Grant Number: 2M01RR000052-44(GCRC)
PI Name: Christensen, James
PI Email: christensenJ@kennedykrieger.org
PI Title: Associate Professor of Physical Medicine and Rehabilitation and Pediatrics
Project Title: Structural, spectroscopic and functional imaging during coma recovery in children and adolescents after traumatic or anoxic brain injury
Specific Aims Hypothesis: The emergence from coma in children after traumatic or anoxic brain injury is based on the achievement of functional reconnections among
a distributed set of neuronal circuits in the
brain.
To test this hypothesis, we have developed the following specific aims:
1. To quantify the morphological changes in brain structure related to
coma, using MRI.
2. To quantify the chemical changes in brain metabolism (NAA, lactate,
etc) that are associated with different stages of coma recovery, using
MR Spectroscopy.
3. To quantify the spatial distribution of brain activation to visual
and auditory stimuli, that are associated with different stages of coma
recovery, using fMRI.
Background and Significance:
Trauma is the leading cause of morbidity and mortality in children, and
traumatic brain injury (TBI) is the most important determinant of the
degree of severity. Consequently, research into TBI recovery and
outcome is a high priority. Coma is a poorly understood condition,
especially in cases of traumatic brain injury (TBI). This stems from
TBI being attributed to diffuse damage of multiple brain regions
through a variety of different Recovery from coma is a gradual
continuum of return of consciousness, a process that is often confusing
to families and staff.
During the early recovery in those with very severe injuries, it can be
difficult to distinguish those who will remain in a persistent
vegetative state from those whose recovery will continue. In addition,
it is difficult to assess who will have a more complete recovery of
neurological function. This inability to adequately assess these
patients stems from a lack of understanding the basic brain mechanisms
involved in recovery from coma. Availability of objective evidence
concerning brain activity during recovery would not only lead to a
better understanding of these recovery mechanisms but could lead to
improved ability to assess long-term outcome, provide focussed
rehabilitation, choose appropriate medical, and improve appropriate
utilization of long-term resources.
The advent of sophisticated imaging techniques now allows us to observe the structural (e.g., MRI), metabolic (MRS), and functional
(fMRI) activity of the brain noninvasively in a manner that previously was not possible. While the scope of our investigations appear
comprehensive, we have designed the studies to be performed all in one scanning session for each evaluation. We are interested in using
these three techniques to serially explore the evolution of structural brain injuries following TBI; the metabolic changes post-injury through
the recovery process by obtaining regional assessments of neural metabolism with longitudinal spectroscopic measures of metabolic brain
activity including NAA and lactate; as well as serial fMRI studies to evaluate the activation of the brain by functional activities during and after
the recovery from coma. These studies will consist of auditory and visual stimuli, administered to determine levels of conscious recognition
throughout the recovery process.
We hypothesize that emergence from coma in children is based on the achievement of functional reconnections among a distributed set of neuronal
circuits in the brain. We plan to be able to monitor the functional reconnection process through fMRI by assessing patients longitudinally before and
after the emergence from coma, a process that for most of our patients is completed within days to weeks. In shock-trauma units and rehabilitation
programs, emergence from coma is defined functionally as the ability of a patient to follow a simple verbal command. Therefore we will focus on brain
responses to sounds
and words (neutral and positively rewarding) and compare them to
responses to visual and other sensory stimulation. We expect that
comparison of networks of activated cortical and subcortical regions
before and after emergence from coma in a series of patients will
reveal critical networks that provide an essential substrate for
consciousness.
Since we are not aware of any similar work in humans, it is hard to predict what the results will be. However we expect that both vertical
caudal-to-rostral hierarchies and horizontal transcortical network connections will be essential for emergence from coma. For example, we expect
that activation of a combination of brainstem, thalamic and cortical pathways rather than simply brainstem structures alone will be essential for
emergence. However, we expect that activation of lower levels plus a single cortical area alone will not be enough. Animal studies suggest that
coincident recruitment of multiple, bilateral cortical association areas beyond primary cortical sensory representations is essential for emergence of
consciousness. We expect to be able to understand this critical mass of connections and their topographic architecture. This work is likely to have
considerable practical therapeutic as well as fundamental neuroscientific value. From a practical standpoint, families and the treatment team are both
anxious to have objective information about what is going on in the brain. fMRI provides a new window on the working brain that should help the watching
and waiting process. In addition, we hope that the technique will help with prognosis and with evaluating objective responses to rehabilitative interventions.
From a fundamental standpoint, we expect that the diversity of traumatic lesions leading to unconsciousness will allow us to approach the consciousness problem
from multiple directions. By
comparing network properties of coma versus emergence in patients with
multiple scattered lesions, we may be able to distill the critical
network links that make consciousness possible.
In addition, some patients are left with noticeable residual deficits
following emergence from coma. Assessment of cortical and subcortical
circuits through the coma recovery process may provide useful insights
as to why full recovery occurs in some cases and not others, and how
this may lead to
focussing of treatment options and the timing of
administration of those treatments.
Institution: KENNEDY KRIEGER RESEARCH INSTITUTE, INC.
707 NORTH BROADWAY, RM 614
BALTIMORE, MD 21205
Fiscal Year: 2005
Project Start: 05-MAR-1997
Project End: 30-NOV-2009