Thalamic and extra-thalamic connections of the Globus Pallidus in the human brain: The ultradirect pathway

A dominant framework for understanding loss and recovery of consciousness, particularly in the context of severe brain injury, focuses on cortico-subcortical recurrent interactions, with a strong emphasis on excitatory thalamofugal projections. Recent work in healthy volunteers and patients, however, suggests a previously unappreciated role for the globus pallidus pars externa in maintaining a state of consciousness – a finding that is consistent with non-human animal work demonstrating the existence of direct (i.e., extrathalamic) pallido-cortical projections as well as their involvement in modulating electrocortical arousal and sleep. Leveraging on the high-quality Human Connectome Project dataset, we report for the first time in humans, in vivo evidence of (direct) pallido-cortical and pallido-thalamic projections, distinguishing between internal and external pallidal regions. Our data confirm, in humans, the existence of an “ultradirect” extra-thalamic pallido-cortical pathway, with the pars externa connecting preferentially, and extensively, to prefrontal cortex and the pars interna primarily connecting to sensorimotor cortical areas. Furthermore, we also report, for the first time in humans, the likely existence of a direct pathway uniting the globus pallidus pars externa and the medio-dorsal areas of thalamus often implicated in maintenance and recovery of consciousness. Consistent with the pallido-cortical connectivity results, the pars interna appeared to predominantly connect with the sensorimotor areas of thalamus. Collectively, these findings demonstrate the existence in humans of an extra-thalamic “ultradirect” pallido-cortical pathway and suggest a central role of the external segment of the globus pallidum in supporting consciousness.