Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI
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|ClinicalTrials.gov Identifier: NCT02148783|
Recruitment Status : Terminated (Recruitment was slower than anticipated. Incomplete neuropsychological outcome measures obtained.)
First Posted : May 28, 2014
Last Update Posted : October 4, 2018
|Condition or disease||Intervention/treatment||Phase|
|Traumatic Brain Injury||Drug: methylphenidate Drug: Placebo||Phase 2|
- 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 (Clinical Trial)|
|Actual Enrollment :||11 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI|
|Study Start Date :||September 2014|
|Actual Primary Completion Date :||August 2018|
|Actual Study Completion Date :||August 2018|
Experimental: methylphenidate administration
All participants will receive oral methylphenidate 60 mg before the second TMS study. The participants will receive oral methylphenidate 60 mg before the second PET scan. Subjects will then be treated with oral methylphenidate, using a forced titration. Dose titration will be incremental within 6 days (dose-escalation phase) , starting at 5 mg orally twice daily for 3 days, and 10 mg twice daily for the next 3 days. Then the dose will be increased to 30 mg twice daily starting from day 7 given twice daily for additional 3 weeks.
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.
Other Name: Ritalin
- 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. [ Time Frame: Four weeks of treatment with methylphenidate. ]
Processing speed will be assessed as a composite score of the following measures:
- Conners Continuous Performance Test (3rd Edition)
- SeaShore Rhythm Test
- Flanker Inhibitory Control and Attention Test
- Pattern Comparison Processing Speed Test
- Relationship between D2/D3 receptor availability in ventral striatum and prefrontal cortex and neuropsychologic deficits. [ Time Frame: Baseline visit ]Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
- Relationship between tonic dopamine release in the ventral striatum and prefrontal cortex with neuropsychologic deficits after TBI. [ Time Frame: Baseline visit ]Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
- 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. ]
- Explore relationship between structural connectivity (measured by Diffusion Tensor Imaging) between the ventral striatum, prefrontal cortex, and ventral tegmental area, and tonic dopamine release in patients with TBI. [ Time Frame: Baseline visit. ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02148783
|United States, Maryland|
|National Institutes of Health, Clinical Center.|
|Bethesda, Maryland, United States, 20814|
|Study Director:||Ramon R Diaz-Arrastia, MD, PhD||Uniformed Services University / NINDS|
|Principal Investigator:||Eric Wassermann, MD||National Institute of Neurological Disorders and Stroke (NINDS)|