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Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models

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Science Translational Medicine  08 Apr 2015:
Vol. 7, Issue 282, pp. 282ra46
DOI: 10.1126/scitranslmed.aaa4050
  • Fig. 1. Premorbid cardiorespiratory dysregulation and brainstem SD in Kv1.1 mutant associated with cortical seizures in vivo.

    (A) Diagram of experimental setup for application of 4AP and recording of EEG and brainstem DC potentials in spontaneously breathing urethane-anesthetized juvenile mice (P18 to P25). (B) Illustration of brainstem recording area (red circle). (C) Time until death in Kv1.1 wild-type (WT) and KO mice after focal 4AP application. (D and E) Representative traces of premorbid sequence of the cortical EEG, brainstem DC current, ECG, and respiration in two Kv1.1 KO mice. Expanded traces shown in the lower half of the panels illustrate the temporal association between loss of cortical EEG activity, brainstem SD, and development of cardiorespiratory arrhythmias. Asterisk, gasping. (D) Immediate postictal EEG flattening tightly coupled to onset of cardiorespiratory dysregulation and brainstem SD. Vertical scale: cortical EEG, 0.35 mV; brainstem DC, 5 mV; ECG, 0.22 mV; respiration, arbitrary units. (E) Delayed cortical suppression and cardiorespiratory shutdown >10 min after final intense seizure activity. The respiratory trace in the box is further expanded and shown in the inset. Vertical scale: cortical EEG, 0.31 mV; brainstem DC, 18 mV; ECG, 0.43 mV; respiration, arbitrary units.

  • Fig. 2. Cardiorespiratory dysregulation and brainstem SD in WT mice associated with cortical seizures in vivo.

    (A to D) Representative traces of premorbid sequence of the cortical EEG, brainstem DC current, ECG, and respiration in one WT mouse (Kv1.1+/+) with expanded traces from time points a, b, and c shown in (B) to (D). In the EEG power spectrum, vertical axis shows EEG frequency band, and the color map indicates power. (B) Interictal cardiorespiratory tone. No deleterious cardiorespiratory rhythms were observed during the interictal period. (C) Ictal apnea and recovery. Cortical seizure triggered a very brief respiratory arrest (red arrow). (D) Breathing during seizure. During sustained seizure, breathing rate slowed but remained regular.

  • Fig. 3. Characterization of premorbid seizures and autonomic deregulation in Kv1.1 KO mice.

    (A) Time delay to the onset of lethal cardiorespiratory failure from the end of intense seizure (left) or the beginning of brainstem SD (right). (B to F) Representative traces showing development of cortical seizures and terminal cardiorespiratory deregulation. Expanded traces are shown in (D) to (F). (B) Recurring high-amplitude seizures until brainstem SD and death. Regular cardiorespiratory tone during baseline (D) and failure during seizure (E). (C) An intense cortical seizure triggering cardiorespiratory deregulation (F), leading to brainstem SD and death.

  • Fig. 4. Characterization of premorbid seizures and autonomic deregulation in the Scn1a (+/R1407X) mouse.

    (A) Stable baseline cardiorespiratory tone. (B) Degenerative cardiorespiratory response during the onset of brainstem SD. Sudden onsets of agonal breathing, cardiac arrhythmias, and cortical EEG suppression preceded the onset of negative DC potential shift in brainstem DC trace. Asterisk, gasping. Vertical scale: cortical EEG, 1.1 mV; brainstem DC, 7.5 mV; ECG, 0.22 mV; respiration, arbitrary units.

  • Fig. 5. Locally evoked brainstem SD triggers cortical suppression and cardiorespiratory collapse.

    Local brainstem SD initiated by KCl microinjection into the dorsal medulla of anesthetized spontaneously breathing mouse. (A) Representative cortical and cardiorespiratory responses in juvenile WT mouse. Brainstem SD transiently suppressed cortical EEG, ECG, and spontaneous respiration. The expanded trace shown below illustrates periodic cortical EEG suppression, bradycardia, and apnea. Gasping was observed during the recovery from apnea. Vertical scale: cortical EEG, 0.15 mV; brainstem DC, 4.5 mV; ECG, 0.2 mV; respiration, arbitrary unit. (B to E) Quantification of central and peripheral consequences of brainstem SD. Duration of bradycardia was longer and the peak heart rate decrease (analyzed every 1-s bin) was lower in Kv1.1 KO mice. There was no difference in the duration of cortical EEG suppression and the duration of apnea. WT, n = 10; Kv1.1 KO, n = 4. *P < 0.05, **P < 0.01; n.s., not significant. We note that 63% (7 of 11) of Kv1.1 KO mice died after SD and were excluded from the analyses. (F) Microinjection of KCl triggered prolonged DC potential shift, followed by death. Vertical scale: cortical EEG, 0.25 mV; brainstem DC, 10 mV; ECG, 0.18 mV; respiration, arbitrary unit.

  • Fig. 6. SD threshold is influenced by age, ion channel deficiency, and tau deletion in brainstem slices.

    SD was triggered in coronal medulla slices by OGD and monitored by IOS. (A) Raw image (a) and montage of video frames (b to e, see movie S1). TS, tractus solitarius; AP, area postrema; X, dorsal motor nucleus of vagus; XII, hypoglossal nucleus. Scale bar, 500 μm (B) IOS and whole-cell recording of NTS neurons showing compromised afferent input after SD onset. Vertical lines in the whole-cell current trace are test responses of membrane resistance to a train of excitatory postsynaptic currents (EPSCs) triggered every 20 s. Im, whole-cell current; ΔT/T0, relative transparency change. (C) Expanded traces of (a) and (b) from (B). (a) stimulation artifacts (red arrows) followed by EPSCs at baseline; (b) EPSC absent during SD. (D) SD onset was significantly faster in slices obtained from juvenile Kv1.1 KO (red). Adult slices showed a marked increase in SD threshold and no genotype difference. (E) The Kv1.1 channel inhibitor DTX-K (50 nM) reduced latency to SD onset in WT (black) but not in Kv1.1 KO slices (red). (F) Scn1a-deficient mice also showed lowered SD threshold (red). (G) Compound Kv1.1/tau deletion (red) abolished low SD threshold in Kv1.1 KO slices. The numbers indicate numbers of slices with SD out of total slices tested. *P < 0.05, **P < 0.01. n.s., not significant.

Supplementary Materials

  • Supplementary Material for:

    Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models

    Isamu Aiba and Jeffrey L. Noebels*

    *Corresponding author. E-mail: jnoebels{at}

    Published 8 April 2015, Sci. Transl. Med. 7, 282ra46 (2015)
    DOI: 10.1126/scitranslmed.aaa4050

    This PDF file includes:

    • Fig. S1. Peri-ictal autonomic abnormality in Kv1.1 KO mouse #1.
    • Fig. S2. Peri-ictal autonomic abnormality in Kv1.1 KO mouse #2.
    • Legend for table S1
    • Legend for movie S1

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Table S1 (Microsoft Excel format). Raw data.
    • Movie S1 (.avi format). OGD-SD in brainstem slice.

    [Download Table S1]

    [Download Movie S1]

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