Neuromodulation for Depression

Andre Brunoni

Associate Professor, Medical School, University of São Paulo

Professor Andre Brunoni is a psychiatrist and currently director of the Service of Interdisciplinary Neuromodulation at the Department and Institute of Psychiatry in São Paulo and also director of the ECT service at the same institution. He finished his PhD degree in brain stimulation at Harvard Medical School and during this period he conducted two trials combining tDCS with antidepressant drugs. Later he did his postdoc with Frank Padberg in Germany at LMU Munich and after returning to Brazil, he received a faculty position as an associate professor. He started running his lab there and expanded his interests to TMS, ECT, precision psychiatry and precision medicine.

How Common Is Depression,

and How Effective Are Current Treatments?

Adult depression is the first or the second cause of disability in the world, depending on the statistics, considering all causes of diseases, including not only mental disorders but also physical disorders. Regardless of a high-income country or a low and middle-income country, depression is still one of the three most important causes of disability. That is because it has a high prevalence, so about 20% of people will have a depressive episode at some point in their lives. It also has symptoms such as low mood and anhedonia (anhedonia is the lack of pleasure to do things), which highly affects the quality of life. So imagine people with low pleasure to do things and low mood, how much these symptoms will affect the quality of their life. These people will not want to work nor enjoy things, and this affects not only their personal life but also their working life.

Treatments for depression are only moderately effective. We have big studies, such as the STAR*D study, that showed that after several lines of treatment, still, 30% of people remain depressed, which means these people are refractory to antidepressant treatments. The study was done 20 years ago, now we have newer and more effective treatments, but we still know from a clinical perspective that with the advancements and precision psychiatry, maybe this scenario will change, but until now the treatment is a trial and error process and we still have very high refractory rates in depression.

What Is Electroconvulsive Therapy (ECT)?

Jonathan: As you mentioned, ECT was developed in the 1940s and thus it’s fairly crude in its basic principles; you have electrodes across the cranium, and by passing relatively significant currents from one to the other, you can induce a generalized epileptic seizure which then spreads throughout the cortex. So that was what you were saying initially – the therapeutic benefit was attributed to that generalized seizure that was induced. However, when you look at the data, it turns out that the location of the electrodes appears to be important for therapeutic and side effects. So, therefore, that would tend to argue that the generalized seizure, which by definition is everywhere, was not the whole story, but the location of the charge delivery was crucial as well, which makes it sound much more like a modern-day neuromodulatory transcranial therapy.

Andre: It is exactly what you said. So it’s electroconvulsive therapy; whilst some people say it electroshocks – we psychiatrists do not like that because it’s associated with stigma. It’s using a very strong EC current to induce seizures, of course with anaesthesia or sedation. However, the same seizure with different patterns of electricity will induce different clinical effects, which is why we think it’s a novel form of neuromodulation.

Is Electroconvulsive Therapy (ECT) a Form of Neuromodulation?

That is an interesting question because ECT was the first non-pharmacological treatment developed in the 40s, but it is very highly effective, and it’s still used nowadays considering that its effect was based on the convulsive effects. However, when it was investigated further, some interesting things were found. Imagine two people having exactly the same type of seizures, the same duration and EEG recording or readout, however, depending on the positioning of the electrodes, i.e. whether they are unilateral or bilateral, it would induce different clinical effects and different adverse effects. This happens because of the pattern of electrical field stimulation, so different evidence pointed out that the electrical field pattern induced in the brain would lead to different clinical effects, and this is a solid indication that it is also a neuromodulation therapy.

What Types of Neuromodulation Existed Historically for Psychiatric Disorders?

I think there is a very large umbrella of types of neuromodulation, and there are even the invasive ones like DBS and VNS. So I would say that ECT and MST are perhaps minimally invasive types of neuromodulation. And then we have the non-invasive types like TMS and tDCS. tDCS is not the most recent one cause if you go to the literature in the 60s, there is a very similar method called brain polarization and in the 1880s there was also a form of galvanic stimulation which has similarities with tDCS, and you can see descriptions in the British journal of psychiatry of this form of galvanic stimulation, 150-200 years ago. But the modern methodology of tDCS was developed in the early 2000s.

What Are Modern Neuromodulation Treatments for Depression?

The first form of using tDCS in depression was done in 2006, actually in a small trial here in Brazil with Felipe Fregni and Paulo Boggio. It’s interesting because it’s a form of brain stimulation where you use a low-current direct current stimulation through electrodes put over the scalp, and then there is a direct current induced from the anode to the cathode. So from one pole to the other pole, you have a positive electrode and then a negative electrode, and then there is a current induced from one electrode to the other. Because there is a deflection in the skin, in the skull, and then also in the fat layer, the current spreads out, so a very large area is stimulated, which makes it the most non-focal of all the brain stimulation methods. TMS is much more focal, for instance. There is a large area that is stimulated, it has a very low intensity as well. So there are these main characteristics from a more physiological point of view, we studied it from a clinical research point of view. Many studies show that it’s effective, and it has both physiological and clinical effects.

How Deep Can tDCS Penetrate the Brain?

TMS is more focal but it penetrates just a few centimetres, and tDCS is less focal, but its circuit has to be closed. So it passes through everything until the current is closed – if the electrodes are too close to one another, then the current shunts. However, if there is enough distance, of course, there is some shunting through the skin, but the current that penetrates it goes through even deeper structures. Now we have very modern studies doing simulations of electrical field modelling. There are validation studies done in animals, but also in people with DBS electrodes – basically doing tDCS in them and with DBS capturing the amount of current. In these studies, it was shown that there is electricity passing even in very deep structures in the brain.

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