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Disruption of the ascending arousal network in acute traumatic disorders of consciousness
Open accessAbstract
OBJECTIVE: To determine whether ascending arousal network (AAn) connectivity is reduced in patients presenting with traumatic coma. METHODS: We performed high-angular-resolution diffusion imaging in 16 patients with acute severe traumatic brain injury who were comatose on admission and in 16 matched controls. We used probabilistic tractography to measure the connectivity probability (CP) of AAn axonal pathways linking the brainstem tegmentum to the hypothalamus, thalamus, and basal forebrain. To assess the spatial specificity of CP differences between patients and controls, we also measured CP within 4 subcortical pathways outside the AAn. RESULTS: Compared to controls, patients showed a reduction in AAn pathways connecting the brainstem tegmentum to a region of interest encompassing the hypothalamus, thalamus, and basal forebrain. When each pathway was examined individually, brainstem-hypothalamus and brainstem-thalamus CPs, but not brainstem-forebrain CP, were significantly reduced in patients. Only 1 subcortical pathway outside the AAn showed reduced CP in patients. CONCLUSIONS: We provide initial evidence for the reduced integrity of axonal pathways linking the brainstem tegmentum to the hypothalamus and thalamus in patients presenting with traumatic coma. Our findings support current conceptual models of coma as being caused by subcortical AAn injury. AAn connectivity mapping provides an opportunity to advance the study of human coma and consciousness.
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TL;DR
In 16 patients with acute severe traumatic brain injury who were comatose on admission, high-angular-resolution diffusion imaging (HARDI) probabilistic tractography showed reduced connectivity in ascending arousal network (AAn) pathways compared with 16 matched controls. The reductions were specific to brainstem-hypothalamus and brainstem-thalamus pathways, supporting subcortical AAn injury as a mechanism of traumatic coma.
Key findings
- Normalized tract number between the brainstem tegmentum and a combined target (hypothalamus, thalamus, basal forebrain) was lower in patients (median 0.08, IQR 0.04–0.1) than controls (median 0.1, IQR 0.09–0.12, p = 0.006).
- Seed-to-target connectivity probability (CP) was significantly reduced for brainstem-hypothalamus (patients 0.04, IQR 0.02–0.07 vs controls 0.08, IQR 0.07–0.09, FWE pc < 0.05) and brainstem-thalamus (patients 0.03, IQR 0.01–0.04 vs controls 0.04, IQR 0.04–0.06, pc < 0.05), but not brainstem-forebrain (patients 0.003, IQR 0.002–0.009 vs controls 0.008, IQR 0.004–0.01, pc = 0.37).
- Of 4 non-AAn pathways, only auditory tracts (inferior colliculus to medial geniculate body) showed reduced CP in patients (0.0007, IQR 0.0002–0.001 vs 0.005, IQR 0.002–0.009, pc < 0.005); motor, extrapyramidal, and cerebellar tracts did not differ (all pc > 0.5).
- AAn CPs were not correlated with days in coma or days until command following (all p ≥ 0.29), nor reduced in prolonged (>2 days) versus brief (≤2 days) coma (all p ≥ 0.27). Peak tract reduction was seen in the left lateral midbrain tegmentum and rostral medial tracts to the hypothalamus.
Methods
- Prospective observational study: 16 consecutive patients (median age 27.5 years, IQR 21.5–33, 12 men) with acute traumatic coma (GCS score of 6 without eye opening, no eye opening for 24 hours) and 16 age- and sex-matched controls (median age 27 years, IQR 21–32.5, 12 men).
- HARDI on a 3T Siemens Skyra scanner in the ICU (2-mm isotropic voxels, 60 diffusion-encoded volumes at b = 2,000 s/m², 10 b0 volumes); preprocessing in FSL, diffusion parameters via bedpostx, and probabilistic tractography with probtrackx2 (5,000 samples per voxel).
