Cortical and thalamic connections of the human globus pallidus: Implications for disorders of consciousness

A dominant framework for understanding loss and recovery of consciousness in the context of severe brain injury, the mesocircuit hypothesis, focuses on the role of cortico-subcortical recurrent interactions, with a strong emphasis on excitatory thalamofugal projections. According to this view, excess inhibition from the internal globus pallidus (GPi) on central thalamic nuclei is key to understanding prolonged disorders of consciousness (DOC) and their characteristic, brain-wide metabolic depression. Recent work in healthy volunteers and patients, however, suggests a previously unappreciated role for the external globus pallidus (GPe) in maintaining a state of consciousness. This view is consistent with empirical findings demonstrating the existence of “direct” (i.e., not mediated by GPi/substantia nigra pars reticulata) GPe connections with cortex and thalamus in animal models, as well as their involvement in modulating arousal and sleep, and with theoretical work underscoring the role of GABA dysfunction in prolonged DOC. Leveraging 50 healthy subjects' high angular resolution diffusion imaging (HARDI) dataset from the Human Connectome Project, which provides a more accurate representation of intravoxel water diffusion than conventional diffusion tensor imaging approaches, we ran probabilistic tractography using extensive a priori exclusion criteria to limit the influence of indirect connections in order to better characterize “direct” pallidal connections. We report the first in vivo evidence of highly probable “direct” GPe connections with prefrontal cortex (PFC) and central thalamic nuclei. Conversely, we find direct connections between the GPi and PFC to be sparse (i.e., less likely indicative of true “direct” connectivity) and restricted to the posterior border of PFC, thus reflecting an extension from the cortical motor zones (i.e., motor association areas). Consistent with GPi's preferential connections with sensorimotor cortices, the GPi appears to predominantly connect with the sensorimotor subregions of the thalamus. These findings are validated against existing animal tracer studies. These findings suggest that contemporary mechanistic models of loss and recovery of consciousness following brain injury must be updated to include the GPe and reflect the actual patterns of GPe and GPi connectivity within large-scale cortico-thalamo-cortical circuits.