Deficits in memory, attention, cognitive, and executive functions are the most common disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is implicated in these neural functions and dopaminergic pathways are recognized to be frequently disrupted after TBI. One of the most widely used DAergic drugs is methylphenidate (Ritalin®). Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake. PET with methylphenidate challenge to measure tonic DA release provides valuable insight into the molecular basis of attention-deficit hyperactivity disorder (ADHD) and addiction, as well as practical information regarding likely effectiveness of therapy (1). The objectives of this study are to use PET imaging with \[11C\]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to measure endogenous DA release in patients who are experiencing problems with cognition, attention and executive function in the chronic stage after TBI. In addition, we will use TMS to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity on and off methylphenidate.
* Males and females (n=30), between the ages of 18 and 55 years in the chronic stage after TBI who experience deficits in neuropsychological function from TBIs incurred 6 months after the injury, will be recruited from military treatment facilities or civilian clinics when presenting for clinical management of TBI or post-concussive symptoms. * 1\. Study participants will be evaluated using brain MRI, psychometric measures adapted from the TBI Common Data Elements, attention tests and information about details of the injury and experience of post-concussive symptoms will be recorded. Transcranial magnetic stimulation (TMS) with placebo and with methylphenidate (60 mg by mouth) challenge will be performed to predict a stimulant response. * 2\. Subjects will be studied with \[11C\]-raclopride PET in two imaging sessions. One session will be after administration of placebo and the other after methylphenidate, 60 mg by mouth. Both placebo and methylphenidate will be given 60 minutes prior to injection of \[11C\]-raclopride to allow for peak uptake of methylphenidate in the brain. The binding potential of \[11C\]-raclopride relative to a non-displaceable reference region (cerebellum), BPND, will be used as a measure of D2/D3 receptor availability. The difference in BPND between methylphenidate and placebo (ΔBPND) is used to measure of tonic DA release. * 3\. Subjects will then be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated. * Outcome measures: The primary outcome is change in information processing speed during neuropsychologic testing.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
11
This is an open-labeled 4 week methylphenidate administration, 30 mg twice daily by mouth. Placebo and methylphenidate will also be administered as a single dose before one of the two PET and TMS sessions, in a single blinded manner (the participant will not know whether active drug or placebo was administered). PET imaging with \[11C\]-raclopride, a D2/D3 receptor ligand will be performed after administration of placebo or oral methylphenidate to measure endogenous DA release in TBI patients. Structural MRI will be performed before methylphenidate administration. TMS after placebo or methylphenidate will be performed to measure intracortical inhibition and dopaminergic activity.
National Institutes of Health, Clinical Center.
Bethesda, Maryland, United States
Relationship between tonic dopamine release (measured by displacement of [11C]-raclopride by oral methylphenidate) and change in processing speed between baseline and after methylphenidate treatment.
Processing speed will be assessed as a composite score of the following measures: 1. Conners Continuous Performance Test (3rd Edition) 2. SeaShore Rhythm Test 3. Flanker Inhibitory Control and Attention Test 4. Pattern Comparison Processing Speed Test
Time frame: Four weeks of treatment with methylphenidate.
Relationship between D2/D3 receptor availability in ventral striatum and prefrontal cortex and neuropsychologic deficits.
Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
Time frame: Baseline visit
Relationship between tonic dopamine release in the ventral striatum and prefrontal cortex with neuropsychologic deficits after TBI.
Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
Time frame: Baseline visit
Relationship between D2/D3 receptor availability and functional connectivity of the prefrontal cortex with nodes of the default mode network.
Time frame: Baseline visit
Relationship between TMS-induced short-interval cortical inhibition of M1 and tonic dopamine release.
Time frame: Baseline visit
Test motivation and reward on and off methylphenidate in TBI patients.
Time frame: Four weeks of treatment with methylphenidate.
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