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Olfactory sniffing signals consciousness in unresponsive patients with brain injuries

Abstract

After severe brain injury, it can be difficult to determine the state of consciousness of a patient, to determine whether the patient is unresponsive or perhaps minimally conscious1, and to predict whether they will recover. These diagnoses and prognoses are crucial, as they determine therapeutic strategies such as pain management, and can underlie end-of-life decisions2,3. Nevertheless, there is an error rate of up to 40% in determining the state of consciousness in patients with brain injuries4,5. Olfaction relies on brain structures that are involved in the basic mechanisms of arousal6, and we therefore hypothesized that it may serve as a biomarker for consciousness7. Here we use a non-verbal non-task-dependent measure known as the sniff response8,9,10,11 to determine consciousness in patients with brain injuries. By measuring odorant-dependent sniffing, we gain a sensitive measure of olfactory function10,11,12,13,14,15. We measured the sniff response repeatedly over time in patients with severe brain injuries and found that sniff responses significantly discriminated between unresponsive and minimally conscious states at the group level. Notably, at the single-patient level, if an unresponsive patient had a sniff response, this assured future regaining of consciousness. In addition, olfactory sniff responses were associated with long-term survival rates. These results highlight the importance of olfaction in human brain function, and provide an accessible tool that signals consciousness and recovery in patients with brain injuries.

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Fig. 1: Measuring sniff responses in patients with DOC.
Fig. 2: The sniff response reflects the level of consciousness in patients with DOC.
Fig. 3: The sniff response is associated with the recovery of consciousness in patients with DOC.
Fig. 4: The sniff response is associated with long-term survival and functional recovery in patients with DOC.

Data availability

Respiration data that support the findings of this study are available from GitLab (https://gitlab.com/liorg/OlfactorySniffingAnalysis/). Source data for Figs. 1–4 are provided with the paper.

Code availability

Custom code created and used in this study is available from GitLab (https://gitlab.com/liorg/OlfactorySniffingAnalysis/).

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Acknowledgements

We thank the patients, their families and their caregivers for their cooperation; and O. Perl, L. Rösler and A. Elite for discussions. Work in the Sobel laboratory is supported by the Rob and Cheryl McEwen Fund for Brain Research. A.A. is supported by the Blavatnik Family Foundation, a Royal Society – Kohn International fellowship (NF150851) and an European Molecular Biology Organization (EMBO) fellowship (ALTF 33-2016).

Author information

Affiliations

Authors

Contributions

Conceptualization: A.A. and N.S.; data collection: A.A., L.R. and L.G.; analysis: A.A., L.R., L.G., A.R. and N.S.; funding acquisition: A.A., N.S. and Y.S.; investigation: A.A., L.R., D.R. and Y.H.; methodology: A.A., L.R., L.G., A.R. and N.S.; project administration: A.A., L.R., D.R., Y.H., G.C., T.G., B.-Z.K., A.O., E.A., Y.S. and N.S.; resources: A.A., L.R., L.G., D.R., Y.H., G.C., T.G., B.-Z.K., A.O., E.A., Y.S. and N.S.; software: A.A., L.R. and L.G.; supervision: A.A., T.A.B., T.G., B.-Z.K., A.O., E.A., Y.S. and N.S.; validation: A.A., L.R. and L.G.; visualization: A.A. and N.S.; writing of the original draft: A.A. and N.S.; writing, review and editing: A.A., L.R., L.G., D.R., Y.H., T.A.B., G.C., T.G., B.-Z.K., A.O., E.A., Y.S. and N.S.

Corresponding authors

Correspondence to Anat Arzi or Noam Sobel.

Ethics declarations

Competing interests

The findings of this manuscript are being used by the Weizmann Institute Office of Technology Licensing (Yeda) for the submission of a patent for a method of the detection of consciousness.

Additional information

Peer review information Nature thanks Hakwan Lau, Johan Lundström, Nicholas Schiff and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 The sniff response reflects the current level of consciousness in patients with DOC.

