A novel integrated perspective linking physiological and psychological consequences of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is the most common neurologic disorder. One
out of 4 patients develops long-lasting cognitive and emotional complaints that
interfere with daily functioning. Therefore, mTBI poses a significant public
health burden. Over the years multifactorial models have been developed, which
aid in the prediction of outcome after mTBI. It has been shown that in addition
to acute injury related factors, such as loss of consciousness and amnesia,
outcome is strongly influenced by pre-existent psychological factors, for
instance coping style and emotion regulation. Despite these scientific efforts,
persistent complaints are still rather unpredictable in individual patients,
for whom injury mechanisms are often comparable.
So far, little is known about the influence of physiological effects of the
injury, such as cellular injury, neuroinflammation, and acute stress, on
outcome after mTBI. Previous functional MRI (fMRI) research has demonstrated
that persistent complaints after mTBI are related to alterations in neural
networks. Therefore, a pivotal question is whether acute physiological effects
lead to disturbances in neural networks that are important for emotion
regulation, and if there is an interaction with pre-existent personality,
coping style, and stress levels, This topic has never been touched upon, and
therefore forms a gap in mTBI research.
With the current study, we aim to conduct biochemical, psychometric, MRI- and
EEG-experiments in order to disentangle the interaction(s) between (acute)
physiological and (long-term) psychological consequences of TBI. Hopefully,
this will lead to a better understanding of the etiology of persistent
complaints and poor outcome, and to starting points for the development of
tailored pharmacological and/or psychological treatments for patients with
mTBI.

Primary Objective:
- To investigate whether or not persistent complaints and poor outcome after
mTBI be explained by an interaction between physiological and psychological
factors.

Secondary Objective(s):
- To identify specific patterns of brain specific protein, cortisol and
cytokine release and HRV in patients with mTBI.
- To determine if cortisol and cytokine release in patients with mTBI differ
from patients with another stressful condition (i.e. orthopedic injury), and
healthy controls.
- To find possible relationships between acute physiological disturbances
(inflammation, stress) in mTBI and altered activity/connectivity of neural
networks, and to determine whether or not this is related to emotion regulation
deficits.
- To identify EEG patterns in the acute and subacute phase after mTBI related
to clinical parameters (loss of consciousness, post-traumatic amnesia, CT-scan
abnormalities) as well as the above mentioned biochemical parameters and
outcome.

A prospective multicentre cohort study in two level-1 trauma centres in the
Netherlands (i.e. University Medical Centre Groningen, and Medisch spectrum
Twente, Enschede).
During a two year period, patients with mTBI that are presented at the ED of
the aforementioned hospitals, will be included and all data will be collected.
Measurements will take place at the following four time points post-injury:

- Timepoint 1 (T1) at the ED.
- T2: at 2 weeks post-injury.
- T3: at 4-6 weeks post-injury.
- T4: at 6 months post-injury.

At T1, data regarding injury- and patient-related characteristics will be
collected. Computed tomography (CT) scans will be performed according to the
Dutch mTBI guidelines. Acute (baseline) post-traumatic complaints will be
assessed by the physician at the ED. When they are full conscious and oriented,
patients receive the study information and informed consent will be obtained.
Time for consideration is 3 days. Because it is standard procedure to draw
blood samples in the emergency setting, two extra blood samples (i.e. 7,5 mL
per sample) will already be collected to minimize the burden. In case informed
consent is not provided, these blood samples will be destroyed. Saliva samples
will be collected immediately after informed consent, and 8 and 16 hours later
. In case of persistent disorientation and amnesia, patients are admitted at
the Neurology ward, and will be given the study information when their mental
state recovers. For saliva collection, spouses or (an)other direct relative(s)
will be asked for premature consent. Material will of course be destroyed when
patients are not willing to participate when they are asked for formal consent.
At discharge, an information sheet is provided containing global information
regarding the general course of recovery after TBI (which is standard
procedure). The EEG study will take place at either the ED or the neurology
ward, depending on whether the patient is admitted to the hospital. EEG will be
performed within 24 hours after injury. Separate informed consent will be
obtained. For patients that are still disoriented and/or have post-traumatic
amnesia, deferred consent will be applied, and official written informed
consent will be obtained when patients are compos mentis. In case the first
emergency contact/partner/family is present, the EEG study will first be
discussed with that person/them. In addition to healthy controls, we chose to
include an orthopaedic control group at the ED, which allows us to control for
a stressful and potentially inflammatory condition without brain injury.
Within two weeks, questionnaires will be send via email or regular mail to
patients, to inquire whether there are residual complaints at T2, and to
measure additional factors, such as anxiety and depression, coping style,
personality characteristics, and emotion regulation skills. At T2, patients
are also contacted by phone, and asked if they are willing to participate in
the additional MRI- and/or hair cortisol studies. It has also been shown that
an evaluation at 2 weeks post-injury is clinically beneficial for patients, as
it offers the possibility to give extra education and reassurance, and if
necessary, arrange referrals to specialists (e.g. neurologist, psychologist,
rehabilitation specialist).
At T3, the follow-up, and additional measurements take place.
At T4, questionnaires will be send by email or via regular mail to determine
outcome and measure persistent complaints. Patients will be reminded once by
phone in case they do not return the questionnaires.

The measurements that are conducted in the study do not have any adverse
consequences for the participants, and there are few if any risks for the
participants. The burden of filling in questionnaires will be minimal (two time
points; the first questionnaires taking approximately 30 minutes, the second 15
minutes). The first vena puncture is routinely performed for patients with
mTBI, and will create no additional burden for this group. For orthopaedic
controls this is not the case, and will create some additional burden. The
second vena puncture (or the first and last for healthy controls) is
short-lasting, but might also be stressing for certain participants.
Electrocardiography (ECG) and saliva collection will create a minimal if any
burden, and are therefore considered non-invasive. For subjects in the
MRI-subgroups, participation is more intensive, as subjects in these groups
have to undergo a 1 hour MRI-scan, and also having to perform an emotion
regulation task during scanning. Hair-collection does not contain any burden,
and based on our experience, does not cause any dramatic cosmetic changes. The
EEG study will lead to limited additional burden. It will take approximately 20
minutes. Although there are no risks associated, it can cause some discomfort
when placing the cap with the electrodes.
There are no additional benefits compared to standard care.