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Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness

  1. Oluwaseun Akeju  Is a corresponding author
  2. Marco L Loggia  Is a corresponding author
  3. Ciprian Catana
  4. Kara J Pavone
  5. Rafael Vazquez
  6. James Rhee
  7. Violeta Contreras Ramirez
  8. Daniel B Chonde
  9. David Izquierdo-Garcia
  10. Grae Arabasz
  11. Shirley Hsu
  12. Kathleen Habeeb
  13. Jacob M Hooker
  14. Vitaly Napadow
  15. Emery N Brown
  16. Patrick L Purdon  Is a corresponding author
  1. Massachusetts General Hospital, Harvard Medical School, United States
  2. MGH/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, United States
  3. Brigham and Women's Hospital, Harvard Medical School, United States
  4. Massachusetts General Hospital, United States
  5. Massachusetts Institute of Technology, United States
Research Article
Cite this article as: eLife 2014;3:e04499 doi: 10.7554/eLife.04499
7 figures and 7 tables

Figures

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.

https://doi.org/10.7554/eLife.04499.003
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.

https://doi.org/10.7554/eLife.04499.004
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.

https://doi.org/10.7554/eLife.04499.005
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.

https://doi.org/10.7554/eLife.04499.008
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.

https://doi.org/10.7554/eLife.04499.009
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.

https://doi.org/10.7554/eLife.04499.013
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.

https://doi.org/10.7554/eLife.04499.015
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.

https://doi.org/10.7554/eLife.04499.016
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.

https://doi.org/10.7554/eLife.04499.017
Author response image 1

Tables

Table 1

CMRglc, awake vs dex-induced unconsciousness

https://doi.org/10.7554/eLife.04499.006
MNI coordinate (mm)
LabelZ-statxyzcluster size (# voxels)cluster p-value
awake > dex-induced unconsciousness
 R middle/inferior frontal gyrus4.3552424179192.95E-12
 R medial orbital gyrus4.222438−16
 L inferior frontal gyrus4.02−523610
 L superior frontal gyrus, medial part4−62040
 L middle frontal gyrus3.94−421838
 L middle frontal gyrus3.86−34866
 R middle frontopolar gyrus3.79−30582
 L lateral orbital gyrus3.58−4628−12
 L medial orbital gyrus3.56−2632−22
 R middle frontal gyrus3.55482044
 R superior frontal gyrus3.4826256
 R inferior frontal gyrus, pars opercularis3.3754164
 L inferior frontal gyrus, pars opercularis3.36−46200
 L superior frontal gyrus, medial part (2)3.33−44222
 inferior rostral gyrus3.15048−10
 R anterior insula2.8240220
 L Posterior Cingulate Gyrus5.56−4−243854432.85E-05
 L precuneus4.27−12−6422
 R precuneus3.8612−6028
 L supramarginal gyrus4.58−40−464228610.0029
 L angular gyrus3.76−48−6834
 R supramarginal gyrus4.5944−464822140.0112
 R angular gyrus434−6244
 R thalamus4.5212−20416100.0444
 L thalamus3.89−14−264
  1. CMRglc, cerebral metabolic rate of glucose; Dex, dexmedetomidine; L, left; MNI, Montreal Neurological Institute; R, right.

Table 2

rCBF, awake vs unconscious

https://doi.org/10.7554/eLife.04499.007
MNI coordinate (mm)
LabelZ-statxyzcluster size (# voxels)cluster p-value
awake > unconscious
 L thalamus5.36−10−1412108764.20E-11
 L midbrain5.28−32−10
 L posterior cingulate cortex5.14−2−4628
 R thalamus5.038−1210
 R midbrain4.44−6−36−12
 L precuneus4.44−2−7032
 R precuneus4.38−7642
 R intracalcarine cortex4.24−844
 L intracalcarine cortex4.18−2−822
 R hippocampus4.1730−34−4
 L supramarginal gyrus/intraparietal sulcus4.03−34−5044
 L hippocampus3.09−26−22−12
 R frontopolar cortex4.71−2464217730.00463
 L frontopolar cortex4.322062−6
 L middle frontal gyrus3.77−223828
 R inferior frontal gyrus, orbital part2.885040−14
 L dorsal anterior cingulate cortex3.9310382212620.0227
 R dorsal anterior cingulate cortex3.75−103820
 L subgenual anterior cingulate cortex3.3−224−10
 R pregenual anterior cingulate cortex3.21642−6
unconscious > awake
 n.s.
  1. L, left; MNI, Montreal Neurological Institute; n.s, not significant; R, right.

Table 3

DMN

https://doi.org/10.7554/eLife.04499.010
MNI coordinate (mm)
LabelZ-statxyzcluster size (# voxels)cluster p-value
awake > unconscious
 R thalamus4.042−1484380.00193
 L thalamus3.9−4−148
 L cerebellum (Crus II)3.93−44−64−442700.0429
unconscious > awake
 R inferior frontal gyrus, pars opercularis3.835612203990.00381
 R inferior frontal gyrus, pars triangularis3.35543210
 L putamen3.47−246−83820.00517
 L insula3.43−36−10−4
  1. DMN, Default Mode Network; L, left; MNI, Montreal Neurological Institute; R, right.

