Pathology in the Brain After mTBI - A Multimodal MRI Study
Condition: Concussion
Study type: Observational [Patient Registry]

Summary: 
      The purpose is to use Diffusion Kurtosis Imaging (DKI), Diffusion Tensor Imaging (DTI) and
      resting state functional MRI to examine tissue damage in the brains of people who have had a
      concussion, both acute and 3 months after the accident. A secondary purpose is to examine
      whether the results of the scans are associated with physical, cognitive and emotional
      problems after concussion.

      It is hypothesized that there will be a change in the diffusion signal measured with DKI in
      the thalamus (THA) and with DTI in the corpus callosum (CC), in the acute stage and at
      follow-up of the mTBI subjects compared with the healthy controls. Secondary it is expected
      that there will be changes in the diffusion signal measured with DKI and DTI in other WM and
      GM area in both the acute stage and at follow up with mTBI subjects compared with healthy
      controls. Also rs-fMRI markers are secondary expected to differ in the two groups. Moreover
      secondarily the MRI markers are tested for correlation with the severity of PCS acutely and
      at follow up after mTBI.
    

Detailed description: 
      More than 25,000 people in Denmark, are each year diagnosed with commotio cerebri as a result
      of head trauma (National Patient Registry, 1996), and foreign studies report that up to 5 to
      15% of these have symptoms that persist beyond 3 months (5). Post commotio symptoms (PCS) are
      typically divided into physical, cognitive and emotional symptoms and include headache,
      fatigue, memory loss, stress, etc.. It is known from previous studies of traumatic brain
      injuries that the cost of the disabling process and the failure to intervene in the long term
      are very costly (11). In Denmark there are to date no systematic or consistent treatment for
      people with persistent symptoms 3 months after commotio cerebri, and a lack of general
      knowledge about the pathology and standardization with regard to diagnosis and prognosis are
      also missing.

      Commotio cerebri, also known as mild traumatic brain injury (mTBI) is often defined as an
      exogenous traumatic stimulus that causes a physiological disruption of brain function
      (American Congress of Rehabilitation Medicine). This includes a biochemical cascade, edema,
      micro-haemorrhages, diffuse axonal injury (DAI) and changes in activity between internal
      networks in the brain (12, 13).

      In severe trauma, conventional scanning methods such as Computer Tomography (CT) and Magnetic
      Resonance Imaging (MRI) can detect bone rupture, edema and micro-haemorrhages, but in mTBI,
      it is often difficult to detect edema or micro-hemorrhages, and the conventional methods is
      often not sensitive enough to show pathology especially beyond the acute period, although
      patients continue to have physical symptoms as well as cognitive and emotional problems (6,
      12).

      More MRI techniques, which are not routinely used in the clinic, has verified both DAI and
      changes in cortical network as compared to healthy controls (12). One of these is the method
      Diffusional tensor imaging (DTI) which can be used to detect the DAI in white matter (WM).
      DTI studies confirm DAI in several WM areas after mTBI (12). Other studies have shown that
      DAI detected by DTI in several places of WM correlates with cognitive problems after mTBI
      (1,2,6,13).

      A more recent and less studied MRI method is Diffusional Kurtosis Imaging (DKI) which can
      display DAI in WM and prove to be more sensitive than the DTI for the detection of damage in
      gray matter (GM) (3, 4). A study in humans showed significant differences between individuals
      with mTBI and healthy controls, in the thalamus and several WM areas (3). This study also
      showed a correlation between DKI markers in the thalamus and the capsula interna with
      cognitive problems in multiple domains after mTBI. DKI is therefore suggested to be used in
      addition to DTI in relation to detect tissue damage in both WM and GM.

      Another MRI method that has shown promising results in relation to mTBI is resting state
      functional MRI (fMRI-rs). Rs-fMRI has shown differences between brain network connectivity in
      mTBI patients compared to healthy controls (9). A study based on the theory Default Mode
      Network (DMN) has also shown a high degree of sensitivity and specificity in a patient
      classification in the subacute phase (8).

      Generally more longitudinal studies, larger publications with more participants and consensus
      on which areas that are associated with MRI verified pathology are still missing. Also the
      correlations between MRI markers with the physical, cognitive and emotional problems are
      still to be solved.

      It is the purpose to use three research based scan methods to detect tissue damage in the
      brains of persons after concussion, both acute and 3 months after the accident. Moreover the
      correlation between MRI makers and the registered physical, cognitive and emotional symptoms
      after concussion are to be examined.

