Dopaminergic brainstem disconnection is common to pharmacological and pathological consciousness perturbation

A network of brain regions called the default mode network breaks down during anesthesia and after brain damage causing disorders of consciousness. The neurochemical reasons for this breakdown were unclear. Using functional MRI, researchers found that the ventral tegmental area, a dopamine-producing brainstem region, disconnects from key default mode network nodes (precuneus and posterior cingulate) during both propofol sedation and disorders of consciousness. Stronger connectivity between the ventral tegmental area and these nodes was associated with a more awake-like configuration of the default mode network. In patients with disorders of consciousness who later improved behaviorally, this connectivity increased toward healthy levels. In a separate group of traumatic brain injury patients, the drug methylphenidate significantly strengthened this connection. The findings suggest that dopamine modulation may be central to maintaining consciousness.

Study at a glance

Abstract

Significance Understanding the neural bases of consciousness is of basic scientific and clinical importance. Human neuroimaging has established that a network of interconnected brain regions known as the default mode network disintegrates in anesthesia and after brain damage that causes disorders of consciousness. However, the neurochemical underpinnings of this network change remain largely unknown. Motivated by preclinical animal work and clinical observations, we found that across pharmacological (sedation) and pathological (disorders of consciousness) consciousness perturbation, the dopaminergic source nucleus, the ventral tegmental area, disconnects from the main nodes of the default mode network. As the severity of this dopaminergic disconnection was associated with default mode network disintegration, we propose that dopaminergic modulation may be a central mechanism for consciousness maintenance. Clinical research into consciousness has long focused on cortical macroscopic networks and their disruption in pathological or pharmacological consciousness perturbation. Despite demonstrating diagnostic utility in disorders of consciousness (DoC) and monitoring anesthetic depth, these cortico-centric approaches have been unable to characterize which neurochemical systems may underpin consciousness alterations. Instead, preclinical experiments have long implicated the dopaminergic ventral tegmental area (VTA) in the brainstem. Despite dopaminergic agonist efficacy in DoC patients equally pointing to dopamine, the VTA has not been studied in human perturbed consciousness. To bridge this translational gap between preclinical subcortical and clinical cortico-centric perspectives, we assessed functional connectivity changes of a histologically characterized VTA using functional MRI recordings of pharmacologically (propofol sedation) and pathologically perturbed consciousness (DoC patients). Both cohorts demonstrated VTA disconnection from the precuneus and posterior cingulate (PCu/PCC), a main default mode network node widely implicated in consciousness. Strikingly, the stronger VTA–PCu/PCC connectivity was, the more the PCu/PCC functional connectome resembled its awake configuration, suggesting a possible neuromodulatory relationship. VTA-PCu/PCC connectivity increased toward healthy control levels only in DoC patients who behaviorally improved at follow-up assessment. To test whether VTA–PCu/PCC connectivity can be affected by a dopaminergic agonist, we demonstrated in a separate set of traumatic brain injury patients without DoC that methylphenidate significantly increased this connectivity. Together, our results characterize an in vivo dopaminergic connectivity deficit common to reversible and chronic consciousness perturbation. This noninvasive assessment of the dopaminergic system bridges preclinical and clinical work, associating dopaminergic VTA function with macroscopic network alterations, thereby elucidating a critical aspect of brainstem–cortical interplay for consciousness.