Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness
- Massachusetts General Hospital, Harvard Medical School, United States
- MGH/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, United States
- Brigham and Women's Hospital, Harvard Medical School, United States
- Massachusetts General Hospital, United States
- Massachusetts Institute of Technology, United States
Figures
Figure 1
Schematic of dexmedetomidine signaling illustrating similarities to the mechanism proposed for the generation of non-rapid eye movement II sleep.
Dexmedetomidine binds to α2 receptors on neurons emanating from the locus ceruleus to inhibit NE release in the POA. The disinhibited POA reduces arousal by means of GABA- and galanin-mediated inhibition of the midbrain, hypothalamic, and pontine arousal nuclei. Dexmedetomidine also acts at the locus ceruleus projections to the intralaminar nucleus of the hypothalamus, the basal forebrain and the cortex and on post-synaptic α2 receptors. 5HT, serotonin; Ach, acetylcholine; BF, basal forebrain; DA, dopamine; Dex; dexmedetomidine; DR, dorsal raphe; GABA, gamma aminobutyric acid receptor subtype A; Gal, galanin; His, histamine; LC, locus ceruleus; LDT, laterodorsal tegmental area; NE, norepinephrine; PAG, periaqueductal gray; POA, preoptic area; PPT, pedunculopontine tegmental area; TMN, tuberomamillary nucleus.
Figure 2 with 1 supplement
CMRglc and rCBF are decreased in both the default mode and the frontal–parietal network brain regions during unconsciousness.
(A) Study outline of healthy volunteers recruited to undergo both baseline and dexmedetomidine-induced unconsciousness PET brain imaging in a random order. (B) Group wise (n = 10) dexmedetomidine-induced unconsciousness vs baseline changes in CMRglc (PET) displayed on the MNI152 standard volume. Significant CMRglc decreases were localized to brain regions that make up the Default Mode and the Frontal-Parietal Networks. (C) Schematic of fMRI obtained concurrently in combined PET/MR visits (n = 10) and MR/only visits (n = 7). (D) Group wise (n = 17) dexmedetomidine-induced unconsciousness vs awake changes in rCBF (fMRI) displayed on the MNI152 standard volume. Significant rCBF decreases were also localized to brain regions that make up the Default Mode and the Frontal-Parietal Networks. The brain regions that were not included in the rCBF estimation are shaded in the darker hue. ACC, anterior cingulate cortex; CMRglc, cerebral metabolic rate of glucose; Dex, dexmedetomidine; dmPFC, dorsomedial prefrontal cortex; fMRI, functional magnetic resonance; IPL, infraparietal lobule; IPL, infraparietal sulcus; PCC, posterior cingulate cortex; R, right; rCBF, regional cerebral blood flow; RSC, restrosplenial cortex; vmPFC, ventromedial prefrontal cortex.
Figure 2—figure supplement 1
PET SUV changes during unconsciousness.
(A) Group wise (n = 10) Dexmedetomidine-induced unconsciousness vs baseline changes in SUV (PET) displayed on the MNI152 standard volume highlighting that only SUV decreases were notable during unconsciousness. (B) Group wise (n = 10) baseline and dexmedetomidine-induced changes in CMRglc (PET) displayed on the MNI152 standard volume. MNI, Montreal neurological institute; PET, positron emission tomography; SUV ,standardized uptake value.
Figure 3 with 1 supplement
Changes in the default mode and the bilateral frontal parietal networks during unconsciousness.