Data are displayed by odorant and sniff. ai, Normalized sniff volume after pleasant odorants (a, d, g), unpleasant odorants (b, e, h) and blank (c, f, i) during UWS (U) sessions (outline; n = 73) and MCS (M) sessions (filled; n = 73) for the first (ac), second (df) and third (gi) sniff after stimulus delivery. Left, each dot represents a session; flat violin plots show the distribution; the red lines denote the median; and the dashed horizontal lines denote the baseline value at 1 NFU. Right, data are the mean ± s.e.m. for each distribution. The P values beneath the distribution denotes its difference from baseline inhalation. The P values above the distributions denote the difference in sniff response across groups. P values were calculated using two-tailed Wilcoxon signed-rank tests for within-group comparisons and Wilcoxon rank-sum tests for between-group comparisons corrected for multiple comparisons. Corrected P values are indicated by an asterisk (*) and uncorrected P values are indicated by a hash (#) symbol (see Methods). *P < 0.05; #P < 0.05. Further analyses are provided in the Supplementary Information.

Extended Data Fig. 2 The sniff response to pure olfactory odorants in patients with DOC.

To estimate whether the effects that we observed were dependent on the contribution of the trigeminal nerve, we exposed a subset of patients to pure olfactory odorants and observed the replication of the effects. The normalized sniff volume after exposure to the pure olfactants of the pleasant odorant (phenylethyl alcohol; a, c, e) and unpleasant odorant (decanoic acid; b, d, f) during UWS sessions (outline; pleasant, n = 56; unpleasant, n = 57) and MCS sessions (filled; pleasant, n = 56; unpleasant n = 56) for the first (a, b), second (c, d) and third (e, f) sniff after odorant delivery. Left, each dot represents a session; flat violin plots show the distribution; the red lines denote the median; and the dashed horizontal lines denote the baseline value at 1 NFU. Right, data are the mean ± s.e.m. for each distribution. The P value beneath the distribution denotes its difference from baseline inhalation—that is, the existence of a sniff response. *P < 0.05; two-tailed Wilcoxon test. Further analyses are provided in the Supplementary Information.

Extended Data Fig. 3 The sniff response is similar with and without tracheostomy.

Normalized sniff volume after pleasant (a, c, e) or unpleasant (b, d, f) odorants during MCS sessions with (W; n = 44) and without (O; n = 29) tracheostomy for the first (a, b), second (c, d) and third (e, f) sniff after odorant delivery. Left, each dot represents a session; flat violin plots show the distribution; the red lines denote the median; and the dashed horizontal lines denote the baseline value at 1 NFU. Right, data are the mean ± s.e.m. for each distribution. The P value beneath the distribution denotes its difference from baseline inhalation—that is, the existence of a sniff response. *P < 0.05; two-tailed Wilcoxon test. About 60% of MCS sessions and 80% of UWS sessions were conducted in patients with a tracheostomy. Although tracheostomy significantly reduces nasal airflow, a measurable portion of nasal airflow remains. For example, we note that the raw data in Fig. 1c, d were obtained with a tracheostomy. Further analyses are provided in the Supplementary Information.

Extended Data Fig. 4 The sniff response during MCS sessions.

The red lines denote the sniff-response threshold (more than 15% change in magnitude and/or 0.35 s.d.): dots within the lines (white background) reflect sessions without a sniff response; dots beyond the lines (shaded background) reflect sessions with a sniff response. ac, Each dot is a MCS session. a, Pleasant odorant. b, Unpleasant odorant. c, Blank. d, Percentage of patients in a MCS (not sessions) with sniff responses (white, 64.5%) and without sniff responses (red, 35.5%) across all three conditions.

Extended Data Fig. 5 The sniff response is prognostic for the recovery of consciousness and long-term survival in patients with DOC.

