Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Abstract

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

Keywords: Spreading depolarization; anoxic depolarization; asphyxial depolarization; brain edema; brain trauma; cerebral blood flow; epilepsy; epileptogenesis; focal ischemia; global ischemia; intracerebral hemorrhage; neurocritical care; neuroprotection; neurovascular coupling; peri-infarct depolarization; spreading depression; spreading ischemia; subarachnoid hemorrhage; vasospasm.

Figure 1.

The full-band ECoG signal contains information on both the negative DC shift that identifies SD and the SD-induced depression of activity. In subdural ECoG recordings using a DC amplifier, SD is observed as a characteristic, abruptly developing negative shift of the slow potential. Note that negative is up for ECoG recordings shown in all figures. The negative DC shift is necessary and sufficient for identification of SD, and the duration of the negativity is a measure of the metabolic and excitotoxic burden imposed on tissue by SD (steps A and B). In recordings with an AC amplifier with lower frequency limit of 0.01 Hz, the negative DC shift is distorted but is observed in the near-DC frequency band between 0.01 and 0.05 Hz as a multi-phasic slow potential change that serves to identify SD (step C). The depressive effect of SD on spontaneous activity is assessed in the higher frequency band between 0.5 and 45 Hz (step D). ECoG frequencies are given on a logarithmic scale in the left panel. Note that the upper frequency limit of the full-band signal depends on the sampling rate, f_s, and the bandwidth merely ranges from 0 to the Nyquist frequency, 0.5 × f_s.

Figure 2.

Spreading depolarization causes spreading depression in electrically active (a) but not in electrically inactive (b) tissue (=isoelectric SD). Recordings of a 53-year-old female with a World Federation of Neurosurgical Societies (WFNS) grade 5, Fisher grade 3 aSAH due to rupture of a middle cerebral artery (MCA) aneurysm. (a) SD is observed as an abrupt, large negative DC shift in raw ECoG recordings (band-pass: 0–45 Hz, traces 3–6). The DC shift shows a sequential onset in adjacent electrodes because it spreads in the tissue at a rate between 1.7 and 9.2 mm/min (oblique arrows). To illustrate the principle of a band-pass filter a circuit diagram of an analog filter is shown between traces 6 and 7 (C = capacity, L = inductance, R = ohmic resistance, V_in = input, and V_out = output voltage). A digital band-pass filter with lower frequency limit of 0.5 Hz and upper frequency limit of 45 Hz is applied to the full-band ECoG to separate the spontaneous activity from lower frequencies on the one hand and ambient AC electrical noise at 50/60 Hz on the other (traces 7–10). Spreading depression is observed as a rapid rundown of spontaneous activity. Note that the spreading depression in traces 7–10 outlasts the DC shift durations in traces 3–6 at all recording electrodes. The recordings in (a) suggest that the cortical region underlying the electrode strip is more or less adequately supplied with energy. This is based on at least five arguments: (i) the negative DC shifts are relatively short-lasting at all recording sites (traces 3–6); (ii) the presence of spontaneous activity before SD indicates that rCBF must be above ∼15–23 mL/100 g/min before SD (traces 7–10); (iii) spontaneous activity quickly recovers from spreading depression at all recording sites; (iv) p_tiO₂ is within the normal range as recorded with an intraparenchymal oxygen sensor (Licox®, Integra Lifesciences Corporation, Plainsboro, NJ, USA) (trace 2) and shows a predominantly hyperoxic response to SD (brown bar); and (v) CPP is stable within the normal range before, during and after the SD (trace 1). (b) During the following night, the patient developed a cluster of recurrent SDs with persistent spreading depression of activity. Accordingly, the SDs (traces 3–6) now occur in electrically inactive tissue (traces 7–10). Such SDs are denoted with the adjective “isoelectric.” The comparison of the SDs (DC shifts in traces 3–6) between (a) and (b) illustrates that SDs associated with and without spreading depression (traces 7–10) are “of the same nature” as already pointed out by Leão in 1947. However, the prolongation of the negative DC shifts of the clustered SDs in (b) (cf. particularly SD2) compared to the isolated SD in (a) indicates that there is now some degree of energy compromise in the recording area. Note also that the response of p_tiO₂ to SD has changed from (a) to (b). Each episode of SD in electrode 3 is now associated with an initial decrease of p_tiO₂ (brown bars) and subsequent increases are reduced or absent in (b) in contrast to the isolated SD in (a).^, Between traces 6 and 7, a scheme of the standard subdural electrode strip is shown.

Figure 3.

