Researchers in the United States have finally discovered how severe depression causes an abnormal brain signal – and how powerful magnetic pulses can quickly relieve patients.

In recent decades, transcranial magnetic stimulation (TMS) has become a widespread practice around the world to treat and cure depression and other mental health conditions, but until now doctors and scientists did not fully comprehend how exactly the technique was affecting the brain.

To understand how doctors came to embrace a technique they didn’t quite master, let’s first go back to 1938, when an Italian man with paranoid schizophrenia was the first person to be given what became known as electroshock therapy (electroconvulsive therapy or ECT) with complete resolution of his symptoms.

Over time, the use of ECT expanded beyond schizophrenia to other conditions, including epilepsy, and doctors started to notice that for a few days after their seizures, patients often felt euphoric or very happy.

“And psychiatrists had the idea that, okay, what if we induced seizures for people who are very, very depressed: could that help them feel better? And that actually led to one of the most effective treatments to this day for depression, which is electroconvulsive therapy,” said Dr Anish Mitra, a postdoctoral fellow in psychiatry and behavioural sciences at Stanford University.

Electroconvulsive therapy (ECT) – which is different to TMS – is a procedure done under general anaesthesia in which small electric currents are passed through the brain, intentionally triggering a brief seizure. It is known to provide rapid and significant improvements for several mental health conditions, including major depressive disorder (clinical depression), one of the most severe forms of mental disorder.

But the electroconvulsive therapy was “burdensome,” said Mitra. It required general anaesthesia and attracted a significant amount of stigma. This led doctors to explore whether it was possible to only stimulate one part of the brain without having to give people such a generalised seizure.

And that’s how transcranial magnetic stimulation (TMS) came about in the 1980s. TMS is different to ECT, in that instead of using electric currents to induce a seizure, it works with magnetic pulses to stimulate the brain in a non-invasive way.

Still, it wasn’t quite clear exactly how TMS helped depressive patients. The leading hypothesis was that it changed the flow of neural activity in the brain, but Mitra remained sceptical – and intent on solving the mystery in the hope of unlocking more effective treatments. 

Brain signals travelling the wrong way

To source where depression was flowing in the brain, Mitra and his team recruited 33 patients who had been hospitalised with major depressive disorder.

Twenty-three of the patients received Stanford Neuromodulation Therapy (SNT) – an accelerated form of transcranial magnetic stimulation – and 10 received a sham version of it. Then they compared data from these patients with that of 85 healthy subjects without depression.

When examining brain scans using functional magnetic resonance imaging (fMRI), a non-invasive imaging technique used to measure and map brain activity, they found an intriguing connection.

In the brain of healthy subjects, the scientists tracked information travelling from a part of the brain that interprets sensory information, called the anterior insula, to another part that assigns a value to that sensory information, called the anterior cingulate cortex.

But in three-quarters of the participants with severe depression, “the way in which the brain was processing emotional signals became really abnormal,” Mitra told Euronews Next, adding that for them, “it was the value system – the anterior cingulate cortex – that was kind of driving things – instead of the sensory information”.

In other words, who’s the sender and who’s the receiver in the brain network seemed to really matter in terms of whether someone is depressed.

‘Depression filter’

The insight was fascinating for Mitra’s team because typically, individuals with depression are unable to experience joy or pleasure from activities that would typically make them happy, “and so you could imagine this [abnormal flow] was a kind of filter: The brain was kind of setting its reward centre to say nothing will make you happy”.

Scientists think that the transcranial magnetic stimulation probably allows resetting this abnormal flow, and once a normal directional flow is restored, the “depression filter” is turned off, Mitra said.

Not all individuals with depression exhibit the same abnormal pattern of neural activity discovered, however, and the reversed brain flow might be less common in milder cases of depression. 

However, whenever present, the abnormal neural activity can serve as a valuable biomarker and ultimately determine the most appropriate treatment for patients experiencing depression.

“The fact that we can look for this biomarker and maybe predict for whom it is going to work and not waste time matters a lot,” said Mitra, adding that an efficient diagnosis and prognosis are essential in providing timely and effective interventions for depressed patients.

The exact location of people’s emotional response networks can differ from person to person, and the identified biomarker could also help doctors determine which part of the brain they should aim at when performing transcranial magnetic stimulation.

The use of brain imaging to study how signals travel through the brain is a relatively new concept, Mitra said, but there are already significant amounts of data and brain imaging available worldwide from individuals who have and haven’t gotten better with depression.

Correlating these existing datasets can draw new valuable conclusions, “such as ‘oh, this type of depression [as seen in the brain images] responds really well to Prozac,” he explained.

While he finds the results exciting, there are still many pending questions.

“We only have access to this tiny fraction of the world’s data on what the brain looks like in depression. So I think this is exciting in terms of a lead for people to follow and see where it takes us,” he said.