Imaging Dopamine Function and It's Impact on Outcome after TBI

Severe traumatic brain injury is a catastrophic event that has devastating familial, economic, and societal consequences. Of patients who are in a minimally conscious state for at least 4 weeks, only approximately 50% will regain consciousness by 1 year (Giacino et al 2002). In the intensive care unit, 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 (Giacino et al 2012) 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 injury-induced 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 reuptake inhibitors, and may require other therapies, such as deep brain stimulation (Schiff 2009). 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 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, 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 2 specific aims: 1. To measure DAT expression upon admission to inpatient rehabilitation (after the acute phase of TBI) using SPECT imaging with the DAT imaging agent123I-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. 2.To measure the responsiveness of the dopamine 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 30 mg methylphenidate (MP). 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 methylphenidate treatment. Specific hypotheses are: 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.