      It is hypothesized that there will be a change in Mean Kurtosis in the thalamus, corpus
      callosum and hippo campus from baseline to follow-up. Secondary we examine change in Mean
      Diffusivity and Fractional Anisotropy in the thalamus, corpus callosum and hippo campus from
      baseline to follow-up and for both DKI and DTI we examine the difference between the mTBI
      subjects and healthy controls in the acute stage and at follow-up. Moreover we examine
      correlation of MRI markers the severity of PCS acutely and at follow up. Finally rs-fMRI and
      default mode network is expected to differ between the two groups

      Materials and methods

      The study design is a controlled observational trial with follow up. 35 individuals with mTBI
      and 35 matched healthy controls (age and sex) are examined. Persons with mTBI are scanned
      within the first 14 days after mTBI and at follow-up 3 months after. Controls are scanned
      only once.

      The MRI scans will be performed on CE-approved MRI scanners at Aarhus University Hospital,
      Noerrebrogade 44, 8000 Aarhus C, Denmark. A standard protocol for MRI will be used containing
      a structural T1, a susceptibility weighted image (SWI) and T2 FLAIR sequence with the purpose
      to visualize anatomy, micro hemorrhages and edema. It is expected that the findings from the
      standard protocol will be present in the acute stage but only for some at follow-up.

      The novelty of the current study is the use of a optimized and newly developed faster DKI
      scan sequence, which makes it possible to use DKI in a clinical setup. In addition, to date
      there has not been provided a follow-up at 3 months after mTBI with DKI (9 months Grossman
      study).

      Symptom Questionnaires:

      Both at baseline and at 3 months follow-up three questionnaires are to be filled out "The
      Rivermead postconcussion symptom questionnaire", " The Symptom Checklist" (SCL-8AD) and The
      Brief Illness Perception questionnaire" (BIPQ). Control Persons will also fill out these
      questionnaires.

      Statistical considerations:

      Power calculations of the upcoming study is based upon a previous studies by Grossman et.
      al.(3) MK in THA at Baseline: 35 mTBI subjects (mean 0.74, sd 0.08), 35 healthy controls
      (mean 0.89, sd 0.04), power = 100% MK in THA at Follow up: 25 mTBI (mean 0.78, sd 0.06), 25
      healthy controls (mean 0.89, sd 0.12) power = 96% An ANOVA will be used to test the
      difference in signal to the two times (<14 days and 3 months after mTBI).

      Additionally, there will be made paired comparison between mTBI individuals. Both primary and
      secondary outcomes will showed in uncorrected and Bonferroni corrected.

      Regions and parameters which show significant differences, will be compared with symptom
      scores using Spearman rank correlation, controlled for age and sex.

      Risks, side effects and disadvantages:

      MRI:

      All project participants will review a checklist compared with contraindications for. There
      is no evidence of harmful effects of MRI, if these precautions are followed. Additionally
      subjects are provided with earplugs to protect from the noise from the scanner.

      The clinical scans will be seen by a neuroradiologist and if abnormality is suspected,
      pictures will be evaluated further. If the abnormality is real the subject will get an
      additional examine and appropriate guidance will be conducted by the involved
      neuroradiologist.

      While the images from the research part is not primarily used for clinical use, there will
      not be made any clinical diagnostic evaluation from these brain scans and they are not
      necessarily evaluated by a person with clinical radiological competence.

      Research Ethics statement:

      The techniques used are non-invasive and does not include methods like intravascular
      catheters, injection of contrast agents or any medication. There is no radiation danger, and
      the studies are not associated with significant side effects, risks or disadvantages for the
      participants.

      The project involves only competent subjects participating voluntarily after adequate verbal
      and written information and written consent. The participation may at any time leave the
      study and the investigation without having to justify it. The study itself does not involve
      treatment and if the subject withdraws his agreement, this does not affect his right to
      present or future treatment

      Recruitment:

      People with concussions will be recruited from the Department of Radiology at Aarhus
      University Hospital. Controls are recruited in the recruitment system Sona Systems and by
      posters with contact information.

      Notification to the Data Protection Agency:

      The project is registered to the data inspectorate in Region Midtjylland's of "Health
      Scientific research in Central Denmark Region". Personal information will be kept
      confidential and will be destroyed after the study is completed. The project is progressing
      in accordance with the Act on Processing of Personal Data
      (http://www.datatilsynet.dk/borger/forskningsprojekter/).

      Publication of results:

      Publication of results from the project will be coordinated by the Project Manager in
      accordance with the guidelines specified in the "Guidelines for Good Scientific Practice"
      (Committee on Scientific Dishonesty, 1998).

      Positive as well as negative, and results that can not be concluded on, will be published in
      international scientific journals.

      Financial support:

      The project is initiated by the Hospital of Hammel Neuro Center. There is no sponsorship or
      secondary economic interests involved in the project.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        35 individuals with mTBI and 35 matched healthy controls (age and sex) are examined.
      
Keywords: Concussion; Mild Traumatic Brain Injury; Traumatic Brain Injury