In the first decade or so after its introduction in 1938, several animal and postmortem human studies appeared that implied that electroconvulsive therapy (ECT) caused various forms of physical damage to the brain, such as hemorrhages large or small, gliosis, or neuronal death.1 Indeed, in an era when prefrontal lobotomy was said to be effective and not infrequently used, “brain damage” of some sort was even hypothesized to be the basis for its undoubted effectiveness; and people opposed to the use of ECT (apparently on personal or philosophical reasons) still occasionally cite studies from this era as an ostensibly scientific basis for their opposition.2 As late as 1977, one physician (drawing mainly on articles published 2 or 3 decades earlier) pronounced, “From a neurological point of view ECT is a method of producing amnesia by selectively damaging the temporal lobes and the structures within them” lumping the technique together with insulin coma, chemical generation of seizures, and prefrontal lobotomy1 and scanting its therapeutic effect. This fear of “brain damage” apparently persists both in the general public3 and among medical professionals.4
This concern presumably stems from the known effects of ECT on memory. Although less problematic than formerly, cognitive side effects remain despite major advances in treatment technique.5 If some form of neuronal injury indeed occurs as a result of ECT, it must either be caused by the effects of exposure to an electrical current or by the physical effects of a seizure.6
Possible Mechanisms of Injury
Electrical Stimulation of the Brain in ECT
Exposure to electricity under some circumstances undoubtedly can alter brain function indefinitely; survivors of lightning strikes or other substantial electrical injury report many psychological and neurological sequelae, including a variety of memory difficulties.7 But such experiences can hardly be considered comparable to the administration of a known amount of charge to a patient under controlled circumstances, with careful monitoring, muscular relaxation, and proper oxygenation. To properly assess any effect of that administration of electrical charge might have, it would be important to determine how much actually gets into the living brain rather than being dissipated by scalp, skin, and meninges, and specifically where within the brain current is most intense.
A handful of studies using cadaveric samples or animal models to investigate how electrical current was propagated within the brain appeared beginning in the 1940s,8,9 but technological restrictions limited the conclusions that could be drawn. In more recent times, studies8,9 modeling spatial distribution of electric field strength have suggested that, with usual ECT technique, virtually the entire brain volume is exposed to suprathreshold electrical stimulation, although electrical field intensity in various regions differs somewhat depending on electrode placement—with greatest effect seen in bitemporal electrode placement. Of note, given the effects of ECT on memory, hippocampal stimulation, in particular, is greatest with bilateral electrode placement and weakest with right unilateral placement.10–12 Thus, if direct electrical stimulation of the sort used in ECT caused neuronal damage, such modeling should help refine searches as to where and what sort of “footprint” might be found.
The Effect of Seizures
There is an extensive literature on the relationship between seizures and neuronal death, far too complex to be reviewed here; the same is true of studies of other neural responses such as gliosis. There is agreement that status epilepticus is neurotoxic, although there is little support for similar effects arising from brief and isolated seizures in the mature (as opposed to developing) brain.13,14 Nonetheless, if electrically induced therapeutic seizures cause either neuronal death or longstanding adverse effects on cell function or connectivity, it would seem that the voluminous “bench” literature regarding the biochemical sequelae of neuronal damage might at least suggest assays by which signals of neuronal damage or death might be identified.
Of course, the reverse holds true as well, and there is a substantial body of evidence to indicate that ECT (like antidepressant medications) may exert its therapeutic effect by encouraging neurogenesis, reversing depression-induced pathological suppression of neurogenesis in the hippocampus and elsewhere.15,16
During the period when ECT was first introduced, and before the introduction of modified ECT, scattered autopsy reports appeared that showed a variety of pathological abnormalities, ranging from microscopic evidence of anoxic encephalopathy and ischemic or other changes such as petechial hemorrhage or hemosiderin deposition to subdural hematoma or subarachnoid hemorrhage.17 Such reports are of dubious relevance in an era in which use of cardiac monitoring, muscular relaxation and, in particular, ventilator support are routine and when more sophisticated pre-treatment evaluation is available.
Although there are relatively few prospective studies, early neuroimaging studies consistently failed to demonstrate structural brain changes after ECT treatment. A 1994 article17 noted that some researchers had found some indication of ventricular dilation, but this relationship disappears when accounting for history of illness. For example, Kolbeinsson et al.18 compared 22 ECT participants to age- and gender-matched patients, finding no effect of ECT on ventricular size.
Older magnetic resonance imaging (MRI) studies similarly did not identify structural changes. Coffey et al.,19 comparing pre-treatment MRI result to post-treatment imaging in 35 participants, found no changes other than some increase in subcortical hyperintensities in four participants, best attributed to progression of small vessel disease.
Interestingly, more recent studies have found changes—but in the direction of localized increases in volume. Nordanskog et al.,20 studying 12 patients who had undergone ECT, found bilateral increases in hippocampal volume 1 week after treatment. Consistent with those findings, Bouckaert et al.,21 studying 28 older patients with unipolar depression (average age 72 years), found increases in gray matter volume in the right caudate, medial temporal lobe, insula, and posterior superior temporal cortex.
