the PhD student newly developed and validated a mild traumatic brain injury (mTBI) mouse model for the project. The juvenile model matches the human part of the study and consists of a modified weight-drop device that delivers mTBI to anesthetized adolescent mice without surgical incision, skull fracture, brain edema, or macroscopic brain damage. The unique feature of this model is that the impact produces a rotational acceleration of the head, which mimics the average patient mTBI. Most importantly, the model produces acute and chronic neurological deficits after mTBI. The Barnes Maze test demonstrates acute deficiencies in spatial memory formation in the mTBI mice. Moreover, we now include the novel automated IntelliCage testing paradigm which captures long-term behavioral deficits (4 months post-injury) in the mTBI mice, specifically drinking disinhibition. Further, we have planned the next step to begin progesterone monitoring following mTBI.
Another important task has been to ensuring stability throughout the pandemic. The constantly changing rules and regulations surrounding the COVID-19 pandemic along with the restrictions to enroll patients in our study have been both time and effort consuming. The PI along with the leadership team has put an emphasis und team building and continues education to provide stability and flexibility so that the team continuously operates on full speed.
WP1: The major achievement since the beginning of the project has been to setup the clinical infrastructure necessary to conduct the human study within NEUROPRECISE. In collaboration with the Dr. von Hauner’s Children’s Hospital, we founded the Concussion Clinic for children and adolescents that experience a mild traumatic brain injury in the Munich area. This infrastructure of clinical care at the highest level of medical excellence did not exist before. The Concussion Clinic is now led by an experienced pediatric neurologist, Dr. Michaela Bonfert, who is also study physician of NEUROPRECISE. We developed an interdisciplinary clinical pathway and organizational algorithm to be able to screen all incoming patients for inclusion and exclusion criteria. Further, we reached out to two Munich-based hospitals as well as to 15 large local pediatric practices, provided information material on mTBI in children and adolescents with the intention to receive transferred patients from these centers. The concussion Clinic now screens patients 5 days a week and is setup to clinically evaluate every eligible patient on the same day.
WP2: Setting up the newly installed MRI scanner dedicated to brain research in the building next door has been the major effort. As one of four managing directors, the PI Dr. Inga Koerte, is shaping excellence in research within this new neuroimaging core unit NICUM (Neuroimaging-Core-Unit-Munich: https://www.mcn.uni-muenchen.de/aktuelles/nicum/index.html). Originally, NICUM was supposed to provide personnel to perform the MRI in this study. However, due to financial constraints, NICUM no longer plans to offer this service. Therefore, the PI Dr. Koerte, developed a training curriculum for research assistants to be trained as MRI operators. The NEUROPRECISE team not only managed to train 8 MRI operators in a short period of time, secured additional funding to pay for these research assistants but most importantly serves as a hall mark for performing research studies within NICUM.
WP3: The animal project began in June 2020. After adequate training, the PhD student newly developed and validated a mild traumatic brain injury (mTBI) mouse model for the project. The juvenile model matches the human part of the study and consists of a modified weight-drop device that delivers mTBI to anesthetized adolescent mice without surgical incision, skull fracture, brain edema, or macroscopic brain damage. The unique feature of this model is that the impact produces a rotational acceleration of the head, which mimics the average patient mTBI. Most importantly, the model produces acute and chronic neurological deficits after mTBI. The Barnes Maze test demonstrates acute deficiencies in spatial memory formation in the mTBI mice. Moreover, we now include the novel automated IntelliCage testing paradigm which captures long-term behavioral deficits (4 months post-injury) in the mTBI mice, specifically drinking disinhibition. Further, we have planned the next step to begin progesterone monitoring following mTBI.
Another important task has been to ensuring stability throughout the pandemic. The constantly changing rules and regulations surrounding the COVID-19 pandemic along with the restrictions to enroll patients in our study have been both time and effort consuming. The PI along with the leadership team has put an emphasis und team building and continues education to provide stability and flexibility so that the team continuously operates on full speed.
While neurotrauma research is experiencing an unprecedented momentum, we still don’t know much about prognosis or effective therapy for TBI. The stratification of patients based on symptom severity or injury mechanism have not been shown to advance the field. Neurosteroids seem to play an important role in recovery from neurotrauma. However, recent therapeutic one-size-fits-all approaches have not yielded beneficial results. Evidence across the board thus points to the need for a novel concept of thinking to capture individual variability in the brain’s response to TBI in order to ultimately enable precision medicine. NEUROPRECISE will provide a new insight into the individual’s response to TBI and will thereby boost our understanding of how to treat the injured brain. In a translational research approach, NEUROPRECISE applies a combination of human cohort study (WP 1 and WP2) with an animal experiment (WP3) to characterize the neurosteroid response in combination with a novel individualized profile of injury. Expected outcome: NEUROPRECISE will accelerate new developments in TBI research by providing a novel way to stratify patient cohorts, to identify targets for treatment, and thereby drive the field towards a new era.