Traumatic Brain Injury | Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI
Traumatic Brain Injury research study
What is the primary objective of this study?
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.
Who is eligible to participate?
Inclusion Criteria: - Age 18 - 55 years, inclusive - A history of having sustained a moderate or severe TBI > 6 months prior to enrollment. Evidence will be any one of the following 3 criteria: 1. GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record) 2. Post-traumatic amnesia > 24 hours 3. TBI-related abnormality on neuroimaging (either CT or MRI). - Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-Concussional Disorder, including: 1. Difficulty in attention or memory. 2. One or more of the following symptoms, which started shortly after the trauma and persist for at least three months: 1. Fatigability 2. Disordered sleep 3. Changes in personality 4. Apathy or lack of spontaneity 3. Symptoms in criteria (a) and (b) must have their onset after trauma, or there was a significant worsening of pre-existing symptoms after trauma. 4. Disturbance from these symptoms causes significant impairment of social or occupational functioning and represents a significant decline from previous level of functioning. - Ability to read, write, and speak English - Ability to give informed consent. Exclusion Criteria: - Evidence of penetrating brain injury. - Contraindication to methylphenidate therapy: 1. Known glaucoma (consistently raised intraocular pressure with or without associated optic nerve damage) 2. Motor tics or a family history of Tourette's syndrome (diagnosed by presence of both multiple motor and one or more vocal tics over the period of a year, with no more than three consecutive tic-free months) 3. Known hypersensitivity to methylphenidate (hives, difficulty breathing, and swelling of face, lips, tongue, or throat). 4. Known severe anxiety or restlessness which prevents from doing day to day activities. 5. Known preexisting hypertension, heart failure, myocardial infarction, or ventricular arrhythmia. 6. Known preexisting psychosis, bipolar illness. 7. History of seizures, or interictal epileptiform discharges (IEDs) on EEG in absence of seizures. 8. Known peripheral vasculopathy, including Raynaud's phenomenon. 9. History of drug dependence or alcoholism. 10. Concomitant treatment with coumadin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). 11. Concomitant therapy with monoamine oxidase inhibitors (such as Marplan (isocarboxazid), Nardil (phenelzine), Emsam (selegiline), and Parnate (tranylcypromine)) 12. Concomitant treatment with blood pressure medication (both for high and low blood pressure). 13. Pregnancy 14. Breastfeeding - History or evidence of disabling pre-existing or co-existing disabling neurologic or psychiatric disorders not related to TBI, such as: 1. Multiple sclerosis, pre- or co-existing 2. Stroke (other than stroke at the time of TBI) 3. Pre-existing disabling developmental disorder 4. Pre-existing epilepsy 5. Pre-existing major depressive disorder, aggressive behavior, hostility 6. Pre-existing schizophrenia - Contraindication to MRI scanning 1. Ferromagnetic metal in the cranial cavity or eye, e.g., aneurysm clip, implanted neural stimulator, cochlear implant, or ocular foreign body 2. Implanted cardiac pacemaker or auto-defibrillator or pump 3. Non-removable body piercing 4. Claustrophobia 5. Inability to lie supine for two hours - Contraindication to TMS, such as metal in the cranial cavity or implanted electronic hardware. - Current participation in other interventional clinical trial - Non-adherence to use of effective method of contraception for females of able to become pregnant for time from enrollment to the study until 2 weeks after completion of the study drug. - Present history of alcohol and substance abuse disorder determined by DSM-IV - Body mass index (BMI) > 30
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Traumatic Brain Injury
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:methylphenidateThis 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.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
methylphenidate administrationAll 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.
Start Date: September 2014
Completed Date: August 2018
Phase: Phase 2
Primary Outcome: 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.
Secondary Outcome: Relationship between D2/D3 receptor availability in ventral striatum and prefrontal cortex and neuropsychologic deficits.
Study sponsors, principal investigator, and references
Principal Investigator: Ramon R Diaz-Arrastia, MD, PhD
Lead Sponsor: Uniformed Services University of the Health Sciences
Collaborator: National Institutes of Health (NIH)
Volkow ND, Wang GJ, Tomasi D, Kollins SH, Wigal TL, Newcorn JH, Telang FW, Fowler JS, Logan J, Wong CT, Swanson JM. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci. 2012 Jan 18;32(3):841-9. doi: 10.1523/JNEUROSCI.4461-11.2012.