Mapping basal ganglia circuitry in altered states of consciousness: from pathology to pharmacology

The precise neuromodulatory mechanisms underlying consciousness and its disorders, despite growing evidence in both animals and humans, remain poorly understood at the subcortical level. The basal ganglia, a key component of the cortico-basal ganglia-thalamo-cortical loop, are known to play a crucial role in mediating consciousness and behavioural responsiveness to the environment. Here, we aimed to present a comprehensive mapping of the distinct contributions of basal ganglia nuclei and their associated neurotransmitter systems in pharmacologically induced and pathological loss of responsiveness. We used functional MRI to provide a systematic investigation of 9 major nuclei (putamen, caudate, nucleus accumbens, globus pallidus external, globus pallidus internal, substantia nigra pars compacta, substantia nigra pars reticulata, ventral pallidus, and subthalamic nucleus) and their functional relationship with 19 major neurotransmitter systems in loss of responsiveness, in both healthy volunteers under propofol anaesthesia (n = 16) and patients with disorders of consciousness (DOC) (i.e. minimally conscious, unresponsive wakefulness syndrome) (n = 22). We found that in pharmacologically-induced loss of responsiveness, the functional connectivity changes of the putamen (Pu) correlated with the norepinephrine transporter (NET), and the globus pallidus external (GPe) with the serotonin transporter (5-HTT) and vesicular acetylcholine transporter (VAChT); additionally, altered connectivity in the ventral pallidum (VeP) was associated with the norepinephrine transporter (NET). In contrast, with pathological-induced loss of responsiveness, we found that connectivity changes of the caudate were associated with the serotonin transporter (5-HTT), dopamine transporter (DAT), and GABAA receptor, and connectivity changes of the substantia nigra pars compacta (SNc) were associated with the cannabinoid (CB1) receptor. Finally, we report that among all basal ganglia nuclei, a key dopamine-rich area of the basal ganglia-the substantia nigra-was found to have the largest DOC subgroup difference in functional connectivity, following stratification based on mental-imagery task responsiveness. Critically, we provide evidence that pharmacological and pathological loss of responsiveness involve distinct neurotransmitter system contributions across individual basal ganglia nuclei, offering a novel framework for targeted therapeutic interventions in patients with disorders of consciousness.