Electroconvulsive Therapy Stimulus Dose Expressed as Volume of Seizure Foci.

Expressing the electroconvulsive therapy (ECT) electrical stimulus dose as the electrical charge (in millicoulombs [mC]) alone overlooks the effect of voltage difference on the ability of the stimulus to induce a convulsion. The charge represents the number of electrons in the stimulus, failing to distinguish between delivering the charge rapidly (with high voltage difference) or slowly, but the rate of charge delivery matters. The same shortcoming applies in taking the stimulus energy as the dose; the energy represents only the total heat liberated by the electrical stimulus, without consideration of the rate of heat release.

There is basic difference between the electrical charge and the seizure induced by the stimulus. A seizure is a physiological event, whereas charge is a physical quantity, as are the components of charge (current, pulse width, frequency, and pulse train duration). Andrade mentioned difficulty in understanding how a wider pulse width could offset a lower frequency or a shorter pulse train duration in constituting a particular stimulus dose. Considering the stimulus energy as the dose has similar difficulties. A connection is needed between physics and physiology, and perhaps the simplest is that the electrical stimulus depolarizes neurons and turns them into regions from which seizure spreads, that is, seizure foci.

The relationship between the electrical charge and the volume of seizure foci seems simplest when considering the concept of seizure threshold. Because a seizure is a physiological event, the threshold can be expressed in terms such as the volume of seizure foci needed to induce a seizure. For electricity to generate enough foci for seizure induction, there are 2 requirements. First, the voltage across the electrodes must be high enough to depolarize neurons. Second, enough electrons must flow between the electrodes, that is, sufficient charge. Although this model is useful in discussion, even at a basic level, the brief pulse stimulus is more complex. This is because one pulse is not enough to induce a seizure.

Repetitive transcranial magnetic brain stimulation depolarizes cortical neurons without inducing seizure, even when causing large skeletal muscle movements. The volume of depolarized neurons (seizure foci) required to induce a seizure is substantially more than produced by repetitive transcranial magnetic brain stimulation. Electroconvulsive therapy involves electrically induced seizures with ephemeral functional seizure foci, not the seizure foci of epilepsy which are persistent and anatomical. The persistence of an epileptic seizure focus presumably allows gradual seizure recruitment over hours or days, one of several basic differences from ECT seizure induction.

The rate of charge delivery matters in seizure induction; it is the current. By Ohm law, higher current corresponds to higher voltage difference between the electrodes. Although the electrical voltage difference can be so low as to not depolarize any brain neurons, with sufficient time, it can eventually deliver any amount of charge. To illustrate, consider a typical transcutaneous electrical nerve stimulation electrical application of 30 mA, 0.26-millisecond pulse width, 100 pulses per second for 30 minutes. This stimulus is well tolerated by fully alert patients and is typically not painful, and some people do not even feel it. The total charge of this stimulation is 351 mC, well above the average seizure threshold. However, applied to the head, it cannot induce a seizure because the current is tiny. At sufficiently high currents and voltage, differences between the electrodes neurons depolarize and produce seizure foci from which seizure activity spreads. Applying still higher voltage differences and currents should produce more seizure foci and perhaps seizures of greater intensity.

A typical 0.5-millisecond pulse width ECT stimulus that we know to be efficient includes hundreds of widely separated pulses. For example, a 151-mC stimulus (of 30 Hz or pulse-pairs per second, 0.5-millisecond pulse width, 5.6-second duration, 0.9 A, and "30% energy") includes 336 pulses. The gap between the end of 1 pulse and the start of the next is 16.17 milliseconds, which is 32.3 times the duration of the pulse itself. The first pulse has a charge of 0.45 mC, well below seizure threshold. Only after at least dozens of pulses pass does seizure induction occur. However, single-neuron studies show that if a neuron is depolarized, it repolarizes within a few milliseconds; this would be well in advance of the next ECT stimulus pulse 16.17 milliseconds later. Consequently, extrapolating from known single-neuron processes to seizure development is not consistent with the induction of seizure by a train of brief pulse stimuli. Moreover, subconvulsive stimuli aggregate despite gaps of 1 to 30 seconds (ie, 1000-30,000 milliseconds) between them. The success of the brief pulse stimulus train implies the presence of a physiological process that summates extremely subconvulsive widely separated pulses into producing seizure foci. This appears similar to transient electrically induced "rapid kindling" in laboratory animals. Because the single-neuron model does not apply, such rapid kindling apparently involves groups of neurons.