(A) The DMN extracted from BOLD signals during the awake (n = 16) and unconscious states (n = 16) and displayed on the MNI152 standard volume. (B) A comparison the DMN network during the unconscious vs the awake state identified the putamen and the vlPFC as regions that exhibited increased functional connectivity during dexmedetomidine-induced unconsciousness. This comparison also identified the thalamus and the cerebellar representation of this network as regions that exhibited decreased functional connectivity during dexmedetomidine-induced unconsciousness. Cortico–cortico functional connectivity within this network was maintained. (C) The right FPN extracted from BOLD signals during the awake and unconscious states (n = 16) and displayed on the MNI152 standard volume. (D) A comparison of the right FPN network during the unconscious vs the awake state identified the infraparietal lobule and a right cerebellar cluster as regions that exhibited increased functional connectivity during dexmedetomidine-induced unconsciousness. This comparison also identified the cerebellar representation of this network as a region that exhibited decreased functional connectivity during unconsciousness. Cortico–cortico functional connectivity within this network was maintained. (E) The left FPN extracted from BOLD signals during the awake and unconscious states (n = 16) and displayed on the MNI152 standard volume. (F) A comparison of the left FPN network during the unconscious vs the awake state identified a right cerebellar cluster and the cerebellar representation of the left FPN as regions that exhibited decreased functional connectivity during dexmedetomidine-induced unconsciousness. Cortico–cortico functional connectivity within this network was maintained. BOLD, blood oxygen level dependent; DMN, default mode network; FPN, Frontoparietal Network; R, right; vlPFC, ventrolateral prefrontal cortex.
Figure 3—figure supplement 1
SUV, CMRglc, rCBF changes during unconsciousness and the relationship to the DMN and bilateral FCNs.
(A) Surface projection of the voxelwise, cluster corrected analysis illustrating overlapping decreases in CMRglc (n = 10) and rCBF (n = 17) in regions corresponding to the DMN, and the bilateral FCNs during unconsciousness. (B) Surface projection of the DMN, rFCN and lFCN extracted from study volunteers (n = 17). These networks were identified from the awake, unconscious, and recovery state BOLD signals.CMRglc, cerebral metabolic rate of glucose; dlPFC, dorsolateral prefrontal cortex; dmPFC, dorsomedial prefrontal cortex; DMN, default mode network; FPN, frontoparietal network; IPL, infraparietal lobule; IPL, infraparietal sulcus; MNI, Montreal neurological institute; PCC, posterior cingulate cortex; rCBF, regional cerebral blood flow; R, right; RSC, retrosplenial cortex; vlPFC, ventrolateral prefrontal cortex, vmPFC, ventromedial prefrontal cortex.
Figure 4
Seed based functional connectivity analysis of the brain region with overlapping changes in CMRglc, rCBF, and functional connectivity.
(A) Brain wide representation of regions connected to the thalamic seed during the awake and unconscious states (n = 16). A comparison of thalamic seed functional connectivity during the unconscious vs the awake state identified the PCC, precuneus, thalamus, visual cortex, IPL and IPS as regions exhibiting decreased functional connectivity during unconsciousness. (B) Overlap of the brain regions with changes in CMRglc, rCBF, and functional connectivity. Notably, the posterior thalamus, PCC and the precuneus exhibited overlapping changes. CMRglc, cerebral metabolic rate of glucose; IPL, infraparietal lobule; IPL, infraparietal sulcus; PCC, posterior cingulate cortex; R, right; rCBF, regional cerebral blood flow.
Figure 5 with 1 supplement
Cortical increase in rCBF is not evident during the recovery of consciousness.
(A) Cluster corrected (n = 10) rCBF comparison of the recovery state vs the unconsciousness state displayed on the MNI152 standard volume highlighting no change in rCBF at recovery. (B) Uncorrected (n = 10) rCBF comparison of the recovery state vs the unconsciousness state displayed on the MNI152 standard volume suggesting that a decrease in rCBF occurred during the recovery state. (C) Cluster corrected (n = 10) rCBF comparison of the recovery state vs the awake state displayed on the MNI152 standard volume highlighting a spatial distribution of rCBF decrease similar to that observed during unconscious vs the awake state (n = 17) comparison. IPL, infraparietal lobule; IPL, infraparietal sulcus; PCC, posterior cingulate cortex; rCBF, regional cerebral blood flow; R, right; RSC, retrosplenial cortex. The brain coverage of rCBF estimation is shown in Figure 1D.
