Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness

The R21 research objective is to examine the safety and efficacy of repetitive transcranial
magnetic stimulation (rTMS) combined with Amantadine (TMS + Amantadine) relative to rTMS
Alone and Amantadine Alone for persons in chronic states of seriously impaired
consciousness. The hypothesis is that provision of rTMS+Amantadine will provide a safe yet
synergistic effect that induces or accelerates functional recovery. This hypothesis is based
on (a) preliminary data indicating partially improved neurobehavioral functioning
mechanistically related to rTMS-induced neural activity and connectivity as well as improved
integrity of white fiber tracts, (b) relationship between dopamine (DA) and common traumatic
brain injury (TBI) impairments, (c) role of DA in mediating consciousness, (d) the
commonality between and DA and rTMS-targeted pathways, (e) clinical efficacy and safety of
Amantadine, (f) mechanisms of action of Amantadine, and (g) the association between rTMS and
Amantadine with up-regulating brain derived neurotrophic factor. The rationale is that
pairing rTMS with Amantadine will have a complementary and synergistic effect on factors
promoting conscious behavior. The specific aims are to: (1) Demonstrate that rTMS+Amantadine
is safely tolerated, (2) Determine neurobehavioral effect of rTMS+Amantadine, and (3)
Characterize pre-and post-treatment neural changes in neural activation. Aim 1 is based on
our preliminary safety data and safety data regarding Amantadine. To address Aims 2 & 3 we
use a repeated measures baseline control design with randomized treatment orders yielding
three treatment groups; rTMS + Amantadine, rTMS Alone and Amantadine Alone. Analyses for
Aims 2 and 3 involve comparing these treatment groups according to neurobehavioral growth
trajectories, mean amount of neural activation and connectivity within and between brain
regions, and indices of fiber tract directionality.

Inclusion Criteria:

- 18-64 years of age

- Suffered a severe brain injury of traumatic origin at least 1-year prior to study
enrollment

- Remain in a state of disordered consciousness

- Brain injuries will include injury with resulting coup-contre-coup injuries,
excluding persons with trauma due to blunt injuries and/or non-traumatic
encephalopathy

Exclusion Criteria:

- Have 1 or more Amantadine contraindications: On monoamino oxidase inhibitor-B,
hypersensitivity/idiosyncrasy to sympathomimetic amines, uncontrolled hypertension,
glaucoma or Congestive Heart Failure

- Have contraindications to Amantadine Dose of 200 mg Daily as determined by estimated
Glomerular Filtration Rate (eGFR) ≤ 60 (ml/min)

- Abnormal results of Liver Function Test at screening

- Receiving anti-epileptic medications to control active seizures or have had a
documented seizure within three months of study enrollment

- Incurred large cortically based ischemic infarction/encephalomalacia subsequent to
TBI

- Have documented history of previous TBI, psychiatric illness (DSM criteria) and/or
organic brain syndrome such as Alzheimer's

- Are using medications which may interfere with Amantadine and cannot be safely
titrated or discontinued

- Are pregnant

- Have implanted cardiac pacemaker or defibrillator, cochlear implant, nerve
stimulator, intracranial metal clips

- Have MRI and/or TMS contraindications such as: History of claustrophobia, metal in
eyes/face, shrapnel/bullet remnants in brain

- Are fully conscious as indicated by a score of 6 on the Motor Function scale and/or a
score of 2 on the Communication scale of the CRS-R,

- Are within first year of injury

- Are <18 years of age and > 65 years of age

- Have an injury or condition due to blunt trauma only or non-traumatic encephalopathy

- Have programmable CSF shunt or are ventilator dependent