- Connectivity probability computed between a dorsal brainstem tegmentum seed (Harvard Ascending Arousal Network Atlas) and hypothalamus, thalamus, and basal forebrain targets, plus 4 non-AAn control pathways; group comparisons used Wilcoxon rank-sum tests with Holm FWE adjustment (Benjamini-Hochberg FDR for voxel-wise analysis).
Limitations
- Stated: HARDI tractography depends on intervoxel coherence in directional water diffusion, so focal edema may produce apparent tract disruption even with structurally intact axons, and it cannot distinguish reversibly from irreversibly injured axons.
- Stated: diffusion measures are dynamic during the acute stage of traumatic axonal injury, and because the injury-to-imaging interval varied between patients, correlations between AAn connectivity and clinical measures should be interpreted with caution.
- Stated: the small sample size may have provided inadequate statistical power to detect a correlation between AAn CP reduction and coma duration; the authors also note that comparing comatose TBI patients to TBI patients with preserved consciousness, rather than to healthy controls, would allow more precise anatomic localization.
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10 Own result · 4 Own method · 4 Own interpretation · 3 No full text of the sources · 1 Check pending · 1 Not checked yet
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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“but not brainstem-forebrain (patients: 0.003 IQR 0.002–0.009; controls: 0.008, IQR 0.004–0.01, pc = 0.37; figure 1B).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These results were unaffected by the exclusion of patient 16 (tables e-2 and e-3 available from Dryad, doi.org/10.5061/dryad.43m733k), the only patient who presented with an extra-axial lesion producing significant brainstem compression.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“and brainstem-thalamus (patients: 0.03, IQR 0.01–0.04; controls: 0.04, IQR 0.04–0.06, pc < 0.05)”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Individual seed-to-target analyses revealed significantly reduced CP for brainstem-hypothalamus (patients: 0.04, IQR 0.02–0.07; controls: 0.08, IQR 0.07–0.09, FWE pc< 0.05”
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nor were they reduced in patients with prolonged (>2 days) relative to brief (≤2 days) coma (all p ≥ 0.27).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We did, however, find a significant group-level CP reduction in auditory tracts (inferior colliculus to medial geniculate body) between patients (0.0007, IQR 0.0002–0.001) and controls (0.005, IQR 0.002–0.009, pc < 0.005; figure 1B).”
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In the paper
“Unlike conventional MRI and diffusion tensor imaging, high-angular-resolution diffusion imaging (HARDI) meets these methodologic requirements by measuring water diffusion along axonal pathways using a multidirectional model designed to detect crossing and branching axons.12”
What the sources say
- Not checked — no full text of the sourcecites [12] Tuch DS, Reese TG, Wiegell MR, Makris N, Belliveau JW, Wedeen VJ. High angular resolution diffusion imaging reveals intravoxel white matter fiber heterogeneity. Magn Reson Med 2002;48:577–582. [DOI] [PubMed] [Google Scholar] source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In traumatic coma, however, up to 44% of patients may not have visible brainstem pathology on conventional MRI sequences.6”
What the sources say
- Not checked — no full text of the sourcecites [6] Weiss N, Galanaud D, Carpentier A, et al. A combined clinical and MRI approach for outcome assessment of traumatic head injured comatose patients. J Neurol 2008;255:217–223. [DOI] [PubMed] [Google Scholar] source
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although severe TBI is known to cause heterogeneous subcortical axonal injury, our findings suggest a spatial specificity for AAn pathways among patients who present with coma.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Another limitation of this small study is its statistical power, which may have been inadequate to identify a correlation between AAn CP reduction and coma duration.”