The use of charge alone to represent stimulus dose assumes that the volume of seizure foci does not simultaneously depend on the voltage difference between the electrodes. Of course, if the current is never changed on a particular ECT instrument, the voltage difference between the electrodes will be the same at all settings, at least for individual patients and the same electrode placement. In other words, if the same current is always used, there is no effect from variations in current.

However, the stimulus current varies among ECT instruments, and some ECT instruments have adjustable current. Seizure thresholds expressed in millicoulombs were substantially higher with stimuli of 0.8 A than with stimuli of 0.9 A, with all other characteristics virtually the same. There are 2 different explanations for this: the higher current is more efficient, or the stimulus dose is greater with higher current. The present report examines the latter explanation with an electrical physics model, expressing the stimulus dose in terms of the volume of seizure foci.

DISCUSSION

The equations indicate that the ECT electrical dose expressed as volume of seizure foci rises with the cube of the stimulus current. Although these calculations are approximate, they represent a refinement over ignoring the effects of current and voltage on the ability of a stimulus to induce a seizure. It is reasonable that the stimulus dose depends on both charge and current because more neurons will depolarize with passage of more electrons and with higher voltage (from higher current). It is also reasonable that this dependence involves the multiplication product of charge and current (cubed) because a low current (and voltage) will not depolarize neurons regardless of charge, whereas a low charge will not depolarize a substantial number of neurons regardless of voltage (and current).

The charge is a quantity of electrons, and it does not involve time in its formulation or units. In contrast, the current involves time, because it is a rate, and is expressed in units of charge per time. Similarly, the existence of electrically induced seizure foci is a rate-dependent phenomenon because these foci develop and decay very rapidly. Electroconvulsive therapy seizure foci are wanted only after the electrical stimulus is administered and then for only a few seconds. Correspondingly, a realistic expression of the ECT stimulus dose should involve a rate such as the current, without removing the rate effect by integrating over time.

Comparison of 2 ECT instruments reported that 0.9-A stimuli (Thymatron® instruments, Somatics, Lake Bluff, Ill) were 61% more effective than stimuli up to 0.8 A (Mecta instruments, Mecta Corp, Lake Oswego, Ore). Specifically, seizure thresholds in millicoulombs were 61% higher with stimuli of up to 0.8 A, although other stimulus characteristics were virtually identical. In this study, bifrontotemporal seizure threshold charge was measured in 88 patients under anesthesia with thiopental and succinylcholine. Electroconvulsive therapy instrument assignment was randomized, and half the patients were treated with each instrument. The patients were of average age 38.2 years, young for an ECT study. All data were collected during the first 2 ECT sessions.

Because the study report 6 did not discuss how the stimulus characteristics (excepting current) of the 2 groups were virtually identical, the details are reviewed here. In this study the pulse width used was 1 millisecond for every patient. Other possible pulse widths were not used and so did not affect the results. The frequency was within the range of 30 to 70 Hz at every stimulus setting except one. Frequency variations within this range do not affect the efficiency of 1-millisecond pulse width stimuli. The exception was at 25% of maximum energy on the Mecta instrument, when 90 Hz was used. The worst-case scenario is that all 8 subjects who seized at 30% of maximum energy but not 25% would have seized at 25% with a lower frequency. Scoring their seizure at 25% instead of 30% decreases overall seizure threshold of the Mecta instrument group by 5%, not a substantial change to the 61% overall group difference. Moreover, the likely scenario is less than this worst case. Regarding the effects of pulse train, the pulse train duration is the product of pulse width and frequency, both of which were already discussed.

Furthermore, at every dose level given, except 25% of maximum energy, the pulse train was longer with Mecta than Thymatron stimuli, which biases only against the result found, not for it. This is because longer pulse train increases stimulus efficiency. The "worst-case scenario" of the exception at 25% of maximum energy is the same as with frequency.

With no substantial difference in pulse width, frequency, or pulse train duration, current is the only remaining difference between the Thymatron and Mecta stimuli. Indeed, all Thymatron stimuli were 0.9 A, and all Mecta stimuli were 0.8 A or less, a consistent difference. Because the Mecta current was sometimes less than 0.8 A, the 61% overall group difference mildly overstates the difference between 0.8 and 0.9 A. However, the use of current less than 0.8 A does not diminish the conclusion that current has a large effect on stimulus dose besides its contribution to stimulus charge.

