Objective: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network. Methods: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness. Results: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks. Conclusions: Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.

Many patients with severe coronavirus disease 2019 (COVID‐19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID‐19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID‐19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness. ANN NEUROL 2020;88:851–854

Background and Objectives In patients with severe coronavirus disease 2019 (COVID-19), disorders of consciousness (DoC) have emerged as a serious complication. The prognosis and pathophysiology of COVID-DoC remain unclear, complicating decisions about continuing life-sustaining treatment. We describe the natural history of COVID-DoC and investigate its associated brain connectivity profile. Methods In a prospective longitudinal study, we screened consecutive patients with COVID-19 at our institution. We enrolled critically ill adult patients with a DoC unexplained by sedation or structural brain injury and who were planned to undergo a brain MRI. We performed resting-state fMRI and diffusion MRI to evaluate functional and structural connectivity compared to healthy controls and patients with DoC resulting from severe traumatic brain injury (TBI). We assessed the recovery of consciousness (command following) and functional outcomes (Glasgow Outcome Scale Extended [GOSE] and the Disability Rating Scale [DRS]) at hospital discharge and 3 and 6 months after discharge. We also explored whether clinical variables were associated with recovery from COVID-DoC. Results After screening 1,105 patients with COVID-19, we enrolled 12 with COVID-DoC. The median age was 63.5 years (interquartile range 55–76.3 years). After the exclusion of 1 patient who died shortly after enrollment, all of the remaining 11 patients recovered consciousness 0 to 25 days (median 7 [5–14.5] days) after the cessation of continuous IV sedation. At discharge, all surviving patients remained dependent: median GOSE score 3 (1–3) and median DRS score 23 (16–30). Ultimately, however, except for 2 patients with severe polyneuropathy, all returned home with normal cognition and minimal disability: at 3 months, median GOSE score 3 (3–3) and median DRS score 7 (5–13); at 6 months, median GOSE score 4 (4–5), median DRS score 3 (3–5). Ten patients with COVID-DoC underwent advanced neuroimaging; functional and structural brain connectivity in those with COVID-DoC was diminished compared to healthy controls, and structural connectivity was comparable to that in patients with severe TBI. Discussion Patients who survived invariably recovered consciousness after COVID-DoC. Although disability was common after hospitalization, functional status improved over the ensuing months. While future research is necessary, these prospective findings inform the prognosis and pathophysiology of COVID-DoC. Trial Registration Information ClinicalTrials.gov identifier: NCT04476589.

Uncertainty in diagnosing disorders of consciousness, and specifically in determining whether consciousness has been lost or retained, poses challenging scientific and ethical questions. Recent neuroimaging-based tests for consciousness have cast doubt on the reliability of behavioral criteria in assessing states of consciousness and generate new questions about the assumptions used in formulating coherent diagnostic criteria. The reflex, a foundational diagnostic tool, offers unique insight into these disorders; behaviors produced by unconscious patients are thought to be purely reflexive, whereas those produced by conscious patients can be volitional. Further investigation, however, reveals that reflexes cannot be reliably distinguished from conscious behaviors on the basis of any generalizable empirical characteristics. Ambiguity between reflexive and conscious behaviors undermines the capacity of the reflex to distinguish between disorders of consciousness and has implications for how these disorders should be conceptualized in future diagnostic criteria.