hedged- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 6
- The quote only partly states this claim. 2
- Probably not a substantial claim. 4
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Brainstem-hypothalamus, brainstem-thalamus, and brainstem-forebrain CPs were not correlated with days in coma or days until command following (all p ≥ 0.29 for Pearson correlation coefficients)”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared to healthy controls, patients showed reduced normalized tract number between the brainstem tegmentum and a target encompassing the hypothalamus, thalamus, and basal forebrain (patients: median 0.08, IQR 0.04–0.1; controls: median 0.1, IQR 0.09–0.12, p = 0.006; figure 1A).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Peak areas of tract reduction were seen within the left lateral midbrain tegmentum and in the rostral medial tracts connecting the tegmentum to the hypothalamus”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among non-AAn pathways, we found no group-level CP differences between patients and controls in motor (ventral pons to posterior limb internal capsule) (patients: 0.12, IQR 0.07–0.16; controls: 0.12, IQR 0.11–0.15), extrapyramidal (substantia nigra to basal ganglia) (patients: 0.02, IQR 0.02–0.02; controls: 0.02, IQR 0.02–0.02), or cerebellar (superior cerebellar peduncle to red nucleus) (patients”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This study was approved by the Massachusetts General Hospital Institutional Review Board. Written informed consent was obtained from each participant or a surrogate.”
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In patients with acute severe traumatic brain injury (TBI), coma is believed to be caused by axonal injury within the ascending arousal network (AAn), a collection of subcortical pathways that connect the rostral brainstem tegmentum to the hypothalamus, thalamus, and basal forebrain.1,2”
What the sources say
- Not matchedcites [1] Edlow BL, Takahashi E, Wu O, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 2012;71:531–546. [DOI] [PMC free article] [PubMed] [Google Scholar]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [2] Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 1982;12:564–574. [DOI] [PubMed] [Google Scholar] source
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Group-level voxel-wise and tract-specific analyses were performed in MATLAB (MathWorks, Natick, MA) with Wilcoxon rank-sum tests. When appropriate, we adjusted p values for multiple comparisons using Holm family-wise error (FWE) adjustment, except for the voxel-wise analysis, in which we used the less-restrictive Benjamini-Hochberg false discovery rate adjustment.”
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While these structural connectivity findings do not prove a causal relationship, they support the role of AAn disruption in the pathogenesis of acute traumatic disorders of consciousness.”
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“Sixteen age- and sex-matched controls (median age 27 years, IQR 21–32.5 years, 12 men) underwent identical imaging.”
plainn = 16- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
The paper relies on this without support.
Reduced connectivity probability measured by HARDI probabilistic tractography in these patients reflects reduced structural integrity of the underlying axons rather than apparent tract disruption from edema or other non-structural causes.
“HARDI reconstruction of axonal pathways depends on intervoxel coherence in directional water diffusion, and focal intracellular or extracellular edema may lead to an apparent tract disruption even when the underlying axons are structurally intact.”
Citations
Cites
High angular resolution diffusion imaging reveals intravoxel white matter fiber heterogeneity
Tuch, D. S., Reese, T. G., Wiegell, M. R., Makris, N., Belliveau, J. W., & Wedeen, V. J. (2002) · Magnetic Resonance in Medicine · doi:10.1002/mrm.10268 · Cited by 1,548 · cited 1×
“Unlike conventional MRI and diffusion tensor imaging, high-angular-resolution diffusion imaging (HARDI) meets these methodologic requirements by measuring water diffusion along axonal pathways using a multidirectional model designed to detect crossing and branching axons.(12) HARDI thus provides an opportunity to mode…”
BackgroundDiffuse axonal injury and traumatic coma in the primate
Gennarelli, T. A., Thibault, L. E., Adams, J. H., Graham, D. I., Thompson, C. J., & Marcincin, R. P. (1982) · Annals of Neurology · doi:10.1002/ana.410120611 · Cited by 1,528
Reticular formation of the brain
(1959) · Electroencephalography and Clinical Neurophysiology · doi:10.1016/0013-4694(59)90072-0 · Cited by 1,124
Some ascending pathways in the brain stem reticular formation.
