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
Study type: Interventional
Phase: Phase 2

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
    

Detailed description: 
      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.

      STUDY POPULATION:

      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 postconcussive symptoms.

      DESIGN:

        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 ( BPND) 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
    

Intervention name(s): Methylphenidate
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Open label methylphenidate administration
Intervention MeSH terms: Methylphenidate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dopamine Receptors; Methylphenidate; Traumatic Brain Injury; C-11 Raclopride; Dopamine Release