Depression: Has Brain Network Modulation Come of Age?

A new review looks at the history and future of neuromodulation in depression treatment.

• Treatments such as electroconvulsive therapy (ECT) and surgery to change the brain networks that underlie mood disorders have come a long way since the late 1930s.
• In the 80 years since its controversial beginning, “neuromodulation” has become a safe and effective form of therapy for mental health conditions.
• Modern techniques include vagus nerve stimulation and noninvasive procedures such as transcranial magnetic stimulation (TMS).
• A newly published review charts the history of neuromodulation, looks at new developments in the field, and considers possible future directions.

About 1 in 6 adults in the United States will experience clinical depression at some point during their life.

Every year, the condition affects approximately 16 million adults in the U.S. alone.

Mainstream treatments do not work well for everyone — researchers estimate that 1–3% of people in the U.S. have treatment-resistant depression.

Currently, the two main treatment approaches for mental health conditions are drugs, such as antidepressants, and psychotherapies — also known as “talking therapies” — such as cognitive behavioral therapy (CBT).

However, there is a third approach that is much less widely used than either drugs or psychotherapy.

Known as neuromodulation, it aims to correct abnormal communication between the parts of the brain that regulate moods, thoughts, and behaviors.

Scientists pioneered this approach in the late 1930s in the form of brain surgery and ECT. However, it fell out of favor with the development of the first drug treatments.

A newly published review by two psychiatrists charts the troubled history of neuromodulation and looks ahead to its promising future. The article appears in The American Journal of Psychiatry.

“Older approaches, based on an extremely limited understanding of the brain regions involved in psychopathology, were crude and (at best) appropriate only for the most severely ill patients,” write Dr. Susan K. Conroy, Ph.D., of Indiana University School of Medicine in Indianapolis, and Dr. Paul E. Holtzheimer, of Geisel School of Medicine at Dartmouth, NH.

However, they also describe a range of surgical and nonsurgical techniques that have emerged over the past 20–30 years that are much safer and more effective.

“Advances in technology have provided a more sophisticated understanding of the neural circuitry of disorders of mood, thought, and behavior, as well as more nuanced ways of interacting with and modulating these circuits,” they write.

Electroconvulsive therapy

In 1938, doctors used an electric current to trigger a brain seizure in a man who was found wandering the streets of Rome in a delusional state — with remarkable success. The man reunited with his wife, returned to work, and was still employed and married a year later, the authors write.

In the absence of any alternative treatments, psychiatrists began to use ECT indiscriminately for a wide range of mental health conditions.

The treatment caused convulsions, which were not only distressing for patients but also risked injury. Early forms of ECT also caused cognitive side effects, including memory loss.

In the 1950s, psychiatrists improved the safety and tolerability of ECT by giving people a short-acting anesthetic and a drug to paralyze their muscles shortly before the procedure.

Subsequent refinements have improved the precision of ECT and reduced its cognitive side effects while maintaining the treatment’s efficacy.

“ECT remains the single most effective treatment for depression,” state the authors.

They concede that there are still some cognitive side effects with modern ECT, though these mostly resolve with time. However, problems with autobiographical memory persist in some individuals.

Focused stimulation

The authors report that a new kind of ECT called focal electrically administered seizure therapy (FEAST) delivers focused electrical stimulation to the person’s right prefrontal cortex.

This approach minimizes cognitive side effects while maintaining efficacy, they write.

Another technique, called magnetic seizure therapy, or MST, uses targeted magnetic stimulation to induce a seizure, which research suggests may further reduce cognitive side effects.

According to the authors, these and other variants of ECT “show great promise.”

They write: “Many thousands of patients have benefited from the lifesaving potential of ECT over the past 80 years, and this treatment will remain a critical part of our repertoire for years to come.”

Image problem

Despite these recent improvements in ECT, this treatment continues to have an image problem, which deters some people from receiving it.

Dr. Samuel Wilkinson, who is an assistant professor of psychiatry at Yale School of Medicine in New Haven, CT, and was not involved in the review, tells the journal’s podcast that ECT had a troubled early history.

He notes that there were “some abuses and misuses” of ECT in the U.S. in the 1950s and 1960s.

“That’s definitely not the case now,” he adds.

He goes on to say that ECT techniques have improved considerably.