Nauta, W. J. H., & Kuypers, H. G. J. M. (1958) · Cited by 570
A Mechanistic Analysis of Nondisruptive Axonal Injury: A Review
Maxwell, W. L., Povlishock, J. T., & Graham, D. I. (1997) · Journal of Neurotrauma · doi:10.1089/neu.1997.14.419 · Cited by 564
Voytko, M., Olton, D., Richardson, R., Gorman, L. K., Tobin, J., & Price, D. L. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-01-00167.1994 · Cited by 520
Edlow, B. L., Takahashi, E., Wu, O., Benner, T., Dai, G., Bu, L., Grant, P. E., Greer, D. M., Greenberg, S. M., Kinney, H. C., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182588293 · Cited by 497
Self-citationReassessment of the structural basis of the ascending arousal system
Fuller, P., Sherman, D., Pedersen, N. P., Saper, C. B., & Lu, J. (2011) · Journal of Comparative Neurology · doi:10.1002/cne.22559 · Cited by 465
Comprehensive cellular‐resolution atlas of the adult human brain
Ding, S., Royall, J. J., Sunkin, S. M., Ng, L., Facer, B. A. C., Lesnar, P., Guillozet‐Bongaarts, A., McMurray, B., Szafer, A., Dolbeare, T. A., et al. (2016) · Journal of Comparative Neurology · doi:10.1002/cne.24080 · Cited by 447
Neuroanatomical correlates of brainstem coma
Parvizi, J. (2003) · Brain · doi:10.1093/brain/awg166 · Cited by 400 · cited 1×
“Evidence that the AAn is essential for consciousness comes from experimentally induced lesions in rodents(3) and cats(4) and mapping of brainstem infarctions in humans.(5) In traumatic coma, however, up to 44% of patients may not have visible brainstem pathology on conventional MRI sequences.”
Background
Cited by
Sorted by citations
Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies
Edlow, B. L., Claassen, J., Schiff, N. D., & Greer, D. M. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-00428-x · Cited by 782
Self-citationThe ascending arousal system shapes neural dynamics to mediate awareness of cognitive states
Munn, B., Müller, E. J., Wainstein, G., & Shine, J. M. (2021) · Nature Communications · doi:10.1038/s41467-021-26268-x · Cited by 188
Provencio, J. J., Hemphill, J. C., Claassen, J., Edlow, B. L., Helbok, R., Vespa, P. M., Diringer, M. N., Polizzotto, L., Shutter, L., Suarez, J. I., et al. (2020) · Neurocritical Care · doi:10.1007/s12028-020-01028-9 · Cited by 146
Self-citationThe feasibility of artificial consciousness through the lens of neuroscience
Aru, J., Larkum, M. E., & Shine, J. M. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.09.009 · Cited by 98
The neuroethics of disorders of consciousness: a brief history of evolving ideas
Young, M. J., Bodien, Y. G., Giacino, J. T., Fins, J. J., Truog, R. D., Hochberg, L. R., & Edlow, B. L. (2021) · Brain · doi:10.1093/brain/awab290 · Cited by 95
Self-citation
Metadata
- Authors
- Snider, S. B., Bodien, Y. G., Bianciardi, M., Brown, E. N., Wu, O., & Edlow, B. L.
- Affiliations
- Harvard University (US)
- Venue
- Neurology
- Published
- 2019-09-24
- Volume
- 93
- Issue
- 13
- Pages
- e1281-e1287
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC7011864
- OpenAlex
- W2972034337
- Semantic Scholar
- dec047f02766750c1a9a89e6712bdfd990904640
- Cited by
- 83
- References
- 18
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 11 · 2023: 12 · 2022: 15 · 2021: 12 · 2020: 9 · 2019: 1
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM104948, P01GM118269)
- National Institute of Neurological Disorders and Stroke (K23NS094538)
- National Institute of Biomedical Imaging and Bioengineering (K01EB019474)
- National Center for Chronic Disease Prevention and Health Promotion (U48 DP000039)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- traumatic coma, disorders of consciousness, traumatic brain injury, hypothalamus, thalamus, connectivity probability, white matter integrity, diffusion tractography
- MeSH terms
- Brain Injuries, Traumatic, Adult, Arousal, Brain Injuries, Brain Stem, Consciousness, Female, Humans, Male, Neural Pathways, Thalamus, Basal Forebrain
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