Instructions how to identify SDs and score depression durations. (a) This illustrates the routine calculations based on monopolar recordings. Raw monopolar ECoG recordings of two neighboring electrodes are shown in the upper two traces (band-pass: 0–45 Hz). The negative DC shift of SD is assessed in these recordings. Near-DC/AC-recordings can be derived from the raw recordings using a digital band-pass filter between 0.01 and 45 Hz (traces 3 and 4) and AC-ECoG recordings using a digital bandpass filter between 0.5 and 45 Hz (traces 5 and 6) (also compare Figure 1). Spreading depression is observed in the AC-ECoG recordings as a rapidly developing reduction in the amplitudes of spontaneous activity which spreads together with SD between adjacent recording sites. The squared spontaneous activity is also called AC-ECoG power. The power in contrast to the simple AC-ECoG signals can be used as a measure to quantify local brain activity over time because there are no negative and positive values that neutralize each other. The integral of the power is based on a method of computing time integrals over a sliding window according to a time decay function. This mathematical procedure provides a smoothed curve easing visual assessment of changes in AC-ECoG power. The method has become standard to score depression durations of SD^,, and is also useful in the screening for IEEs.^, Depression durations of SD are scored beginning at the initial decrease in the integral of power and ending at the start of the recovery phase (cf. *). The caveat is added that the interrater reliability of this method is high in our experience but there remains a certain degree of subjectivity. Table 2 gives the formulas for the calculations in LabChart (ADInstruments, Oxford, UK). (b) SD-induced depression durations can be scored in either each of the six monopolar ECoG channels as in (a) or each of the five bipolar ones as in (b) to determine the longest recorded depression duration of all channels for each SD in minutes. Bipolar recordings have the theoretical advantage that they are more robust in the clinical setting because the external reference can get lost during patient movements or nursing procedures. However, this can be prevented when the external reference is secured with collodion-saturated gauze. Although depression period assessments can vary considerably between the two configurations, they were not consistently greater or lesser for either; addition of a second active electrode in the bipolar derivation could either augment or dilute effects observed in a single active electrode. TDDDs were similar between mono- and bipolar recordings. This suggests that there is in general no advantage of bipolar versus monopolar recordings in assessing either the degree or duration of spreading depression. SPCs are even more distorted in bipolar than in monopolar recordings but they are still sufficient to identify SDs. (c) The local recovery from SD requires activation of energy-dependent membrane pumps such as Na, K-ATPases. A short-lasting DC shift thus indicates that there is enough ATP to fuel the local membrane pumps for the recovery from SD at the recording site. This feature renders the local negative DC shift duration a useful measure for: (i) the local tissue energy status and (ii) the local risk of injury (excitotoxicity) at the recording site. Accordingly, the upper two traces indicate that the tissue is more energy compromised at electrode 5 than 2 because the negative DC shift of SD is longer (gray lines). Note that despite the prolonged recovery phase the initial DC deflection still occurs rapidly. The local information on the energy status is lost when only the near-DC is recorded as in traces 3 and 4. SPCs in near-DC/AC recordings thus merely serve as an identifier of SD. (d) A spreading convulsion is an SD in which epileptic field potentials arise on the tailing end of the DC shift.^,,

Figure 4.

Spreading hyperemia versus spreading ischemia in response to SD. Recordings of a 47-year-old male with WFNS grade 4, Fisher grade 3 aSAH due to rupture of an anterior communicating artery aneurysm, recording on day 9 after the initial bleeding. (a) The upper three traces show the large negative DC shift that indicates SD. The SD propagates from electrode 4 to electrode 3 at a rate of 3.5 mm/min and to electrode 5 at 5.6 mm/min assuming an ideal linear spread along the strip (band-pass: 0–45 Hz). Traces 4–6 show the spreading depression of spontaneous activity in response to SD (band-pass: 0.5–45 Hz). Traces 7–9 give the responses of rCBF to SD as measured with optodes neighboring electrodes 3–5 using laser-Doppler flowmetry. Trace ten depicts p_tiO₂ in proximity to electrode 5 whereas trace 11 shows CPP which remains within the normal range. The event is interesting since SD causes spreading hyperemia at optode 3 (= normal hemodynamic response). Accordingly, the negative DC shift is short-lasting at electrode 3. In contrast, spreading ischemia is coupled to the SD at optode 5 (= inverse hemodynamic response). Accordingly, the negative DC shift is longer-lasting and spreading depression of activity is more pronounced and longer-lasting at electrode 5 than at electrode 3. p_tiO₂ shows a hypoxic response to SD. Note that the SD starts at electrode 4 but a full-blown inverse response is only observed at optode/electrode 5. (b) As illustrated in the left panel (refers to the situation at electrode/optode 5 in (a), spreading ischemia results from a vicious circle in which the sustained neuronal depolarization triggers a perfusion deficit by severe vasoconstriction. The perfusion deficit leads to energy depletion. The energy depletion causes failure of neuronal and glial membrane pumps. The failure of the membrane pumps prevents cortical repolarization. Therefore, the release of vasoconstrictors persists which maintains the process.^,, The prolonged negative DC shift is the necessary electrophysiological criterion that defines spreading ischemia.^, An initial hypoperfusion in response to SD can hence not be rated as a spreading ischemia if is not accompanied by a prolonged negative DC shift. On the right, a scheme of the normal hemodynamic response to SD is shown for comparison (refers to the situation at electrode/optode 3 in (a)). Note that normal and inverse hemodynamic responses to SD do not follow an all-or-nothing principle but show a continuum toward increasing pathology. It may also be added that a hyperemic response to SD does not preclude that the respective SD damages the tissue at the recording site.^,

Figure 5.

