Electroconvulsive Therapy: The Mystery of Mechanism

February 22, 2022

Written by: Margaret Gardner

One might think that having seizures – uncontrolled electrical firing in the brain – would only worsen the symptoms of psychiatric disease such as depression and psychosis. Yet since noticing that epilepsy actually seemed to protect against schizophrenia in the early 1900s, doctors have used several methods to induce seizures as a treatment for severe mental illnesses¹. Nowadays, modern electroconvulsive therapy (ECT) uses small, brief pulses of electricity to safely cause seizures in patients under anesthesia². As with many treatments for psychiatric illness, the exact reasons why ECT improves symptoms is still unclear. Many studies have sought to answer this open question by assessing whether ECT improves various measures of brain activity that are often abnormal in mental illnesses, such as signaling of molecules, immune activation, and the volumes and connectivity of brain regions.

Signaling Molecules
Brain function relies on chemical signals that travel between cells, passing information. Some studies find that the activity of two such chemical messengers, serotonin and dopamine, is abnormal in people experiencing depression or psychosis, suggesting that ECT could improve symptoms by correcting these abnormalities³. Studies in animals have supported this hypothesis, showing that ECT increases both serotonin and dopamine signaling⁴. However, human research has produced varying outcomes. Some studies report no change in serotonin levels after ECT. Others have found that, like antidepressant medications, ETC reduces the number of receptor proteins that receive serotonin signals ^3,4. You can think about this finding by imagining that you work at the local pizza restaurant, and every so often you’ll put a stack of menus (serotonin) in each of the mailboxes (receptor proteins) along a street (the cell); if half the residents decide they’re sick of receiving your unsolicited menus and get rid of their mailboxes (receptors), there won’t be as many for you to put your menus (serotonin) into. This lowered serotonin signaling and/or the ways that the cell works to compensate for it may be how ECT reduces depression. Human studies show dopamine signaling might increase after ECT, though results are mixed and may differ depending on individual genetics^3,5,6.

Immune Activation
The immune system, which is activated by infection and stress, releases its own set of signaling molecules that might cause or worsen mental illnesses^6,7. While the immune system provides essential protection against viruses and bacteria, long-term immune activation can cause damage to both the brain and the body, potentially leading to psychiatric symptoms^7,8. The stress of the seizure caused by ECT actually seems to cause a short-term increase in inflammatory signals, the messengers of immune activation that can cause damage if left unchecked. But with repeated treatment, these levels ultimately reduce below their starting point, allowing the brain to recover from this hyperactive inflammation^6,7. You can think about this proposed relationship like boiling pasta; you need some heat (inflammation turned on by the immune system) for the pasta to cook (i.e. for normal brain function), but if there’s too much for too long, your pasta pot is going to boil over and make a mess of your stove (the brain will have trouble functioning properly). ECT – while it briefly turns the heat on the over-boiling pot even higher – turns the stove back down to where it should be, allowing your pasta to stop bubbling over (i.e. reducing psychiatric symptoms) and finish cooking to al dente perfection.

Brain Volume and Neurotrophins
Another group of chemical signals that affect the brain are neurotrophins, a family of molecules that help cells in the brain survive, grow, and rewire connections with each other9. These neurotrophins can protect against or reverse loss of brain volume, which is often associated with psychiatric illness5,10. ECT has been shown to increase the levels of one such neurotrophin, brain-derived neurotrophic factor (BDNF), in both humans and animals^3,6. This increase in BDNF was also associated with improvement of psychiatric symptoms³. Similarly, ECT leads to an increase in the volume of brain regions that are often impacted by psychiatric disorders, though this increase in volume may not necessarily be the cause of symptom improvement^3,10.

Functional Connectivity
Healthy brain function requires the precise coordination of activity across many different brain regions. This process is commonly dysfunctional in psychiatric disease^5,11. Studies measuring electrical activity and blood flow in the brain have shown ECT reduces activation in areas involved in stress, cognition, and emotion, which may be overactive in those experiencing symptoms like depression, anxiety or unusual thoughts^3,5,12. Different imaging techniques that monitored the harmonized activation of brain regions when people are at rest (awake but not thinking about anything in particular) found that activity between these rest-related regions becomes more coordinated after ECT^3,11. Meanwhile, other networks of interconnected brain regions may become less coordinated, i.e. their activity is less strictly dependent upon one another ¹¹. In both cases, these changes can help restore the balance of activity coordination across brain regions, known as functional connectivity, that is thrown off in mental illness: one needs enough functional connectivity that different parts of the brain can work together to accomplish specific tasks, but not so much connectivity that they start ignoring other regions. The magnitude of these changes – overall reduced activation in some areas and more balanced coordination between areas – were associated with greater symptom improvement in some but not all studies^3,11.

Studies investigating each of these hypotheses have found mixed results, and much work remains before we can know what mechanisms – or mix of mechanisms – ECT activates to alleviate mental illness. There are several reasons why ECT’s methods remain so elusive; studies are often small, use different stimulation parameters (e.g. how long an electrical pulse is given for and where exactly in the brain it is applied), and compare ECT to “control” conditions that participants may be able to distinguish from real ECT treatment. Furthermore, the biological causes of psychiatric illnesses are themselves heterogeneous and unclear, making the task of finding consistent changes amongst individuals receiving ECT even more difficult. Despite these challenges, gaining an understanding of ECT’s mechanisms could reveal important knowledge about the biological basis of psychiatric disease and drive the development of new, more precise treatments. Therefore, while the mystery remains unsolved for now, researchers remain on the case, hunting for new clues to the mechanism of ECT.

References:

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