Data are shown by patient rather than by session. The red lines denote the threshold of a sniff response (more than 15% change in magnitude and/or 0.35 s.d.). ac, Each dot is a session with the strongest sniff response of a patient in a MCS (n = 19). a, Pleasant odorant. b, Unpleasant odorant. c, Blank. d, Percentage of patients in a MCS with sniff responses (white, 64.5%) and without sniff responses (red, 35.5%) across all three conditions. eg, Each dot is a session with the strongest sniff response of a patient with UWS; empty dots represent patients who later recovered (transitioned to MCS; n = 16) and filled dots represent patients who did not recover and remain unconscious (n = 8). e, Pleasant odorant. f, Unpleasant odorant. g, Blank. h, Percentage of patients with UWS who later transitioned to MCS (left, recovered) and who remain unconscious (right, unrecovered) with sniff responses (white; recovered, 62.5%; unrecovered, 0%) and without sniff responses (red; recovered, 37.5%; unrecovered, 100%) across all three conditions. ik, Each dot is a patient with DOC (MCS and UWS; n = 43); filled black dots represent patients who died during the study and coloured dots represent patients who survived during the study (mean ± s.d., 37.3 ± 14.1 months after brain injury). i, Pleasant odorant. j, Unpleasant odorant. k, Blank. l, Percentage of patients with DOC with sniff responses (left) who survived (white, 91.7%) and who are deceased (D) (red, 8.3%) and of patients with DOC without sniff responses who survived (white, 36.8%) and are deceased (red, 63.2%). mo, Relation between the functional independence measure and normalized sniff volume. Each dot is a patient with UWS who survived during the study (n = 12). m, Pleasant odorant. n, Unpleasant odorant. o, Blank. r represents Spearman correlation.

Extended Data Fig. 6 Dependence of the predictive value on sniff-response thresholds in patients with UWS.

a, The receiver-operating characteristic (ROC) for a range of sniff-response volume thresholds for a sniff-response volume variability threshold of 0.35. b, The ROC for a range of sniff-response volume variability thresholds for a sniff-response volume threshold of 0.85 (15% reduction). c, Distance from a randomized predictor for a range of sniff-response volume thresholds for a sniff-response volume variability threshold of 0.35. d, Distance from randomized predictor for a range of sniff-response volume variability thresholds for a sniff-response volume threshold of 0.85. e, Area under the curve (AuC) for different sniff-response volume variability thresholds. f, Area under the curve for different sniff-response volume thresholds. n = 24. Further analyses are provided in the Supplementary Information.

Extended Data Fig. 7 Dependence of the sensitivity and specificity on sniff-response thresholds.

a, Sensitivity (true-positive rate (TPR)) for a range of sniff-response volume and sniff-response volume variability thresholds. b, Specificity (true-negative rate (TNR)) for a range of sniff-response volume and sniff-response volume variability thresholds. c, Distance from a randomized predictor for a range of sniff-response volume and sniff-response volume variability thresholds. Further analyses are provided in the Supplementary Information.

Extended Data Fig. 8 Dependence of the predictive value on the relation between conditions.

a, ROC for a range of differences in the sniff-response volume between the unpleasant odorant and the blank. b, The true-positive and true-negative rates for a range of differences in the sniff-response volume between the unpleasant odorant and the blank. c, ROC for a range of differences in the sniff-response volume between the pleasant odorant and the blank. d, The true-positive and true-negative rates for a range of differences in the sniff-response volume between the pleasant odorant and the blank. e, ROC for a range of differences in the sniff-response volume between the pleasant and unpleasant odorants. f, The true-positive and true-negative rates for a range of differences in the sniff-response volume between the pleasant and unpleasant odorants. n = 24. Further analyses are provided in the Supplementary Information.

Extended Data Table 1 Patient information
Extended Data Table 2 Damage to olfactory-related brain areas

Supplementary information

Supplementary Information

This file contains control analyses, one supplementary table, and associated text.

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Arzi, A., Rozenkrantz, L., Gorodisky, L. et al. Olfactory sniffing signals consciousness in unresponsive patients with brain injuries. Nature 581, 428–433 (2020). https://doi.org/10.1038/s41586-020-2245-5

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