Changes in Glutamatergic Neurotransmission of Severe TBI Patients

Disorders of consciousness (DOC) produced by severe traumatic brain injuries (TBI) lack systematic evaluation and treatment strategies. Accumulating evidence points to the important and general role of impaired anterior forebrain mesocircuit function following multi-focal brain injuries that produce widespread deafferentation or neuronal cell loss (Schiff, 2010, Fridman et al. 2014). Among important sources of neuromodulation of this mesocircuit, alteration of dopaminergic innervations as a result of impaired biosynthesis of dopamine, neurotransmitter release, or its direct binding to dopamine receptors is implicated as having a critical contribution (Fridman and Schiff, 2014, Giacino et al. 2012). Parallel deficits of long-range excitatory glutamatergic neurotransmission likely play an equally crucial factor in all DOCs (Fridman and Schiff, 2014), as shown in non-human primates where a decrease of cortical glutamate levels occurs following dopamine depletion of substantia nigra (SN), and likely the ventral tegmentum (VT) (Fan et al., 2014). In a Phase 0 clinical trial exploring the pharmacodynamics underlying DOC (NINDS R21-NS093268) the investigators have shown that chronic TBI patients have an underlying presynaptic dopamine deficit in SN and VT that is not reversed by blocking only dopamine reuptake but is reversed by increasing dopamine synthesis using the dopamine precursor L-DOPA (Fridman et al., 2018)*. No prior studies, however, have provided direct measurements of glutamatergic deficits in DOC. Moreover, no systematic evaluation of glutamatergic neurotransmission has been carried in post-TBI DOC patients following dopaminergic modulation. This gap in knowledge is critically important as only one therapeutic intervention has shown modest effectiveness in subacute and chronic stage of TBI (Giacino et al., 2012) targeting glutamatergic neurotransmission without addressing impaired dopaminergic biosynthesis (Fridman et al., 2018)*.

Here the investigators develop a novel and systematic assessment focusing on the role of the integrity of dopaminergic-glutamatergic systems in DOC. The investigators approach allows for evaluation of the integrity of glutamatergic innervations to key neuronal populations within the anterior forebrain mesocircuit. Using a similar approach (i.e., molecular neuroimaging and pharmacological challenges), the investigators have identified that patients with DOC exhibit: 1) a widespread presynaptic deficit affecting the resting dopamine synaptic activity; 2) a widespread presynaptic deficit affecting the induced dopamine release after pharmacological stimulation with amphetamine; and, 3) a partial postsynaptic deficit. The investigators long-term goal is to understand how neuromodulation of the anterior forebrain mesocircuit in DOC can be optimally manipulated for diagnosis and therapy. The investigators working hypothesis is that patients with DOC following TBI have alterations of glutamatergic function that can be partially reversed by dopamine replacement. The rationale that underlies the proposed research is that identification of a glutamatergic down-regulation in DOC as well as identification of the key regulator of this down-regulation (i.e., secondary to a deficit in the synthesis of dopamine) will allow the development of complementary diagnostic methods to predict patients' responses to specific therapies and, further improve the efficacy of neuropharmacological treatments to induce recovery of consciousness following severe TBI by rational polypharmacy. The investigators will develop quantitative measurements to test this hypothesis under the following Specific Aims:

Specific Aim 1a. To identify and characterize impaired glutamatergic neurotransmission deficits in posttraumatic DOC.

The investigators will assess in-vivo the availability of free metabotropic glutamate receptor 5 (mGluR5) at rest in patients with DOC and normal volunteers (NV) following N-methyl-D-aspartate receptor (NMDA-R) blockade with amantadine (AMT) utilizing [18F]FPEB-PET. The investigators working hypothesis is that patients with DOC will demonstrate:

1. a glutamatergic deficit in anterior forebrain mesocircuit that is identified by a lower mGluR5 availability at rest; and 2) a failure to decrease mGluR5 occupancy following stimulation with AMT.

Specific Aim 1b. To determine the reversibility of glutamatergic neurotransmission deficits in response to dopamine replacement in posttraumatic DOC.

In DOC patients with a demonstrated glutamatergic deficit the investigators will assess the availability of free mGluR5 at rest and following NMDA-R blockade with AMT by means of [18F]FPEB-PET after premedication with L-DOPA. The investigators hypothesize that impaired glutamatergic neurotransmission in DOC can be partially restored by providing the dopamine precursor L-DOPA and thus supporting dopamine biosynthesis and subsequent release of a circuit- level inhibition at the level of the thalamus (mesocircuit hypothesis). Impaired biosynthesis is proposed to arise secondary to a posttraumatic enzyme tyrosine hydroxylase deficiency affecting the biosynthesis of dopamine.

The investigators expected outcomes are anticipated to identify biomarkers to better define future therapeutic interventions in TBI patients with DOC. These results are expected to have an important positive impact because the identified biomarkers are highly likely to provide new therapeutic targets to induce recovery and therefore decrease disability and social cost in this large population of severe brain injured patients.