Current Research

Site-Specific Project One: Comparative effectiveness research in traumatic brain injury rehabilitation

Shahid Shafi, M.D., M.P.H., Principal Investigator

The broad aim of our research is to improve functional outcomes of patients with TBI utilizing comparative effectiveness research (CER). The current proposal aims to identify variations in clinical practices and patient outcomes and identify evidence-based best clinical practices in acute rehabilitation of TBI patients.

Traumatic brain injury is a leading cause of death, disability, and years of productive lives lost. Patients with significant neurologic and functional deficits after TBI are treated at inpatient rehabilitation centers. Comprehensive rehabilitation has been shown to improve functional outcomes and successful reintegration of TBI patients into the community. To ensure optimal quality of care, many of these centers are accredited by the Commission for Accreditation of Rehabilitation Facilities (CARF).

TBIMS is the largest prospective, longitudinal, multicenter study of recovery and outcomes following TBI. TBIMS centers provide state-of-the-art multidisciplinary system of rehabilitation care. However, we have recently found significant differences in risk-adjusted functional outcomes of TBI patient among TBIMS centers.

Conceptually, clinical outcomes depend upon patient characteristics (such as underlying condition and severity of disease) and quality of care. Hence, differences in patient outcomes that remain after accounting for differences in patient characteristics must be attributed to the quality of care provided.

Donabedian principles of quality management suggest that patient outcomes depend upon structures and processes of care. It is not known if the observed differences in patient outcomes among TBIMS centers are due to differences in their structures and resources or due to differences in clinical practices among centers. Adoption of evidence-based best practices in routine clinical care remains suboptimal, with a little over half the patients receiving recommended care.

We have recently demonstrated similar gaps in acute management of TBI patients at Level I trauma centers. Differences in rehab practices and their impact on outcomes of TBI patients have not been studied. Attempts at measuring quality of rehabilitation care are further hampered by a paucity of evidence-based measures of quality in rehabilitation as well as a lack of consensus on best practices.

The goal of this study is to measure variations in clinical care and functional outcomes of patients with TBI treated at inpatient rehabilitation centers and to identify evidence-based best practices in TBI rehab care. The findings will form the basis for future studies to minimize variations in care by improved adoption of evidence-based practices across rehabilitation centers,

Project Aims

Specific Aim 1: To measure variations in patient outcomes across TBIMS centers. To achieve this aim, we will use TBIMS multicenter data to measure patient outcomes at discharge from inpatient rehabilitation using Disability Rating Scale (DRS) and Functional Independence Measure (FIM). Outcomes will be adjusted for patient characteristics that may affect their outcomes such as age, severity of TBI, computed tomography (CT) scan findings, duration of post-traumatic amnesia, pre-injury functional status, and functional status at the time of rehabilitation admission.

Specific Aim 2: To measure variations in inpatient rehab treatment across TBIMS centers. To achieve this aim, we will obtain a representative sample of patients from 4 centers and measure type, intensity, and duration of specific rehabilitation interventions provided during inpatient stay. Interventions will be grouped by rehab disciplines (eg, physical/occupational, speech/language, cognitive, medical, psychosocial, social work/case management) and their impact on patient outcomes will be measured.

Specific Aim 3: To develop a set of evidence-based best practices for inpatient rehabilitation of TBI patients. To achieve this aim, we will undertake a systematic review of literature to develop a list of recommended practices. We will then refine and update this list utilizing Delphi methodology through a panel of experts and patients/families drawn from TBIMS centers.

Site-Specific Project 2: Imaging Dopamine Function and Its Impact on Outcome after Traumatic Brain Injury

Michael Devous, Ph.D., Principal Investigator

Severe TBI is a catastrophic event that has devastating familial, economic, and societal consequences. Of patients who are in a minimally conscious state for ≥ 4 weeks, only approximately 50 percent will regain consciousness by 1 year. In the ICU, step-down units, or on the ward, drugs-enhancing dopamine (DA) signaling are widely used off-label in patients recovering from TBI in an attempt to augment vigilance or accelerate cognitive recovery and rehabilitation.

Although there are anecdotal reports and small case series supporting this practice, only amantadine therapy has been shown in rigorous studies to alter the pace of recovery. A single recently published randomized, controlled trial provides convincing evidence that amantadine, a weak DA agonist, modestly hastens the rate of recovery from the minimally conscious state.  Other neuropharmacologic therapies working on DA systems are commonly used off label to enhance arousal and behavioral responsiveness, on the premise that injuryÔÇÉinduced derangements in DA neurotransmission can be improved through agents such as DA re-uptake inhibitors.

However, the benefits of such therapies are modest and inconsistent, and very little is known about the optimal timing, dose, or duration of therapy. One possible explanation for the variance of effectiveness in studies of DA re-uptake inhibitors in TBI is the heterogeneity of the injury and different degrees of dysfunction of DA circuits. Patients whose injury results in severe loss of DA innervation of limbic and cortical structures, or those whose injury resulted in loss of tonic DA release despite preservation of DA terminals, would not be expected to respond favorably to therapy with DA re-uptake inhibitors and may require other therapies, such as deep brain stimulation. Direct knowledge of the integrity of DA circuits in severely injured patients after TBI should allow more effective therapy targeted at supplementing DA neurotransmission.

To address this issue, we propose to employ Single Photon Emission Computed Tomography (SPECT) imaging of the DA transporter (DAT) as patients begin rehabilitation in order to assess damage to the presynaptic DA system. We will measure tonic DA release by measuring displacement of the DAT ligand induced by an acute dose of methylphenidate (MP), in order to assess the potential for response to therapeutic intervention. DAT imaging with SPECT is a recently FDA-approved, widely available procedure that could be used routinely in TBI patients if it is shown to be effective in predicting treatment response. To that end, we have two specific aims.

Project Aims

Specific Aim 1: To measure DAT expression upon admission to inpatient rehabilitation (after the acute phase of TBI) using SPECT imaging with the DAT imaging agent I-Ioflupane. This procedure will provide a quantitative assessment of presynaptic DA function at the beginning of a 4-week clinical trial with methylphenidate as the primary treatment.

Specific Aim 2: To measure the responsiveness of the DA system in the same initial imaging session by measuring the ability of endogenously release of DA to displace ioflupane following an acute oral dose of methylphenidate 30 mg.

Our primary hypothesis is that resting DAT binding, or the ability of the DA synapses to release dopamine in response to pharmacologic challenge will be predictive of patient response to MP treatment.

Specific hypotheses

Primary Hypothesis: Higher tonic DA release (ioflupane displacement after oral MP dose) will be associated with improvement over 4 weeks, independent of baseline DAT binding.

Secondary Hypothesis 1: TBI patients as a group will have lower DAT binding than non-injured controls.

Secondary Hypothesis 2: Higher levels of DAT binding at baseline will be associated with better improvement over the subsequent 4 weeks.