Figure 5—figure supplement 1
Cortical decrease in rCBF persists during the recovery of consciousness.
Statistically significant rCBF clusters from Figure 1D were extracted and intersected with the Harvard–Oxford cortical and subcortical map arbitrarily thresholded at 30. Subjects were aligned to LOC/ROC and then median baseline normalized rCBF values obtained for each time point. For LOC (n = 17) and ROC (n = 16), an average of baseline-normalized rCBF values corresponding to the 2 min immediately preceding and post LOC/ROC behavioral time points are represented. The decreased rCBF values from baseline observed during the LOC were sustained during the ROC. L, left; LOC, loss of consciousness; Post, posterior; rCBF, regional cerebral blood flow; R, right; ROC, return of consciousness.
Figure 6
Functional connectivity changes observed during recovery of consciousness.
(A) The DMN extracted from BOLD signals obtained during the recovery state (n = 15) displayed on the MNI152 standard volume. (B) A comparison the DMN network during the recovery vs the awake state identified the thalamus as the only region with partial recovery of functional connectivity. (C) The right FPN extracted from BOLD signals during the recovery state (n = 15) and displayed on the MNI152 standard volume. (D) A comparison of the right FPN during the recovery vs the awake state showed that right cerebellar cluster from Figure 3B,C now exhibited decreased right FPN functional connectivity. (E) The left FPN extracted from BOLD signals during the recovery state (n = 15) and displayed on the MNI152 standard volume. (F) A comparison of the left FPN during the recovery vs the awake state showed that right cerebellar cluster from Figure 3B,C now exhibited increased left FPN functional connectivity. (G) Brain wide representation of regions connected to the thalamic seed during the recovery state (n = 15) displayed on the MNI152 standard volume. (H) A comparison of thalamic seed functional connectivity during the recovery vs the awake state identified the PCC and thalamus as regions with increased functional connectivity at recovery. BOLD, blood oxygen level dependent; DMN, default mode network; FPN, Frontoparietal Network; PCC, posterior cingulate cortex; R, right.
Author response image 1
Tables
Table 1
CMRglc, awake vs dex-induced unconsciousness
| MNI coordinate (mm) | ||||||
|---|---|---|---|---|---|---|
| Label | Z-stat | x | y | z | cluster size (# voxels) | cluster p-value |
| awake > dex-induced unconsciousness | ||||||
| R middle/inferior frontal gyrus | 4.35 | 52 | 42 | 4 | 17919 | 2.95E-12 |
| R medial orbital gyrus | 4.22 | 24 | 38 | −16 | ||
| L inferior frontal gyrus | 4.02 | −52 | 36 | 10 | ||
| L superior frontal gyrus, medial part | 4 | −6 | 20 | 40 | ||
| L middle frontal gyrus | 3.94 | −42 | 18 | 38 | ||
| L middle frontal gyrus | 3.86 | −34 | 8 | 66 | ||
| R middle frontopolar gyrus | 3.79 | −30 | 58 | 2 | ||
| L lateral orbital gyrus | 3.58 | −46 | 28 | −12 | ||
| L medial orbital gyrus | 3.56 | −26 | 32 | −22 | ||
| R middle frontal gyrus | 3.55 | 48 | 20 | 44 | ||
| R superior frontal gyrus | 3.48 | 26 | 2 | 56 | ||
| R inferior frontal gyrus, pars opercularis | 3.37 | 54 | 16 | 4 | ||
| L inferior frontal gyrus, pars opercularis | 3.36 | −46 | 20 | 0 | ||
| L superior frontal gyrus, medial part (2) | 3.33 | −4 | 42 | 22 | ||
| inferior rostral gyrus | 3.15 | 0 | 48 | −10 | ||
| R anterior insula | 2.82 | 40 | 22 | 0 | ||
| L Posterior Cingulate Gyrus | 5.56 | −4 | −24 | 38 | 5443 | 2.85E-05 |
| L precuneus | 4.27 | −12 | −64 | 22 | ||
| R precuneus | 3.86 | 12 | −60 | 28 | ||
| L supramarginal gyrus | 4.58 | −40 | −46 | 42 | 2861 | 0.0029 |
| L angular gyrus | 3.76 | −48 | −68 | 34 | ||
| R supramarginal gyrus | 4.59 | 44 | −46 | 48 | 2214 | 0.0112 |
| R angular gyrus | 4 | 34 | −62 | 44 | ||
| R thalamus | 4.52 | 12 | −20 | 4 | 1610 | 0.0444 |
| L thalamus | 3.89 | −14 | −26 | 4 | ||
-
CMRglc, cerebral metabolic rate of glucose; Dex, dexmedetomidine; L, left; MNI, Montreal Neurological Institute; R, right.
