Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI
Condition: Cognition Disorder; Attention Deficit Disorder; Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Attention Deficit Disorder with Hyperactivity; Cognition Disorders
Intervention: Methylphenidate
Intervention description: Subjects will 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.
Intervention MeSH terms: Methylphenidate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Dopamine Receptors; Methylphenidate; Traumatic Brain Injury; C-11 Raclopride; Dopamine Release

Summary:

      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. Methylphenidate increases synaptic DA levels by binding to
      presynaptic dopamine transporters (DAT) and blocking re-uptake.

      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
    

Eligibility criteria:

        -  INCLUSION:

        To be included in the protocol, study participants must meet the following criteria:

          1. Age 18 - 55 years, inclusive

          2. 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). (Some missing
                  information about the initial injury (i.e., documentation of initial GCS) is not
                  necessarily exclusionary if the bulk of the available history indicates that the
                  patient suffered a TBI and meets the inclusion criteria)

          3. Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for

             Post-Concussional Disorder, including:

             a) Difficulty in attention or memory. b) One or more of the following symptoms, which
             started shortly after the trauma and persist for at least three months: i)
             Fatigability ii) Disordered sleep iii) Changes in personality iv) Apathy or lack of
             spontaneity c) Symptoms in criteria (a) and (b) must have their onset after trauma, or
             there was a significant worsening of pre-existing symptoms after trauma.

             d) Disturbance from these symptoms causes significant impairment of social or
             occupational functioning and represents a significant decline from previous level of
             functioning.

          4. Ability to read, write, and speak English

          5. Ability to give informed consent.

        EXCLUSION:

          1. Evidence of penetrating brain injury.

          2. 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

          3. 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

          4. 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

          5. Contraindication to TMS, such as metal in the cranial cavity or implanted electronic
             hardware.

          6. Current participation in other interventional clinical trial

          7. 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.

          8. Present history of alcohol and substance abuse disorder determined (by DSM-IV).

          9. Body mass index (BMI) > 40