Changes in Glutamatergic Neurotransmission of Severe TBI Patients

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.

Conditions

• Disorder of Consciousness
• Traumatic Brain Injury

Interventions

DRUG

Amantadine + L-DOPA

Amantadine 150 mg L-DOPA 375mg/carbidopa 75mg

DRUG

NMDA blocker

NMDA blocker

Sponsors & Collaborators

• Weill Medical College of Cornell University

  lead OTHER

Principal Investigators

• Esteban A Fridman, MD, PhD · Weill Medical College of Cornell University

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2020-09-23

Primary Completion

2023-05-30

Completion

2023-06-30

FDA Drug

Yes

Countries

• United States

Study Locations