Despite this recent evidence of volume increase, it is possible that modest degrees of cell loss or neuronal damage not resulting in cell death might be missed by imaging studies. However, other techniques have also failed to find evidence. Using proton magnetic resonance spectroscopic imaging in 17 participants to compare baseline levels of N-acetylaspartate, free choline, acetylcholine, phosphocholine, and glycerophosphocholine to levels after five or more treatments, Ende et al.22 found no change in N-acetylaspartate levels whereas choline levels increased by an average of 16%. Other researchers have attempted to identify markers of neuronal or glial degeneration (in cerebrospinal fluid, testing for tau, neurofilament, and S-100 beta proteins23 and in serum, testing for neuron-specific enolase, and protein S-10024 beta), again with negative results.
Presumably because of the low risk of mortality from ECT, there have been few opportunities to perform postmortem studies of patients after ECT treatment. Although the few case reports on patients who received treatment using modern technique showed no evidence of cellular damage, the paucity of information suggests that findings to date should be interpreted with caution. In 1985, Lippman et al.25 described the brain of an 89-year-old woman who had had more than 1,250 treatments over 3 decades, beginning in the early 1940s. Her last treatment had been 12 years prior to her death, and she was described as having been only “marginally functional” during that time. Brain examination was unremarkable; “moderate cerebral cortical atrophy, to a degree consistent with an 89-year-old patient” was found, and the authors noted that “histological signs of ageing were less pronounced than expected.” Examination of areas expected to have been particularly susceptible to hypoxic damage (cerebellar Purkinje cells and Ammon horn) was unremarkable.
A 92-year-old woman who had developed major depression at age 70 years and who had received a total of 91 ECT treatments, the last about 1 year prior to her death, was reported to have had brain findings that were grossly normal; microscopic examination showed “no evidence of cell loss or gliosis in the dentate granule cell layer, the hippocampus, or the subiculum…”26
Anderson et al.27 reported on a case of an 84-year-old man who had had atypically late and atypically severe bipolar disorder, with first onset at age 57 years. Prior to his death (from duodenal adenocarcinoma), he had undergone 422 ECT treatment sessions, the last 25 days prior to his demise. Gross examination of the brain showed that it was “remarkably well preserved for age” but was remarkable otherwise only for an extremely hypoplastic section of the right vertebral artery. Microscopic examination included samples from the middle frontal cortex bilaterally, amygdala with adjacent anterior entorhinal cortex and temporal neocortex, hippocampus with adjacent parahippocampal neocortex, inferior parietal cortex, medial occipital cortex, basal ganglia, thalami, midbrain, pons, medulla, and cerebellum. “A few acutely ischemic neurons in the pyramidal layer of the right hippocampus” were identified, but no other histopathology was noted. Immunostaining for hyperphosphorylated tau protein showed only rare neurofibrillary tangles and neuropil threads; no tangles or neuritic plaques were found in the hippocampus or any area of neurocortex. No subpial gliosis was identified.
To summarize, several conclusions can be drawn. First, neuroimaging studies do not demonstrate overall brain volume loss, which might occur if ECT caused loss of neurons, glia, small vessels, or neuropil. Second, ECT does not result in an increase in serum or cerebrospinal fluid markers of neuronal or glial damage. Finally, if ECT caused neuronal death, petechial hemorrhage or the like (as suggested in early reports), presumably postmortem studies from people treated using modern ECT technique would have shown evidence of such insult, which has not been the case.
Early on, after the introduction of ECT, several case reports and studies appeared that suggested ECT might somehow cause damage to neurons, glia, or small blood vessels in the brain. Such reports were often difficult to interpret because of methodological shortcomings or (in clinical reports) by the confounding effects of other neuropathology. As ECT technique improved, such studies became less salient and indeed of only historical interest, so that by 1984, Weiner28 could write:
For the typical individual receiving ECT, no detectable correlates of irreversible brain damage appear to occur. Still, there remains the possibility that either subtle, objectively undetectable persistent deficits, particularly in the area of autobiographic memory function, occur, or that a rarely occurring syndrome of more pervasive persistent deficits related to ECT use may be present. Clearly, more research directed toward answering these questions needs to be carried out.
Over the 35 years since then, a great deal more research has been carried out. It is of course impossible to prove a negative, and so Weiner's cautious conclusions remain valid; there is always room for further improvements in technique and advances in basic science, and these should suggest further hypotheses to be tested—including the less likely proposition that ECT routinely causes any significant adverse neurological effects. Not only has there been no additional evidence to suggest that ECT is associated with any form of brain injury, there is mounting evidence that the brain changes ECT does cause are likely to be beneficial, not harmful—at least in the case of healing the damage caused by the underlying disorder of depressive illness.
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