Table 2
rCBF, awake vs unconscious
| MNI coordinate (mm) | ||||||
|---|---|---|---|---|---|---|
| Label | Z-stat | x | y | z | cluster size (# voxels) | cluster p-value |
| awake > unconscious | ||||||
| L thalamus | 5.36 | −10 | −14 | 12 | 10876 | 4.20E-11 |
| L midbrain | 5.2 | 8 | −32 | −10 | ||
| L posterior cingulate cortex | 5.14 | −2 | −46 | 28 | ||
| R thalamus | 5.03 | 8 | −12 | 10 | ||
| R midbrain | 4.44 | −6 | −36 | −12 | ||
| L precuneus | 4.44 | −2 | −70 | 32 | ||
| R precuneus | 4.3 | 8 | −76 | 42 | ||
| R intracalcarine cortex | 4.2 | 4 | −84 | 4 | ||
| L intracalcarine cortex | 4.18 | −2 | −82 | 2 | ||
| R hippocampus | 4.17 | 30 | −34 | −4 | ||
| L supramarginal gyrus/intraparietal sulcus | 4.03 | −34 | −50 | 44 | ||
| L hippocampus | 3.09 | −26 | −22 | −12 | ||
| R frontopolar cortex | 4.71 | −24 | 64 | 2 | 1773 | 0.00463 |
| L frontopolar cortex | 4.32 | 20 | 62 | −6 | ||
| L middle frontal gyrus | 3.77 | −22 | 38 | 28 | ||
| R inferior frontal gyrus, orbital part | 2.88 | 50 | 40 | −14 | ||
| L dorsal anterior cingulate cortex | 3.93 | 10 | 38 | 22 | 1262 | 0.0227 |
| R dorsal anterior cingulate cortex | 3.75 | −10 | 38 | 20 | ||
| L subgenual anterior cingulate cortex | 3.3 | −2 | 24 | −10 | ||
| R pregenual anterior cingulate cortex | 3.21 | 6 | 42 | −6 | ||
| unconscious > awake | ||||||
| n.s. | ||||||
-
L, left; MNI, Montreal Neurological Institute; n.s, not significant; R, right.
Table 3
DMN
| MNI coordinate (mm) | ||||||
|---|---|---|---|---|---|---|
| Label | Z-stat | x | y | z | cluster size (# voxels) | cluster p-value |
| awake > unconscious | ||||||
| R thalamus | 4.04 | 2 | −14 | 8 | 438 | 0.00193 |
| L thalamus | 3.9 | −4 | −14 | 8 | ||
| L cerebellum (Crus II) | 3.93 | −44 | −64 | −44 | 270 | 0.0429 |
| unconscious > awake | ||||||
| R inferior frontal gyrus, pars opercularis | 3.83 | 56 | 12 | 20 | 399 | 0.00381 |
| R inferior frontal gyrus, pars triangularis | 3.35 | 54 | 32 | 10 | ||
| L putamen | 3.47 | −24 | 6 | −8 | 382 | 0.00517 |
| L insula | 3.43 | −36 | −10 | −4 | ||
-
DMN, Default Mode Network; L, left; MNI, Montreal Neurological Institute; R, right.
