The End of Sad

The End of Sad

In an experimental procedure at Toronto Western Hospital, surgeons drill holes into a patient’s skull, slide rods deep into the tissue, and send an electrical current to the frontal lobe. It’s used to treat depression, Alzheimer’s, obsessive-compulsive disorder and even obesity. Someday, it could also reveal the darkest secrets of the brain

Shock tactics: The battery pack and electrodes that stimulate Debra Prupas’s brain often set off store alarms at the mall

When she was eight years old, Debra Prupas realized there was something wrong with her. She felt a heaviness, like she was enclosed by a fog, and wanted to lie in bed and do nothing for days in a row. The feeling passed, but it returned many times throughout her life.

Prupas, now a 52-year-old litigator at the Toronto office of the Department of Justice, didn’t consider getting help until 1991, after a breakup with a boyfriend. Her psychiatrist diagnosed her with chronic depression and prescribed small doses of Prozac. It worked at first, but the heaviness crept back. She was given other drugs: sertraline, trazodone, mirtazapine, vanlafaxine, phenel­zine, bupropion, nefazodone, norpramin, citalopram and paroxetine. The psychiatrist tried to enhance the effects of the medications with lithium. Some regi­mens would brighten her mood for several months, but inevitably her depression would return. “It was like somebody turned the lights down,” she says. “Colours would literally fade.”

She went to a new psychiatrist, who recommended electro­convulsive therapy. At first she was reluctant, remembering the treatments in One Flew Over the Cuckoo’s Nest and worrying about the possibility that the procedure would leave gaps in her memory. Over four weeks, Prupas subjected herself to a dozen electrically induced seizures. They didn’t work.

By 2005, her condition had grown more serious. She couldn’t get out of bed and would miss work for days on end. Commitments would pile up on her—it was too much effort to shower, to dress, to take the streetcar to her downtown office tower, to ride the elevator to the 33rd floor, to answer e-mails. She began to think about suicide as a solution.

And then she heard about a study at Toronto Western Hospital—an experimental brain surgery for people with severe depression. The process, called deep brain stimulation, was risky, but the possibility of relief was tantalizing. She couldn’t keep going the way things were. Prupas signed up to be considered for the trial. At the beginning of 2006, she got the call: she’d been accepted.

Deep brain stimulation was first studied in the U.S. in the 1940s as an alternative to pre-frontal lobotomy. It was later tested on rats in Montreal, as part of an attempt to counter severe pain by targeting pleasure centres in the brain. The procedure involves inserting electrodes into the brain and sending an electric current to target areas, changing the way neurons behave. Although no one knows exactly how it works, the current can modulate activity in those zones. The rats got so much satisfaction from zapping themselves by stepping on levers that they stopped doing anything else and died of starvation. In the 1960s, DBS was used on cancer patients, and it helped alleviate pain in certain cases. Then, in the 1970s, neuroscientists started wondering whether it could help people with movement disorders, such as Parkinsonian tremor. The common practice for Parkinson’s patients who weren’t responding to drugs was to cut or burn a spot in the brain that was known to be causing problems. However, if the surgeon missed the target, any adverse effects were permanent. DBS, on the other hand, although just as invasive, is largely reversible. If the electrical current causes an unwanted reaction, you can simply turn it off.

Power point: DBS patients have a cellphone-sized, 3.5‑volt battery pack sewn under the skin of their chest (Image: Courtesy of Medtronic Inc.)

Researchers at Toronto Western are at the forefront of experiments using deep brain stimulation. A team led by neurosurgeon Andres Lozano was the first in North America to test DBS on human Parkinson’s patients in 1993. Since that time, more than 60,000 people have received DBS to control movement disorders. DBS has also been used as an experimental treatment for eating disorders and Alzheimer’s.

Data collected during the DBS trials has allowed the researchers at Toronto Western to map different parts of the brain. They’ve realized it’s busier than previously thought. “People used to say you’re only using 10 per cent of your brain,” Lozano says. “That’s not true. You use 100 per cent of your brain.” Until surgeons went in and recorded activity in that other 90 per cent, many people assumed nothing was happening. “People would say that if you take out this part, you look the same. You still walk, you still talk. But guess what? If you take out this part, you might not feel sadness anymore.”