Evolution of a brain infarct early after aSAH. Thirty-eight-year-old male with WFNS grade 5, Fisher grade 3 aSAH due to rupture of an anterior communicating artery aneurysm. (a) In the left panel, SD of moderate duration is shown that occurred on day 1 after the initial bleeding. Note the negative DC shift propagating from electrode 6 to 5 in traces 5 and 6 (green arrow). The DC shift is accompanied by spreading depression followed by recovery of the activity in traces 7 and 8 (green arrow). The upper two traces show MAP (intraarterial line in the radial artery) and CPP (= MAP-ICP [intraventricular measurement]). Trace 3 gives rCBF as measured with laser-Doppler flowmetry (PeriFlux System 5000, Perimed AB, Järfälla, Sweden) at a distance of 3 cm from electrode 5. Note the slight increase of rCBF around the time point of SD appearance (upwards pointing red arrow = normal hemodynamic response). Trace 4 displays p_tiO₂ as measured with an intraparenchymal oxygen sensor at a distance of about 2 cm from electrode 5. Autoregulation seems disturbed since the small decrease of MAP and CPP at the end of the recording episode causes a simultaneous decrease in rCBF and p_tiO₂. From the beginning, p_tiO₂ is below the normal range. However, the true value may be somewhat underestimated by the Licox® sensor because Clark-type polarographic probes consume oxygen. In the right panel, it seems that disturbance of autoregulation causes a serious problem shortly after the preceding SD in the left panel. MAP rapidly falls from 120 to 75 mmHg and CPP from 105 to 60 mmHg (downwards pointing black arrow). Although these values are still in the normal range, rCBF falls simultaneously by about 30% and p_tiO₂ falls below the detection limit. About 40s after p_tiO₂ has reached the lower detection limit SD starts in electrode 6 in a distance of about 3 cm from the oxygen sensor and spreads to electrode 5 at a rate of 2.1 mm/min (traces 5 and 6). In contrast to the preceding SD in the left panel, the negative DC shift only recovers 1 hr later (stars in traces 5 and 6) after MAP, CPP, rCBF, and p_tiO₂ have spontaneously recovered to prior levels. Interestingly, the SD in the right panel is associated with spreading depression of activity in a similar fashion to the preceding SD (traces 7 and 8). This indicates that rCBF must still have been above ∼15–23 mL/100 g/min at electrodes 5 and 6 when the SD invaded the underlying cortex. Most likely, the SD triggered spreading ischemia in this region. Otherwise it would be difficult to explain why the DC shift was prolonged to such an extent. Accordingly, rCBF at a distance of 3 cm from electrode 5 now shows a decrease in rCBF around the time point of SD appearance (downwards pointing arrow = inverse hemodynamic response). Another suspicious decrease in rCBF is seen 20 min later. Note also that spreading depression of activity in traces 7 and 8 is now persistent in contrast to the previous spreading depression in the left panel. (b) From left to right: the computed tomography (CT) scan on admission (day 0) shows the initial intracerebral hemorrhage. The red arrow indicates the later position of electrode 6. No evidence of ischemic damage is found in this area on day 0. The next CT was performed 2 days after the event in (a). The red arrow points to electrode 6 of the subdural recording strip. An electrode artifact precludes assessment of the recording area in the second CT. However, new infarcts in the territory of the left anterior cerebral artery and right temporal lobe are observed. The third picture shows a fluid attenuated inversion recovery (FLAIR) MRI on day 9. In addition to the territorial infarct in the left anterior cerebral artery territory, cortical necroses in the right frontal recording area, anterior cortex neighboring the interhemispheric cleft, insular and parietotemporal cortex are observed. The fourth picture gives the FLAIR image at 7 months depicting the widespread brain infarcts including the recording area. At this time point the patient showed severe left-sided hemiparesis and lower moderate disability on the extended Glasgow Outcome Scale.

Figure 6.

