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.
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).
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.
Pregnant or breastfeeding women
Contraindications to MRI
Known allergy to the PET radiotracer or its excipients.
History of conditions affecting the dopaminergic system
Single group
LBT-999
DrugLBT-999 administration for PET imaging
Striatal 18F-LBT-999 binding potential
characterization of dopaminergic network metabolic abnormalities in the TBI-COMA group. This will be assessed by comparing the binding potential (BP) of 18F-LBT-999 to presynaptic dopamine transporters in the striatum (caudate nuclei and putamen) between TBI-COMA patients and healthy controls, as measured by PET imaging
Dopaminergic Network Binding (TBI-COMA vs Controls)
The BP of 18F-LBT-999 in dopaminergic transporters across the dopaminergic network (striatum, pallidum, substantia nigra) and brainstem (Ventral tegmental area (VTA)) will be assessed via PET in both TBI-COMA patients and healthy controls and compared between these groups
Group Comparisons (TBI-COMA vs. TBI-REC):
The BP of 18F-LBT-999 in the regions of interest (ROIs) described above will be compared between the TBI-COMA and TBI-REC groups
Structural and Functional Correlations
Relationships between dopaminergic network metabolic changes (PET) and structural or functional changes (MRI) will be explored in all TBI patients (TBI-COMA and TBI-REC): Metabolic Changes: BP of 18F-LBT-999 in dopaminergic network ROIs and brainstem. Structural White Matter Changes: Diffusion tensor imaging (DTI) tractography of nigrostriatal pathways, expressed as fractional anisotropy (FA) and mean diffusivity (MD). Structural Gray Matter Changes: Voxel-based morphometry (VBM) analysis in predefined ROIs and cortical regions linked to consciousness (e.g., default mode network - DMN: posterior cingulate cortex, medial prefrontal cortex), expressed as gray matter density (GMD). Functional Changes: Resting-state functional connectivity in the dopaminergic network and DMN, assessed via BOLD fMRI
Motor Behavioral Signatures
Motor behavior in TBI-COMA and TBI-REC groups will be evaluated using the Movement Disorders society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS score). A 4-part scale for which the maximum score is 16 points for part 1, 52 for part 2, 108 for part 3, 23 for part 4). A higher score indicates more severe symptoms
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