If you had the opportunity to electrocute your brain to treat your mental illness, would you do it? For millions of people worldwide suffering from treatment-resistant depression, this may well be one of the new ways out of their suffering, research shows.

How to cure a brain

The brain is an incredibly complicated and fascinating organ. Built of about 100 billion neurons communicating with each other via trillions of connections called synapses, the brain can go awry in many different ways. When that happens, modern science and medicine often struggle to understand and cure illnesses that affect millions. A well-known example of this is psychiatric illnesses. These diseases, characterised by a disturbance in emotional or cognitive functions, currently affect 1 in 8 people, or 970 million people worldwide [1]. Major depressive disorder (MDD) is the second most common neuropsychiatric disorder in the world, with over 280 million people suffering from symptoms such as irritable mood, fatigue and feelings of hopelessness. Unfortunately, many unanswered questions remain about the cause of this brain disorder and its cure.

Signals in the brain are sent and received by chemicals known as neurotransmitters. A well-known example is serotonin, which is crucial for regulating mood, appetite and sleep quality [2]. Serotonin levels are often low in depressed people, which has inspired the development of medication known as antidepressants aiming to fix this imbalance. The most commonly prescribed type of antidepressants is called selective serotonin reuptake inhibitors (SSRIs, e.g. Prozac) [3]. Normally, after serotonin is released into the synapse, it needs to be removed quickly to limit the strength of the signal transmitted to the neighbouring neuron (Figure 1), This is done by large proteins known as serotonin reuptake transporters (SERT) that actively pump the neurotransmitter back into the neuron These proteins are blocked by the SSRIs. As a result, it takes longer for serotonin to leave the synapse, and the signal sent to the neighbouring neuron is stronger.

However, it is now apparent that the story of chemical imbalance is not a complete picture. While the effect of antidepressants on the neurotransmitter system is immediate, scientists have noticed that they only relieve symptoms after two or more weeks of taking the drugs [4]. This is linked to the theory that the true effect of antidepressants takes longer to manifest because the brain needs time to change its structure and form new connections leading to an improved mood. This delay may demotivate people from keeping up with their treatment. Even worse, almost a third of patients with MDD are found to be treatment-resistant, which means that traditional pharmaceutical treatments do not work. If left untreated, depression can lead to severe suffering and life-threatening consequences. New methods with quicker onset are obviously necessary – and the answer may lie in physics.

Plugging it in

The revolution in depression treatment might come in the form of NIBS – non-invasive brain stimulation. While the idea of using electricity for therapy may seem modern, the history of this method dates back over 80 years. The concept is attributed to the Hungarian psychiatrist Ladislas Meduna, who hypothesised about epilepsy as a possible cure for mental illnesses in 1935 [5]. Building upon this idea, Italian doctors Cerletti and Bini pioneered the use of electricity to intentionally trigger epileptic seizures for therapy in 1938.

Since then, electroconvulsive therapy, or ECT, has become the most popular method of non-pharmaceutical psychiatric treatment [6]. It is often recommended as first-line treatment for patients at high risk of suicide and treatment-resistant patients. However, media portrayals, like the 1975 Milos Forman film One Flew Over the Cuckoo’s Nest have fuelled controversy surrounding ECT, painting it as a cruel and abusive method. Furthermore, ECT administration is inconvenient, requiring general anaesthesia and muscle relaxants. There have also been reports of memory damage, prompting researchers to search for alternative and safer treatment methods.

Electromagnetic imaging studies have found that abnormal activity in an area of the brain known as the left dorsolateral prefrontal cortex is correlated with the severity of depression [7]. This region is involved in many cognitive and executive functions, and it has come to focus as a potential new target for stimulation therapy. A well-known example of this approach is called Transcranial Magnetic Stimulation or TMS (Figure 2) [8]. It was first invented in 1985 and approved for use in clinical settings in 2008. During a TMS session, patients are administered a 10 Hz magnetic field through a coil placed on the scalp for 37.5 minutes daily over six weeks. Clinical trials have shown positive results, making TMS a popular non-pharmaceutical treatment [9]. However, its length, low response rate and slow onset of effects have motivated researchers to develop faster methods. 

An alternative has emerged under the name of intermittent theta burst stimulation (iTBS), a subtype of TMS. It involves delivering three 50 Hz pulses at 20-milisecond intervals [10]. This mimics the natural theta-frequency activity patterns of the hippocampus, a brain region involved in memory and cognition found to be less active in depressed patients [6]. The protocol induces long-term changes in neuronal connections and a rise in brain oxygen levels. One of iTBS’s advantages over TMS is the short duration of individual sessions, only three minutes while providing comparable antidepressant effects.

Beyond TMS and iTBS, alternative treatments using electrical currents have resurfaced since the 1960s. Transcranial direct current stimulation involves applying a low-amplitude (1-2 milliampere) current for about 20 minutes directly to the scalp through electrodes [11]. While tDCS does not actively produce brain activity, it influences the excitability (likelihood of becoming active) of the neurons under the electrode. On the other hand, transcranial alternating current stimulation (tACS) involves the use of waveform electrical currents that regularly change voltage from negative to positive [12]. This synchronizes brain activity with the electrical signal frequency, enhancing cognitive and memory-related functions. Studies have shown that these protocols are effective in relieving depression symptoms. In particular, tDCS is well-tolerated, affordable and easy to administer. Recent advancements even allow patients to undergo tDCS treatment remotely via at-home devices [13]. This approach, which includes remote support from licensed mental health professionals and understandable instructions, can be adopted for patients with a wide range of neurological conditions and improves the accessibility of tDCS treatment [14].

Although these treatments show great promise, their efficacy is still a subject of ongoing research. Inconsistencies in stimulation intensity and timing have led to conflicting results and uncertain conclusions. An improvement in treatment efficacy could be achieved by tailoring the protocols to individual patients, as many factors, including symptoms and circadian rhythm [15], may strongly affect their brain’s response. As research progresses and evidence-based protocols are developed, we may witness the widespread use of NIBS methods in clinical depression treatment, offering hope for those battling depression and other serious brain illnesses.

References 

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10.   Cheng CM, Li CT, Jeng JS, Chang WH, Lin WC, Chen MH, et al. Antidepressant effects of prolonged intermittent theta-burst stimulation monotherapy at the bilateral dorsomedial prefrontal cortex for medication and standard transcranial magnetic stimulation-resistant major depression: a three arm, randomized, double blind, sham-controlled pilot study. Eur Arch Psychiatry Clin Neurosci. 2022 Dec 9;1–10.
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