Dopaminergic Disruption Induced by Traumatic Coma: Dopaminergic Pathways Abnormalities and Biomarkers of Recovery Using MRI and 18F-LBT-999 PET

Dopaminergic Disruption Induced by Traumatic Coma: Multimodal Neuroimaging Approaches to Characterize Dopaminergic Pathways Using 18F-LBT-999 PET

The neural correlates of consciousness have been studied at the macroscopic level. However, the neurochemical basis of these processes remains poorly understood. The mesocircuit theory challenges the cortico-centric view of consciousness. It highlights the role of subcortical regulation by dopaminergic circuits, including the ventral tegmental area and striatal loops. Experimental data show the importance of dopamine in consciousness recovery. Animal TBI studies link dopamine deficits to loss of consciousness and recovery. In humans, imaging studies show disrupted dopaminergic networks in chronic consciousness disorders. Yet, early-phase dopaminergic disruptions in acute coma remain underexplored.

Molecular imaging with PET or SPECT offers insights into dopamine system disturbances. The novel radiotracer 18F-LBT-999 enables detailed imaging of dopaminergic circuits, providing better spatial resolution and quantification than SPECT.

This proof of concept study aims to explore acute subcortical dopaminergic loop disruptions. It will combine 18F-LBT-999 PET with structural and functional MRI in post-traumatic coma.

Methods : Patients with severe traumatic brain injury (TBI) admitted to the intensive care unit state will be evaluated within 30 days post-injury. Participants will undergo clinical assessment after sedation clearance and will be categorized into three groups: (1) TBI-COMA (severe TBI with persistent coma), (2) TBI-REC (severe TBI with recovery of command-following), and (3) healthy controls. All participants will undergo clinical evaluations, anatomical and functional MRI, and molecular imaging: 18F-LBT-999-PET. Neurological outcome (CRS-r scale), Disability rating scale (DRS), Quality of life (QUOLIBRI) and axtrapyramidal symptoms (MDS-UPDRS) will be assessed at 3 month.

Primary Hypothesis: Acute post-traumatic severe TBI patients with persistent coma (TBI-COMA) show reduced presynaptic dopamine receptor levels in the striatum, compared to healthy controls.

Secondary Hypotheses:

• Dopaminergic disruptions correlate with the severity of consciousness impairment, differentiating TBI-COMA and TBI-REC groups.
• Structural damage in the striatum and nigrostriatal tract, identified via MRI, aligns with dopaminergic abnormalities.
• Multimodal imaging findings during the acute phase can predict long-term neurological and quality-of-life outcomes.
• Characterizing structural, functional, and metabolic variations in dopaminergic networks may guide personalized pharmacological treatments.

Inclusion Criteria:

For All Participants:

• Aged 18-65 years.
• Affiliated with or beneficiary of a social security system.
• Signed informed consent provided by the participant or a trusted representative (for patients).

For all TBI Participant

• Hospitalized for a non-penetrating traumatic brain injury (TBI) occurring within the last 30 days, with traumatic coma (Glasgow Coma Scale (GCS) < 10 and motor score (M) < 6) at hospital admission.
• Sedative treatments discontinued for more than 48 hours.
• Clinically stable (no hemodynamic, respiratory, or metabolic instability requiring specific interventions that contraindicate medical transfer to the imaging center).

For the TBI-COMA Group:

- Severe TBI characterized by prolonged coma, defined as an initial GCS < 10 with M < 6, and no recovery of consciousness at inclusion (GCS < 10 with M < 6).

For the TBI-REC Group:

• Severe TBI characterized by prolonged coma, defined as an initial GCS < 10 with M < 6, with recovery of consciousness evidenced by simple command-following (GCS ≥ 10 with M = 6) at inclusion.
• For Healthy Controls:

Matched by age (± 2 years) and sex to patients in the TBI-COMA group.

Exclusion Criteria:

For All Participants:

• Pregnant or breastfeeding women
• Contraindications to MRI
• Known allergy to the PET radiotracer or its excipients.
• History of conditions affecting the dopaminergic system
• Individuals under legal protection measures
• Current treatment with dopaminergic agonists or antagonists.

For Patients Only:

• Coma due to causes other than TBI.
• Decompressive craniectomy resulting in anatomical alterations incompatible with standardized image analysis (e.g., midline shift > 2 cm).

For Healthy Controls Only:

• Women of childbearing potential without effective contraception.
• Women unwilling to maintain effective contraception during the 30-day study period.