Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury

Abstract

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.

Keywords: 11C-raclopride; basal ganglia; central thalamus; dopamine 2-like receptors; minimally conscious state.

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Tested model of dopamine neurotransmission. (A) 11C-raclopride-PET-MRI fusion of Patient MCS1 displaying VST, AST and SMST and central thalamus. (B) Monosynaptic nigrostriatal pathway from substantia nigra (SN) and, mesolimbic and mesothalamic pathways from ventral tegmentum (VT) to target nuclei, respectively. (C) The dopaminergic terminal at rest in target structures from B shows background tonic dopamine (DA) leaving unoccupied D2LR. In normal volunteers (NV), 11C-raclopride binds at rest to the unoccupied D2LR (shown in the first blue square in the top row). Dopamine transporter reuptake (DTA) blockade with amphetamine in normal volunteer initiates a pharmacologically-induced phasic responses that increases dopamine levels at the synaptic cleft reducing D2LR occupancy by 11C-raclopride (second blue square in the top row). Lack of this physiological reduction following amphetamine is a marker of a presynaptic deficit as predicted to occur in MCS (bottom row: first and second red squares for rest and post-amphetamine conditions, respectively). In this setting reversal of the presynaptic dopaminergic deficit is expected with administration of a single high-dose of the dopamine precursor l-DOPA (bottom: green square).

Figure 2

Background and pharmacologically-induced phasic dopamine responses measured using 11C-raclopride. (A) Box plot for background D2LR occupancy in 12 normal volunteers (NV) and seven MCS patients: reduction in BPnd of VST, AST, and central thalamus in MCS (one-sided permutation test); no difference in SMST. (B) Box plot shows %ΔBPnd-amphetamine for phasic responses in 11 normal volunteers and six MCS patients: lower reduction in ΔBPnd of VST, SMST, and central thalamus in MCS (one-sided permutation test) indicating a presynaptic deficit of the three main pathways; no difference in AST.

Figure 3

Elicitation of dopamine response with l-DOPA administration. (A) Box plot shows %ΔBPnd in 11 normal volunteers (NV) using amphetamine (AMPH), six MCS patients using amphetamine, and four MCS using l-DOPA. A clear reversibility of the presynaptic deficit from ventral tegmentum (VT) and substantia nigra (SN) follows a single dose of l-DOPA, reaching physiological values obtained from normal volunteers. (B) 11C-raclopride-PET-MRI fusion displaying a restoration of the physiological reduction in binding potentials (BP) following administration of l-DOPA in Patient MCS1. (C) Mesencephalon (midbrain) axial anatomic high-resolution MRI in a representative normal volunteer and the five MCS patients that performed the 11C-raclopride-PET after a single dose of 375 mg of dispersible l-DOPA. All patients (Patients MCS1, MCS3, MCS4 and MCS7) demonstrated higher dopamine release following l-DOPA administration show relative preservation of the midbrain structures, compared with anatomical image from Patient MCS5, who did not respond to a single dose of l-DOPA, which reveals extensive bilateral damage within the substantia nigra and ventral tegmentum.