Terminal spreading depolarization and electrical silence in death of human cerebral cortex

Abstract

Objective: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury.

Methods: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate-Comfort Care order followed by terminal extubation.

Results: Withdrawal of life-sustaining therapies produced a decline in brain tissue partial pressure of oxygen (p_ti O₂ ) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed "nonspreading depression," developed during the steep falling phase of p_ti O₂ (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7-14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6-6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter.

Interpretation: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295-310.

Figure 1

Terminal spreading depolarization (SD) during death in the human brain in comparison to terminal SD during death in the rat brain. (A) In Patient 1, the first direct current (DC) change after terminal extubation was a very slow, homogeneous DC positivity (not shown; cf Table 1) that began before the circulatory arrest. Terminal SD then started at electrode 4 (transition from dark blue to red DC traces) after the arterial pressure had reached its minimum (brown trace). Systemic arterial pressure was recorded in the radial artery. The 2 insets show the arterial pressure fluctuations during the initial period and during the arrest of the systemic circulation. Note that there is still evidence of cardiac cycles in the right inset, but the cardiac output is too low to maintain a sufficient systemic pressure (electromechanical dissociation). This increasingly pulseless electrical activity of the heart disappeared 30 seconds thereafter. Spontaneous brain activity had ceased in response to the barbiturate thiopental several hours before the circulatory arrest. Therefore, no nonspreading depression of activity occurred (not shown). (B) Projection of the electrodes of a typical subdural, collinear recording strip on a human brain. (C) Dying process after circulatory arrest in a rat. (D) Original cranial window experiment using 2 subdural Pt/Ir plate electrodes for use in humans (DC/AC‐ECoG) and a laser‐Doppler flowmetry (LDF) probe (regional cerebral blood flow [rCBF]). Note the steep falls in arterial pressure and rCBF that mark the moment of circulatory arrest. In animals, the typical sequence of nonspreading depression followed by terminal SD during global cerebral anoxia–ischemia has been extensively documented since its first description in 1947.7, 11, 12, 13, 14 Note the similarity between the patterns of the terminal SD in the rodent experiment and in the patient (red arrows in A and C). In both cases, the terminal SD propagated from one electrode to the next corresponding with previous evidence from experiments in animals in vivo and in brain slices.7, 12, 13, 14 In contrast to the spread of the terminal SD, the nonspreading depression (cf asterisks) is seen in the rodent recordings as a silencing of the spontaneous electrical activity (alternating current [AC]–electrocorticography [ECoG]: 0.5–45Hz) that develops simultaneously across the array of the regional 2 electrodes (cf Figs 3B, 4B, 5A, 5C, and 6 for nonspreading depression in patients). In the clinic, it has become conventional to review the raw signal alongside a leaky integral of the total power of the bandpass‐filtered (AC‐ECoG) data and measure depression duration based on the latter.16, 23 Therefore, the integral of power is shown here to display the pattern of nonspreading depression when this type of data presentation is chosen (light blue traces, cf Patient 3 in Fig 4A and Patient 7 in Fig 6). The experiment was performed in a male Wistar rat (300g, 12 weeks old, supplied by Charles River, Sulzfeld, Germany) anesthetized with 100mg/kg body weight thiopental–sodium intraperitoneally (Trapanal; BYK Pharmaceuticals, Konstanz, Germany), tracheotomized, and artificially ventilated (Effenberger Rodent Respirator; Effenberger Med.‐Techn. Gerätebau, Pfaffing/Attel, Germany; approved by the Office for Occupational Safety and Health and Technical Security Berlin [G0152/11]). Sudden circulatory arrest was induced in the rat by injection of 10ml of air into the heart via the femoral vein. This explains why mean arterial pressure rapidly dropped in the rat in contrast to the patient, in whom the circulatory arrest developed gradually after extubation. The Supplementary Table provides the statistical description of 5 rats with a previously healthy brain in which death resulted from sudden circulatory arrest after air injection into the femoral vein and heart under thiopental anesthesia. aSAH = aneurysmal subarachnoid hemorrhage.

Figure 2

Similar to the terminal spreading depolarization (SD) in subdural recordings, the terminal SD in recordings with depth electrodes shows an initial and a late negative direct current (DC) component. (A) The computed tomogram of Patient 5 displays the intraparenchymal electrode array in the left frontal hemisphere with no lesions present. (B) The late component, the so‐called negative ultraslow potential (NUP), is similar to the negative DC shifts of prolonged SD, but specifically refers to a negative potential component generated by progressive recruitment of neurons into cell death in the wake of SDs (terminal SD at electrode 3 of Patient 5).16 AC = alternating current; ECoG = electrocorticography.

