Specification of background dopaminergic synaptic activity in disorders of consciousness following severe traumatic brain injury

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

? DESCRIPTION (provided by applicant): 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, we propose to investigate the specific contribution of presynaptic and postsynaptic dopamine function in posttraumatic DOC. The aim of the present study is to measure the expression of D2/D3 receptors in the main dopaminergic pathways using [11C]raclopride-PET at rest and following a short pharmacological challenge with dextroamphetamine and dextroamphetamine + L-DOPA. Using this novel technique in DOC we characterized in 2 patients in chronic minimally conscious state a presynaptic deficiency to synthesize and/or release dopamine at rest, and a failure to increase the dopamine level at the synaptic cleft following stimulation with dextroamphetamine. Both phenomena were unseen in a control group of 8 normal volunteers. In addition, both subjects showed a selective postsynaptic deficit in the central thalamus, the core hub structure of the anterior forebrain mesocircuit. It is unknown whether this pattern presynaptic and postsynaptic dopaminergic failure is specific for these 2 patient subjects or is more generally seen across the population of subjects with DOC. Moreover, when identified presynaptic deficits as found in these subjects may be secondary to a failure of biosynthesis of dopamine and therefore in principle reversible by providing the main biological substrate of the synthesis process. We therefore propose to investigate patients with posttraumatic DOC using [11C]raclopride-PET at rest and following short pharmacological challenges aimed at increasing dopamine release and dopamine biosynthesis.