Dopaminergic modulation of human consciousness via default mode network connectivity

Abstract

Decades of preclinical studies indicate that dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain modulate animal behavior and cognition (1). The role of dopaminergic VTA neurons in wakefulness, and hence consciousness, emerged more recently from VTA stimulation experiments utilizing pharmacologic (2, 3), electrophysiologic (4), optogenetic (5, 6), and chemogenetic (7) methods, as well as behavioral experiments in dopamine knockout mice (8). Yet, confirmation of VTA modulation of human consciousness has until now been elusive—inferred from pharmacologic studies of dopaminergic therapies (9) and positron emission studies of dopamine receptor dynamics (10), but unconfirmed due to a lack of suitable techniques for measuring VTA function in humans. This absence of a translational link between animal and human VTA function has hindered the construction of a comprehensive subcortical–cortical connectivity model of human consciousness and impeded the development of new therapies to promote recovery of consciousness in patients with severe brain injuries (11). In PNAS, Spindler et al. report groundbreaking results from complementary observational and interventional studies that shed light on VTA modulation of human consciousness, bridging the gap between animal and human VTA research (12). In a series of resting-state functional MRI experiments performed in healthy volunteers undergoing propofol-induced sedation ( n = 24), patients with chronic disorders of consciousness (DoC) caused by severe brain injuries ( n = 22), and patients with traumatic brain injury treated with methylphenidate ( n = 12), Spindler et al. (12) provide convergent evidence that the subcortical VTA modulates human consciousness via connectivity with the cortical default mode network (DMN). Although VTA neurons connect with multiple regions of the cerebral cortex via monosynaptic and polysynaptic pathways that traverse the mesocortical, mesolimbic, and nigrostriatal bundles (13), the experiments here focus on VTA connectivity with the precuneus/posterior cingulate cortex (PCu/PCC), a well-established “hub node” of the … [↵][1]1Email: bedlow{at}mgh.harvard.edu. [1]: #xref-corresp-1-1