Figure 3

Comparison of spreading depolarization (SD)‐induced spreading depression versus nonspreading depression followed by terminal SD in death. (A) In Patient 2, electrocorticography (ECoG) and laser‐Doppler flowmetry displayed 5 SDs, which induced spreading ischemias (SIs) of up to 190‐second duration, spreading depressions of activity, and spreading suppressions of low‐frequency vascular fluctuations.22 Spreading ischemia concurred with disturbed autoregulation. Accordingly, tissue partial pressure of oxygen (p_tiO₂) seemed to follow the fluctuations of mean arterial pressure (MAP; cf asterisks). Oxygen is known to interfere with platinum. Accordingly, the fluctuations of p_tiO₂ are reflected in the direct current (DC) recordings (cf dark blue asterisks). (B) Discontinuation of the life‐sustaining measures caused progressive decline in MAP, regional cerebral blood flow (rCBF), and p_tiO₂. Nonspreading depression (cf X's) rendered the brain isoelectric within 338 seconds after onset of the decline in MAP or, respectively, 220 seconds after rCBF had fallen to 20% of baseline. A very slow, homogeneous DC positivity (cf Table 2) started simultaneously with the drop in p_tiO₂ (cf asterisks). Superimposed on this DC positivity, the terminal SD started in electrode 3, 53 seconds after complete cessation of spontaneous activity (transition from dark blue to red DC traces). From electrode 3, terminal SD spread to the other electrodes. Note that the terminal SD shows an initial and a late negative DC component (cf Fig 2B and Table 2). AC = alternating current.

Figure 4

Electrocerebral silence in death can develop in a spreading or nonspreading pattern. (A) In Patient 3, the first direct current (DC) change after discontinuation of the life‐sustaining measures was again a very slow, homogeneous DC positivity (cf Table 2). However, electrocorticography (ECoG) showed a deviation from the 2 previous cases, because terminal spreading depolarization (SD; transition from dark blue to red DC traces) started in electrode 3 at 7 minutes before the circulatory arrest. In this moment, spontaneous brain activity was still present. Accordingly, the terminal SD induced spreading depression at electrode 3 (cf light blue asterisks). From electrode 3, SD spread to the other electrodes. During the SD‐induced spreading depression, a pulse artifact, similar to previous observations,32 developed at electrode 4. Finally, nonspreading depression rendered the remaining spontaneous brain activity isoelectric while the terminal SD was still propagating. (B) Patient 4 suffered from malignant hemispheric stroke. Discontinuation of life‐sustaining measures caused progressive decline in mean arterial pressure, regional cerebral blood flow, and tissue partial pressure of oxygen (p_tiO₂) followed by nonspreading depression (cf X's) and terminal SD. First DC change was a very slow, homogeneous DC positivity. Similar to Patient 2, it started together with the decline in p_tiO₂. Note the fall in brain temperature after the circulatory arrest. (C) Patient 4's longest time of terminal SD arrival difference between 2 neighboring electrodes is displayed. AC = alternating current.

Figure 5

Nonspreading depression followed by terminal spreading depolarization (SD) recorded with intraparenchymal electrode arrays. (A) In Patient 5, similar to Patients 2 and 4, nonspreading depression occurred while tissue partial pressure of oxygen (p_tiO₂) showed the final drop (cf asterisks). When the electrocorticography (ECoG) became isoelectric, mean arterial pressure had fallen to 18mmHg and p_tiO₂ to 0.6mmHg. The first direct current (DC) change was a very slow, homogeneous DC positivity. Similar to Patient 2 and 4, it started together with the decline in p_tiO₂. The terminal SD started superimposed on the homogeneous DC positivity 73 seconds after nonspreading depression had rendered the ECoG isoelectric. (B) shows an overlay of electrodes 3, 4, and 6 from recordings in A, illustrating the time of SD arrival difference of the terminal SD. (C) The end‐of‐life recordings in Patient 6 showed nonspreading depression (cf asterisks) similar to A. Also, the diffuse changes of the DC potential are similar to A. Although the part of the curve where the terminal SD starts may be derived from the comparison with A, occurrence of the terminal SD is more speculative in C, because amplitudes are smaller and spread between electrodes was less obvious. AC = alternating current.

Figure 6

Scalp electroencephalographic (EEG) recordings indicated that nonspreading depression occurs simultaneously not only at intracranial electrodes, but also throughout the hemisphere. In Patient 7, approximately 10 minutes after terminal extubation, a slow, homogeneous direct current (DC) shift was observed on intraparenchymal DC/alternating current (AC)–electrocorticography (ECoG) and scalp DC/AC‐EEG electrodes in synchrony with the decline in oxygen saturation (not shown) and tissue partial pressure of oxygen (p_tiO₂), a final intracranial pressure spike, and declining cerebral perfusion. Nonspreading depression (cf light blue asterisks) was then observed across intraparenchymal and scalp electrodes during the fall of p_tiO₂. Asystole for 20 seconds began 3 minutes later (not shown), only 13 seconds before the start of terminal SD. Note the correlate of the terminal spreading depolarization (SD) in the scalp DC/AC‐EEG. Brain temperature was recorded in this case. Note the transient rise in brain temperature during terminal SD followed by decline thereafter.