Table 4
rFCN
| MNI coordinate (mm) | ||||||
|---|---|---|---|---|---|---|
| Label | Z-stat | x | y | z | cluster size (# voxels) | cluster p-value |
| awake > unconscious | ||||||
| L cerebellum (Crus II) | 3.99 | −36 | −70 | −40 | 472 | 0.000724 |
| L cerebellum (VIIb) | 3.83 | −34 | −62 | −50 | ||
| L cerebellum (VI) | 3.28 | −28 | −62 | −32 | ||
| unconscious > awake | ||||||
| R cerebellum (VI) | 4.02 | 12 | −68 | −28 | 693 | 1.97E-05 |
| R cerebellum (Crus II) | 3.67 | 26 | −78 | −42 | ||
| R cerebellum (Crus I) | 3.24 | 20 | −74 | −24 | ||
| R precuneus | 2.99 | 26 | −60 | 18 | 519 | 0.000323 |
| R parietal operculum | 4.1 | 58 | −12 | 12 | 516 | 0.00034 |
| R insula | 3.23 | 44 | −4 | 0 | ||
| R cerebellum (Crus I) | 4.28 | 44 | −56 | −32 | 292 | 0.0212 |
| R fusiform gyrus | 3.59 | 30 | −42 | −20 | ||
| L angular gyrus | 3.72 | −38 | −86 | 20 | 272 | 0.0319 |
| L angular gyrus | 3.56 | −48 | −78 | 30 | ||
-
L, left; MNI, Montreal Neurological Institute; R, right; rFCN, right Frontoparietal Control Network.
Table 5
lFCN
| MNI coordinate (mm) | ||||||
|---|---|---|---|---|---|---|
| Label | Z-stat | x | y | z | cluster size (# voxels) | cluster p-value |
| awake > unconscious | ||||||
| R cerebellum (Crus II) | 4.24 | 38 | −74 | −50 | 1223 | 5.33E-09 |
| R cerebellum (VIIb) | 4.1 | 38 | −56 | −50 | ||
| R cerebellum (VI) | 4.08 | 28 | −62 | −32 | ||
| R intracalcarine cortex | 3.58 | 4 | −86 | −2 | ||
| L middle frontal gyrus | 3.89 | −32 | 12 | 54 | 490 | 0.000341 |
| L superior frontal gyrus, medial part | 3.52 | −4 | 32 | 46 | ||
| unconscious > awake | ||||||
| n.s. | ||||||
-
L, left; lFCN, left Frontoparietal Control Network; MNI, Montreal Neurological Institute; n.s, not significant; R, right.
Table 6
Thalamic seed
| MNI coordinate (mm) | ||||||
|---|---|---|---|---|---|---|
| Label | Z-stat | x | y | z | cluster size (# voxels) | cluster p-value |
| awake > unconscious | ||||||
| R thalamus | 5.33 | 12 | −12 | 8 | 3445 | 4.05E-16 |
| L posterior cingulate cortex | 4.95 | −6 | −36 | 30 | ||
| R posterior cingulate cortex | 4.73 | 6 | −28 | 34 | ||
| L thalamus | 4.48 | −16 | −10 | 10 | ||
| R caudate nucleus | 3.44 | 12 | 10 | 18 | ||
| L globus pallidus | 3.44 | −12 | 2 | −2 | ||
| L precuneus | 4.03 | −6 | −56 | 36 | 1230 | 1.79E-07 |
| R precuneus | 3.71 | 12 | −60 | 36 | ||
| R angular gyrus | 4.07 | 36 | −60 | 50 | 1094 | 9.54E-07 |
| R supramarginal gyrus | 3.67 | 48 | −48 | 36 | ||
| R cerebellum (crus II) | 4.07 | 8 | −76 | −30 | 906 | 8.76E-06 |
| R cerebellum (crus I) | 3.84 | 22 | −88 | −22 | ||
| R intracalcarine cortex | 3.75 | 2 | −100 | 4 | ||
| L cerebellum (crus I) | 3.14 | −20 | −84 | −28 | ||