The present calculated result of 42% to 60% greater dose than indicated by the charge alone with 0.9 A than 0.8 A stimuli matches the experimental observation.6 Obtaining this same result by 2 entirely different means, calculation and experimental observation, is strong validation. For clinical application, in view of the 42% to 60% range in calculated results and the mildly less than 61% expectation if 0.8 A had been used uniformly, a 50% difference seems a simple average estimate of the dose difference of a specific charge between 0.8 and 0.9 A. No other published comparisons were found between stimuli of different currents that were otherwise similar. However, from one study to another, there are unexplained large variations in seizure threshold. For example, using apparently the same ECT apparatus and method, mean bifrontotemporal seizure thresholds were 131 and 158 mC for 2 groups and 104.4 mC for a third group. These unexplained variations suggest that these studies should not be compared with each other.

The model described previously applies better to bilateral ECT placements than to right unilateral ECT because the unilateral electrodes are approximately in a plane. This location should flatten the current distribution through the brain. Accordingly, for unilateral ECT, instead of being cubed, the current term in the foci dose equation should have an exponent between 2 and 3, approximately 2.5. These equations indicate 34% to 47% greater stimulus dose than shown by charge alone at 0.9 than at 0.8 A.

One practical application of the foci dose equations is in comparing doses between ECT instruments that use differing currents or between different currents in an instrument with more than one selectable current. If, during a patient's ECT course, treatment at one current (eg, 0.8 A) is replaced by treatment at another (eg, 0.9 A), the equivalent dose should be found in seizure foci units, not in charge. However, knowing that the difference is 50% simplifies conversion. If a patient receives a stimulus of 576 mC at 0.8 A, the equivalent dose at 0.9 A is 384 mC.

Another application is in using the age-based stimulus dosing method at currents besides 0.9 A. In this method, the initial stimulus expressed as the percentage of the instrument's maximum dose (eg, % energy) is set to half the patient's age in years for a bilateral electrode placement (ie, 30% of maximum for a 60-year old). This method has been found successful only with 0.9-A instruments, and did not reliably induce a seizure at 0.8 A. At 0.9 A, this "half-age" method corresponds to a charge of 2.5 mC per year of age. By the present results, this translates to 3.7 mC/y at 0.8 A, which is three quarters of age. Similarly, "full-age" dosing for unilateral ECT, which is 5 mC per year of age at 0.9 A, corresponds to 7 mC/y and 1.4 times age at 0.8 A. In other words, in this dosing method, the "percent of age" that should be used depends on the ECT current as well as the electrode placement.

This dose characterization method helps in evaluating a previous report of unusual ECT stimuli. Cronholm and Ottosson reported using an "Elther ES" device delivering bitemporal ECT stimuli of 0.1-millisecond pulse width at 15 pulses per second and 2.1 A. A 50-year-old patient would receive this stimulus for 10 seconds; this has a charge of 31.5 mC. The authors implied that this device is desirable and efficient because the stimulus charge is very low. By the simple foci formula, this stimulus dose is 400 foci units, equaling that for stimuli of 0.8 A at 576 mC or 0.9 A at 400 mC. This is a high dose. This conversion reveals that Elther ES device stimuli are not particularly efficient or desirable. Inefficiency might result from its extraordinarily brief pulse width, unusually high current, exceptionally slow pulse delivery rate, or the combination of these peculiar characteristics.

The background section noted 2 competing explanations of the observation that greater charge was needed to induce seizure at lower current. Restating physiologically, either a higher current is more efficient in generating seizure foci or the volume of seizure foci is greater with higher current (or both). According to the present results, the larger volume of seizure foci accounts for approximately all of the effect of higher current. This implies that higher currents are probably not more effective than corresponds to the volume of seizure foci they generate, at least in the range studied.

The volume of seizure foci is used in this report as a mathematical tool for expressing and comparing stimulus doses. Explicit measurement of seizure foci is not needed in this or for the clinical implications discussed. Nevertheless, measurement of electrically induced seizure foci should help to understand the ECT stimulus dose. Because ECT foci are ephemeral, measurement should be more technically difficult than the identification of epileptic foci by functional near-infrared spectroscopic brain mapping.