“[O]ne of the biggest problems with ECT is the fear of cognitive side effects — the fear of memory problems, and a number of people over the years have substantially improved ECT techniques to reduce the risk of those memory problems and made it so it’s much, much safer,” he says.

Dr. Wilkinson is the senior author of a study that found an association between ECT and lower risk of suicide and death from all causes in older people with mental health conditions. The study paper appears in the same issue of the journal as the review.

Surgery

In the 1930s, scientists discovered that the frontal lobes of the brain — via their connections with other brain regions — played a vital role in the control of mood, thinking, and behavior.

In an attempt to correct this, Egas Moniz, a Portuguese neurologist, developed a type of surgery called prefrontal leucotomy to disrupt the long-distance nerve connections, or “white matter,” between the front of the brain and other regions.

Later, neurologists developed an even more radical surgery to sever these connections, known as a prefrontal lobotomy.

The review authors write that in the 1950s, the adverse effects of these procedures came to light, along with ethical issues surrounding consent and “inhumane anesthetic techniques.”

Around the same time, the first antipsychotic and antidepressant medications became available.

“Thus, the leucotomy and lobotomy appropriately fell out of favor,” they write.

Much more refined, precise surgeries that are guided by brain imaging have become available for severe, treatment-resistant depression and obsessive-compulsive disorder (OCD).

These include image-guided cingulotomy and capsulotomy, which the authors say have few complications or side effects.

Deep brain stimulation

The authors write that advances in brain-imaging techniques revolutionized scientists’ understanding of the neural circuits that underlie mental health conditions and neurological disorders.

This improved understanding has led to the development of deep brain stimulation (DBS), which involves a surgeon implanting electrodes in key regions of the brain to treat not only neurological conditions such as Parkinson’s disease, but also various mental health conditions, including depression.

The authors note that although surgery for DBS involves a small risk of bleeding and infection in the brain, it is “well-tolerated and generally safe.”

Vagus nerve stimulation (VNS) involves the implantation of an electrical pulse generator under the skin of the chest and its connection to the vagus nerve in the neck. VNS is an effective treatment for depression that avoids the need for brain surgery.

The pulses stimulate the vagus nerve, part of the parasympathetic nervous system, which helps relieve anxiety and regulate mood.

Researchers are studying a less invasive form of the technique called transcutaneous VNS, which delivers electrical pulses to the vagus nerve through the skin.

Noninvasive brain stimulation

In the 1990s, neurologists developed repetitive transcranial magnetic stimulation (rTMS), which avoids any need for surgery.

An rTMS device delivers rapidly alternating magnetic pulses through the skull, inducing an electric current in the underlying region of the brain’s cortex.

Depending on the frequency of the pulses, this procedure makes the nerves either more or less excitable.

Using cutting-edge imaging techniques, neuroscientists had already discovered that a region at the front of the brain on the left, known as the left dorsolateral prefrontal cortex, played a pivotal role in mental health.

Successful clinical trials of rTMS for depression have focused on this region.

The authors report that the procedure is well-tolerated, does not require an anesthetic, and has no cognitive side effects.

However, a person must attend a clinic 5 days a week for a month to receive the treatment.

A new form of the therapy, accelerated rTMS, involves several sessions in one day, which may improve the person’s symptoms more quickly.

Which treatment will work best?

The authors write that identifying who will benefit most from a particular form of neuromodulation “remains a trial-and-error process.”

However, researchers are rapidly improving their ability to use brain imaging to assess the activity of neural networks. This could, one day, allow them to tailor treatments to individual patients.

“I am cautiously optimistic,” Dr. Holtzheimer told Medical News Today.

“It seems reasonable to me that we will be able to identify markers of specific types of neural network dysfunction that a specific neuromodulation strategy could target,” he added.

But he cautioned that validating these biomarkers through clinical trials will be challenging.

Open to change

The review also raises the tantalizing prospect of combining neuromodulation with psychotherapy.

ECT, for example, temporarily boosts the ability of the brain to adapt and change, known as “neuroplasticity.”

The rationale is that psychotherapy would optimize the benefits of this window of increased flexibility after the treatment.

“I’m extremely excited about this possibility, but it should be made clear that there is no current evidence-based approach that does this for any psychiatric condition, as far as I know,” said Dr. Holtzheimer.

“[W]e need careful research to clarify the best way to combine neuromodulation with other interventions,” he emphasized.

Source: https://www.medicalnewstoday.com/articles/depression-has-brain-network-modulation-come-of-age