| L supramarginal gyrus | 4.6 | −38 | −52 | 42 | 831 | 2.21E-05 |
| L angular gyrus | 3.43 | −32 | −76 | 48 | ||
| unconscious > awake | ||||||
| L inferior frontal gyrus, pars opercularis | 4.21 | −56 | 14 | 8 | 1458 | 1.80E-08 |
| L superior temporal gyrus | 4.2 | −62 | −10 | 4 | ||
| L middle temporal gyrus | 4.04 | −50 | −2 | −22 | ||
| L insula | 3.55 | −38 | 4 | −6 | ||
| R paracentral lobule | 3.77 | 4 | −32 | 58 | 963 | 4.41E-06 |
| L paracentral lobule | 3.64 | −10 | −38 | 58 | ||
| R superior frontal gyrus, lateral part | 3.44 | 14 | −6 | 56 | ||
| R precentral gyrus | 3.23 | 14 | −20 | 66 | ||
| L postcentral gyrus | 3.2 | −16 | −44 | 72 | ||
| R superior frontal gyrus, medial part | 2.86 | 10 | 2 | 50 | ||
| R postcentral gyrus | 2.72 | 16 | −38 | 70 | ||
| R superior temporal gyrus | 5 | 48 | −42 | 10 | 868 | 1.39E-05 |
| R middle temporal gyrus | 4.53 | 44 | −28 | −6 | ||
| R precentral gyrus | 3.51 | 54 | −2 | 46 | ||
| L postcentral gyrus | 4.03 | −62 | −8 | 36 | 453 | 0.00401 |
| L precentral gyrus | 3.77 | −60 | −4 | 36 | ||
| L superior temporal gyrus | 3.97 | −66 | −44 | 10 | 340 | 0.0244 |
-
L, left; MNI, Montreal Neurological Institute; R, right.
Table 7
Recovery
| MNI coordinate (mm) | ||||||
|---|---|---|---|---|---|---|
| Label | Z-stat | x | y | z | cluster size (# voxels) | cluster p-value |
| DMN, recovery > unconscious | ||||||
| R thalamus | 3.3 | 2 | −8 | 4 | 78 | 0.0345 |
| L thalamus | 3 | −4 | −4 | 8 | ||
| DMN, unconscious > recovery | ||||||
| n.s. | ||||||
| rFCN, recovery > unconscious | ||||||
| n.s. | ||||||
| rFCN, unconscious > recovery | ||||||
| R cerebellum (VI) | 3.92 | 14 | −70 | −28 | 246 | 0.00172 |
| R cerebellum (Crus I) | 3.81 | 22 | −76 | −28 | ||
| R cerebellum (Crus II) | 3.06 | 24 | −80 | −38 | ||
| lFCN, recovery > unconscious | ||||||
| R cerebellum (VI) | 3.58 | 12 | −66 | −30 | 118 | 0.012 |
| R cerebellum (Crus I) | 3.29 | 38 | −58 | −32 | 93 | 0.0232 |
| R cerebellum (Crus II) | 3.05 | 32 | −64 | −42 | ||
| lFCN, unconscious > recovery | ||||||
| n.s. | ||||||
| Thalamic seed, recovery > unconscious | ||||||
| posterior cingulate cortex | 3.53 | 0 | −40 | 22 | 367 | 0.00367 |
| L thalamus | 3.49 | −10 | −22 | 12 | 348 | 0.00471 |
| L putamen | 2.51 | −14 | 4 | 2 | ||
| Thalamic seed, unconscious > recovery | ||||||
| n.s. | ||||||
-
DMN, default mode network; L, left; lFCN, left Frontoparietal Control Network; MNI, Montreal Neurological Institute; n.s, not significant; R, right; rFCN, right Frontoparietal Control Network.
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Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness
eLife 3:e04499.
https://doi.org/10.7554/eLife.04499