Table 4

rFCN

https://doi.org/10.7554/eLife.04499.011
MNI coordinate (mm)
LabelZ-statxyzcluster size (# voxels)cluster p-value
awake > unconscious
 L cerebellum (Crus II)3.99−36−70−404720.000724
 L cerebellum (VIIb)3.83−34−62−50
 L cerebellum (VI)3.28−28−62−32
unconscious > awake
 R cerebellum (VI)4.0212−68−286931.97E-05
 R cerebellum (Crus II)3.6726−78−42
 R cerebellum (Crus I)3.2420−74−24
 R precuneus2.9926−60185190.000323
 R parietal operculum4.158−12125160.00034
 R insula3.2344−40
 R cerebellum (Crus I)4.2844−56−322920.0212
 R fusiform gyrus3.5930−42−20
 L angular gyrus3.72−38−86202720.0319
 L angular gyrus3.56−48−7830
  1. L, left; MNI, Montreal Neurological Institute; R, right; rFCN, right Frontoparietal Control Network.

Table 5

lFCN

https://doi.org/10.7554/eLife.04499.012
MNI coordinate (mm)
LabelZ-statxyzcluster size (# voxels)cluster p-value
awake > unconscious
 R cerebellum (Crus II)4.2438−74−5012235.33E-09
 R cerebellum (VIIb)4.138−56−50
 R cerebellum (VI)4.0828−62−32
 R intracalcarine cortex3.584−86−2
 L middle frontal gyrus3.89−3212544900.000341
 L superior frontal gyrus, medial part3.52−43246
unconscious > awake
 n.s.
  1. L, left; lFCN, left Frontoparietal Control Network; MNI, Montreal Neurological Institute; n.s, not significant; R, right.

Table 6

Thalamic seed

https://doi.org/10.7554/eLife.04499.014
MNI coordinate (mm)
LabelZ-statxyzcluster size (# voxels)cluster p-value
awake > unconscious
 R thalamus5.3312−12834454.05E-16
 L posterior cingulate cortex4.95−6−3630
 R posterior cingulate cortex4.736−2834
 L thalamus4.48−16−1010
 R caudate nucleus3.44121018
 L globus pallidus3.44−122−2
 L precuneus4.03−6−563612301.79E-07
 R precuneus3.7112−6036
 R angular gyrus4.0736−605010949.54E-07
 R supramarginal gyrus3.6748−4836
 R cerebellum (crus II)4.078−76−309068.76E-06
 R cerebellum (crus I)3.8422−88−22
 R intracalcarine cortex3.752−1004
 L cerebellum (crus I)3.14−20−84−28
 L supramarginal gyrus4.6−38−52428312.21E-05
 L angular gyrus3.43−32−7648
unconscious > awake
 L inferior frontal gyrus, pars opercularis4.21−5614814581.80E-08
 L superior temporal gyrus4.2−62−104
 L middle temporal gyrus4.04−50−2−22
 L insula3.55−384−6
 R paracentral lobule3.774−32589634.41E-06
 L paracentral lobule3.64−10−3858
 R superior frontal gyrus, lateral part3.4414−656
 R precentral gyrus3.2314−2066
 L postcentral gyrus3.2−16−4472
 R superior frontal gyrus, medial part2.8610250
 R postcentral gyrus2.7216−3870
 R superior temporal gyrus548−42108681.39E-05
 R middle temporal gyrus4.5344−28−6
 R precentral gyrus3.5154−246
 L postcentral gyrus4.03−62−8364530.00401
 L precentral gyrus3.77−60−436
 L superior temporal gyrus3.97−66−44103400.0244
  1. L, left; MNI, Montreal Neurological Institute; R, right.

Table 7

Recovery

https://doi.org/10.7554/eLife.04499.018
MNI coordinate (mm)
LabelZ-statxyzcluster size (# voxels)cluster p-value
DMN, recovery > unconscious
 R thalamus3.32−84780.0345
 L thalamus3−4−48
DMN, unconscious > recovery
 n.s.
rFCN, recovery > unconscious
 n.s.
rFCN, unconscious > recovery
 R cerebellum (VI)3.9214−70−282460.00172
 R cerebellum (Crus I)3.8122−76−28
 R cerebellum (Crus II)3.0624−80−38
lFCN, recovery > unconscious
 R cerebellum (VI)3.5812−66−301180.012
 R cerebellum (Crus I)3.2938−58−32930.0232
 R cerebellum (Crus II)3.0532−64−42
lFCN, unconscious > recovery
 n.s.
Thalamic seed, recovery > unconscious
 posterior cingulate cortex3.530−40223670.00367
 L thalamus3.49−10−22123480.00471
 L putamen2.51−1442
Thalamic seed, unconscious > recovery
 n.s.
  1. 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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