Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI

OBJECTIVES:

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

- 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:

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:

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