Changes in Glutamatergic Neurotransmission of Severe TBI Patients
Status:
Recruiting
Trial end date:
2023-06-30
Target enrollment:
Participant gender:
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.