Changes in Glutamatergic Neurotransmission of Severe TBI Patients

• Status: Recruiting
• Trial end date: 2023-06-30
• Target enrollment: 0
• Participant gender: All

Summary

Studies in patients with disorders of consciousness (DOC) after severe brain injury implicate dysfunction of the anterior forebrain mesocircuit dysfunction a key underlying mechanism. The anterior forebrain metabolism in DOC is markedly downregulated across brain regions underpinning highly elaborated cognitive behaviors demonstrating a collapse of the level of synaptic background activity required for consistent goal-directed behavior and arousal regulation. Since dopamine levels are one of the primary controllers of the level of synaptic background activity within these forebrain structures and in regulating excitatory glutamatergic homeostasis, the investigators propose to investigate the specific contribution of presynaptic dopamine function in glutamatergic neurotransmission in posttraumatic DOC. The aim of the present study is to measure metabotropic glutamate receptors 5 occupancy in the main gutamatergic structures of the brain using (3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile)-positron emission tomography ( [18F]FPEB-PET) at rest and following a short pharmacological challenge with amantadine, an N-methyl-D-aspartate receptor (NMDA-R) antagonist, following L-DOPA, and amantadine + L-DOPA. Using this novel technique in DOC the investigators will characterize the relevance of a presynaptic deficiency to synthesize and/or release dopamine in the final regulation of excitatory interneurons of the anterior forebrain mesocircuit.

It is unknown whether glutamatergic neurotransmission is affected across the population of subjects with DOC and, if this condition is secondary to a presynaptic dopaminergic failure of the anterior forebrain mesocircuit (i.e., down-regulation). Since the investigators previously identified the existence of a presynaptic dopaminergic deficit in these subjects due to a failure in the biosynthesis of dopamine, the investigators will evaluate if by providing the main biological substrate of the biosynthesis process (i.e., L-DOPA) the glutamatergic system regains homeostasis. The investigators therefore propose to investigate patients with posttraumatic DOC using [18F]FPEB-PET at rest and following short pharmacological challenges aimed at increasing glutamate and dopamine release.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Weill Medical College of Cornell University
• Treatments: Amantadine; Levodopa; N-Methylaspartate

Criteria

Patients Subjects with DOC

Inclusion criteria:

• Age between 18 and 75 years of age, inclusive.

• Patients with disorder of consciousness (vegetative state, minimally conscious state, emerged from minimally conscious state) following severe brain injuries.

• Male or non-pregnant female.

• Medically stable.

• Informed consent from a Legally Authorized Representative.

Exclusion criteria:

• Medical instability.

• Clinical history of moderate to severe hypertension or heart arrhythmia.

• Use of stimulants or dopamine blocker during the 24 hours previous to the study.

• Absence of a legally authorized representative (LAR) to sign the consent form.

Normal Volunteers

Inclusion criteria:

• Age between 18 and 75 years old, inclusive.

• Absence of cardiological, neurological and/or psychiatric diseases.

• Absence of familiar antecedents of sudden death of unknown reason.

• Male or non-pregnant female.

• Informed consent signed.

Exclusion criteria:

• Caffeine or alcohol intake in the last 24 hours previous to the study.