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Two different coma models

Two different coma models. Yaohui Tang Max-Planck-Institute for Biological Cybernetics. What is coma?. Coma is a state of unconsciousness, which is marked by a lack of awareness and response to external stimulus. Steven Laureys , et al, The Lancet, 2004.

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Two different coma models

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  1. Two different coma models Yaohui Tang Max-Planck-Institute for Biological Cybernetics

  2. What is coma? • Coma is a state of unconsciousness, which is marked by a lack of awareness and response to external stimulus. Steven Laureys, et al, The Lancet, 2004

  3. Cerebral metabolism in different brain states Conscious Locked-in syndrome MCS Vegetative state Steven Laureys, et al, The Lancet, 2004

  4. Important pathways and brain nucleus for arousal • Reticulo-thalamo-cortical pathway (widely accepted) Basilar artery occlusion (BAO) • Thalamus-Basal forebrain (BF)-Parabrachial nucleus-precoeruleus area (PB-PC) Neurotoxin stereotaxic injection (NSI)

  5. Basilar artery • One of three major arteries feeding the circle of Willis • Situated on the ventral surface of the brainstem • Supplies the major portion of the blood flow to the brainstem SCA: superior cerebellar artery AICA: anterior inferior cerebellar artery PICA: posterior inferior cerebellar artery Tracey Baird, et al, Neurocritical Care, 2004

  6. Basilar artery occlusion Single point occlusion Two points occlusion D-M M-P D-P

  7. Purpose: develop a reproducible rat model of brain stem ischemia • In 11 rats, the basilar artery was occluded at a single point along its length. • 12 rats underwent occlusion at twopoints 3 mm apart at various sites along the length (above AICA or below AICA) Basilar artery

  8. Results Single-point or two-point BAO reduced peak-to-peak amplitude of the cortical SEPs by >50% within 15 minutes The SEPs gradually recovered over 3-4 hours, and the response amplitudes exceeded baseline values in seven of the 17 rats by 4 hours after occlusion. By 24 hours after basilar artery occlusion, amplitudes and latencies returned to baseline values.

  9. HE staining No infarct in any rat with single-point basilar artery occlusion Two-point occlusion above or below the AICA produced brain stem infarcts Two-point BAO below AICA Two-point BAO above AICA

  10. Conclusion • Basilar artery occlusion at any single point between the foramen magnum and the circle of Willis in 11 rats did not produce histologically detectable infarcts in the brain at 12-24 hours. • Two-point occlusions of the basilar artery in 12 rats produced variable infarcts between the occlusion sites but no ischemic lesions elsewhere. • Basilar artery occlusions invariably suppressed cortical somatosensory evoked potentials by >50%.

  11. Background • Arousal pathway passed through the paramedian midbrain reticular formation and bifurcated at the diencephalon into two branches, into the thalamus and hypothalamus • Most neurons participating in these pathways from the rostral pons and caudal midbrain: Noradrenergic locus coeruleus Serotoninergic dorsal pedunculopontine Laterodorsal tegmental nuclei Parabrachialnucleus However their functions in awake/sleep are unknown.

  12. Methods 1st part • Pathogen-free adult male Sprague-Dawley rats (275–300 g) • Lesions of the thalamus: injecting 50 nl of a 10% solution of ibotenic acid bilaterally • Lesions of the basal forebrain: injecting a 0.1% solution of either IgG192-saporin or orexin-saporin (OX-SAP) at four different sites (ibotenic acid cause rats to die; high dose (125ng) OX-SAP kill all noncholinergic neurons and 88% of cholinergic neurons; 100ng OX-SAP kill all noncholinergic neurons and 19% of cholinergic neurons) • To kill cholinergic BF neurons specifically, 1ug IgG 192-saporin was injected into the lateral ventricle. • EEG/EMG were continuous recorded on day 7 postoperatively. • c-Fos immunohistochemistry (anindirect indicator of neurons firing, it gives a rough indication of the degree to which neurons have been receiving excitatory inputs that elevate cyclic AMP or intracellular calcium)

  13. 2nd part • Using cholera toxin subunit B (CTB) to retrogradely trace inputs to the BF and thalamus from sites in the brainstem to define the cell groups • In situ hybridization for the vesicular glutamate 2 transporter (VGLUT2), to determine which of these cells were likely to be glutamatergic.

  14. 3rd part • Using local injections of orexin-saporin to ablate neurons in the parabrachial nucleus and precoeruleus region • EEG/EMG were continuous recorded at 7 days postoperatively. • c-Fosimmunoreactivity

  15. Results Ibotenic acid induced lesions of the thalamus

  16. Effects of thalamus lesions onc-Fosexpression and Sleep-wake behavior

  17. A slight decrease in theta power during the subjective night after thalamus lesion

  18. Summary 1 • Thalamus lesions, even with an extensive lesion, did not affect EEG/EMG pattern, sleep/wake pattern, c-fos expression and behavior, except a slight decrease in theta power during the subjective night. • No coma-like syndrome was observed.

  19. Nonselective lesions of the BF 10 days after OX-SAP, 7/11 rats exhibited a coma-like state • EEG at all times was dominated by sub-delta (<1 HZ EEG) activity.

  20. Effects of BF lesions on thec-Fosexpression A dozen cholinergic cells are the only surviving Neurons Minimal c-fos expression in neocortex High expression in TMN and LC

  21. C-Fosexpression on nonselective and selective lesions of the BF

  22. Effects of BF lesions on the EEG pattern induced by continuous stimulation By continuous gentle touch, rats maintained a tonically active EMG. EEG showed a monotonous slow-wave activity

  23. No coma-like behaviors were induced in Ch BF lesions or Non-Ch BF lesions

  24. Summary 2 • BF is a critical relay for maintaining the waking pattern of behavior, EEG and cFos expression. • Both cholinergic and noncholinergic (mainly GABAergic) BF neurons work jointly in control of cortical arousal. Either component alone is capable of supporting cortical arousal. Source of inputs to the BF neurons?

  25. Retrograde tracer CTB injection to S1 to search which provides arousal inputs to the BF • Large numbers of neurons in the medial PB (MPB) • Small number in the PC • Almost all the CTB labeled cells in the PC and PB also expressed VGLUT2, indicating PB/PC provide glutamatergic inputs to the BF

  26. PB/PC lesions induced by OX-SAP injection Comatose happened 10 days after injection

  27. LPB and MPB lesions increased sleep

  28. Bulk of EEG power was <1 HZ after PB/PC lesion

  29. Low level of c-Fos in the neocortex

  30. Effects of PB/PC lesions on the EEG pattern induced by continuous stimulation By continuous gentle touch, rats maintained a tonically active EMG. EEG showed a monotonous slow-wave activity

  31. Summary 3 • PB/PC is critical for achieving and maintaining an activated EEG and a waking state. • PB/PC-BF-neocortical axis controls neocortical arousal

  32. Important points of the study • 1. Challenge widely accepted view of comatose model (thalamus) • 2. Provide solid evidence that PB/PC-BF-Cortex may constitute a critical pathway for maintaining a waking cortical state.

  33. Thanks for your attention

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