Persistent spreading depression of spontaneous activity can be associated with short-lasting, very stereotypical SDs. Fifty-seven-year-old male with WFNS grade 1, Fisher grade 3 aSAH due to rupture of an MCA aneurysm. Traces 1–5 give the raw ECoG recordings (band-pass: 0–45 Hz) at electrodes 2–6 showing the propagation of stereotypical negative DC potential shifts across the cortex indicating a cluster of SDs (oblique arrows). Traces 6–10 display the changes in spontaneous activity in the AC-ECoG recordings (band-pass: 0.5–45 Hz). Note that the first SD is an isoelectric SD at electrode 6 but a spreading depression at electrodes 2–5. From one SD to the next, the isoelectricity then expands in the tissue so that the third SD is only a spreading depression at electrode 2 but an isoelectric SD at electrodes 3–6. In other words, spreading depression causes the zone of electrically inactive tissue to grow. Experimental evidence in fact suggests that the zone of electrically inactive tissue can even expand into surrounding, adequately perfused tissue. This view is supported here by the observation that, for example, the third negative DC shift at electrode 3 is indistinguishable from the second one although the third SD is an isoelectric SD but the second SD a spreading depression at electrode 3. Another interesting detail is that electrodes 5 and 6 are significant for a shallow negative DC shift between the recurrent SDs (*). This could represent a NUP as explained in the text. Modified with permission from Oliveira-Ferreira et al.

Figure 7.

Development of a very prolonged negative DC shift during a cluster of recurrent SDs. Fifty-one-year-old female with WFNS grade 5, Fisher grade 3 aSAH due to rupture of an MCA aneurysm. Traces 1–4 show the raw ECoG (band-pass: 0–45 Hz) of electrodes 3–6. Note the long-lasting negative DC shift propagating from electrodes 6 to 4 which develops out of the cluster and lasts for 90 min at electrode 6. Traces 5–8 give the corresponding changes of the AC-ECoG activity (band-pass: 0.5–45 Hz). Note that the depression durations become progressively longer with each SD until a persistent depression of AC-ECoG activity develops simultaneously with the very prolonged negative DC shifts. Traces 9 and 10 show recordings of rCBF using optodes close to electrodes 3 and 4. In trace 10, note that rCBF displays a prolonged decrease followed by a delayed hyperemia in response to the long-lasting SD at electrode 4 (cf. * in traces 2 and 10). This rCBF response fulfills the criteria of spreading ischemia. By contrast, in trace 9, the rCBF responses to the last SDs are characterized by increases, and the corresponding SDs in trace 1 (electrode 3) are shorter-lasting. p_tiO₂ is shown in trace 11 and CPP in trace 12. CPP remains within the normal range and does not provide an explanation for the local events. However, p_tiO₂ is below 15 mmHg which is defined as the threshold of compromised p_tiO₂ following current guidelines. Note that a decline of p_tiO₂ starts with the fourth SD while CPP remains stable (cf. “x” in traces 4 and 11). The recorded SDs start from electrode 6 and the prolongation of the negative DC shifts was most pronounced at this electrode. Consistently, electrode 6 was closer to a large intracerebral hemorrhage which showed progression of the perilesional edema in serial neuroimages. Modified with permission from Oliveira-Ferreira et al.

Figure 8.

Pathophysiology of focal cerebral ischemia. In the experimental literature, the ischemic core has been roughly defined by a perfusion level below ∼15 mL/100 g/min, the inner penumbra (ip) by a perfusion level below ∼20 mL/100 g/min and the outer penumbra (op) by a perfusion level below ∼55 mL/100 g/min (a). The first electrophysiological change in response to ischemia is nonspreading depression of activity which is complete in core and inner penumbra about 30–40 s after the onset of ischemia (c, left panel). At this time point, ischemia has not induced SD yet. The first SD starts in the ischemic core at one or more points in the tissue typically 2–5 min after the onset of ischemia. In the core, the negative DC shift is usually persistent but its duration becomes progressively shorter-lasting along its path in the tissue while the SD spreads against the gradients of oxygen, glucose and perfusion into the adequately supplied surrounding tissue (b, right panel). With greater distance from the inner ischemic penumbra, nonspreading depression is less and less complete and SD therefore induces increasing degrees of spreading depression. Spreading depression thus causes the zone of electrically inactive tissue to expand beyond the inner ischemic penumbra. Experimental evidence suggests that the zone of electrically inactive tissue even grows into surrounding, adequately perfused tissue (c, right panel). Following the first SD after onset of an ischemic insult, further SDs develop in the ischemic zone in a recurring pattern that creates the characteristic pattern of temporal clustering. A subdural electrode strip may thus detect newly developing ischemic zones via (i) clustered SDs and/or (ii) impaired recovery of spontaneous activity even if the recording device is placed remotely from the ischemic zone. In the figure, electrodes 1 and 2 would show a cluster of isoelectric SDs although the strip is located outside of the ischemic zone.

Box 1.

Basic analysis of baseline activity, SDs and IEEs in neurocritical care.