Early experiments with deep brain stimulation were performed on rats. They got so much satisfaction from zapping themselves by stepping on levers that they stopped doing anything else and died of starvation

Advances in imaging techniques have given researchers a better view of what goes on in the brain. With PET scans and functional MRIs, we’re able to examine in real time which areas become active when people think or feel certain things. Helen Mayberg, a neurologist at the University of Texas at San Antonio, was using imaging to study depression when she zeroed in on two parts of the brain, called Brodmann area 25, or the subcallosal cingulate. These zones are deep in the brain, just behind the eyes—one in the right hemisphere and the other in the left. When area 25 is engaged, the cognitive areas in the frontal lobe—identified with executive functions, like planning and decision making—become unusually quiet. When patients are given antidepressants or are treated successfully with cognitive therapy or electroconvulsive therapy, area 25 calms down and other areas in the frontal lobe become more active, as they are in non-depressed patients. Mayberg wondered what would happen if, for severely depressed patients not responding to other treatments, you went in and quieted down area 25 directly.

In 2001, Mayberg heard about Lozano’s research at Toronto Western and contacted him to talk about using DBS for severe depression. Lozano was intrigued. They began researching the possibilities and applied for funding from public and private donors on both sides of the border.

Two years later, Mayberg and Lozano launched a clinical trial. To be accepted into their study, the patients had to have tried at least four recognized treatments. They had to score a minimum of 20 on the Hamilton depression scale, in which a patient scoring above seven is considered depressed. In 2006, another group of patients joined the study. Out of the first 20 patients to get DBS for depression, Debra Prupas, who scored 23 on the Hamilton scale, was patient number 14.

In the years leading up to her surgery, Prupas had struggled to keep the appearance of being happy, as though she could will her illness away. She’d bought a house in Scarborough, adopted a baby girl from China, and met Bern Grush, a high-spirited tech entrepreneur, whom she married in 2000. When she told him about her condition, he was surprised. Depressed people were lethargic and uncommunicative and suicidal, he thought. That wasn’t the Debra he knew. She had been adept at hiding her sadness. In 2003, during one of her happy periods, they’d even adopted another daughter. But as her condition worsened, she became that stereotype of a depressed person her husband had first imagined.

Wiretap: Two electrode rods deliver a charge to target areas of the brain, changing the way neurons behave (Image: Courtesy of Medical Body Scans/Photo Researchers Inc.)

Prupas knew the procedure was risky. Approximately four in every 1,000 Parkinson’s patients operated on with DBS have either died from the surgery or had serious and irreversible brain damage. As well, by altering circuits in the brain, DBS could have long-term effects on cognition and personality that aren’t reversible. She didn’t care. She’d made up her mind to go ahead. She told only her husband, a friend and her boss. She wasn’t afraid of dying—she was more fearful that the treatment wouldn’t work.

On March 6, 2006, she entered the pre-operative care unit on the second floor of Toronto Western, changed into a hospital gown and met up with a group of neurosurgeons. They took her to the third floor, where an MRI-safe aluminum frame, or halo, was fastened to her head. After administering a local anaesthetic, they twisted four screws into her cranium—two above her eyebrows and two at the back of the head, behind her ears. She told them it hurt, so they gave her more anaesthetic. But even then, she could feel the pressure from the screws squeezing into her skull. Two vertical bars framed the front of her face, holding up a thicker bar that encircled her head at nose level. The contraption was so heavy that Prupas had trouble holding her head up.

As they wheeled her toward the MRI unit, the magnitude of what she was doing hit her. “Has it really come to this?” she thought to herself and started crying. She was being pushed in a wheelchair along a hospital corridor with screws in her skull. She took a few deep breaths to calm herself down. Then a technician helped her lie on the bed that slides into the MRI, fitting the halo into a special headpiece. She lay immobile in the machine for 45 minutes as it whirred and banged. With the frame in place for the imaging, the surgeons were able to calculate exact coordinates for area 25 and plot their route.

In the operating room back on the second floor, a crowd had formed. Lozano and his team stood near two tall towers of electrical equipment. They were joined by an electrophysiologist, an anaesthetist, nurses, a camera crew from 60 Minutes, who were pre­paring a story on DBS research, and Mayberg. After Prupas was wheeled in, Lozano fixed her frame to the operating bed, so she wouldn’t be able to move during the surgery. Then he shaved her head; he’d offered to shave just a strip from ear to ear, but she said she didn’t want a reverse mohawk, and so he shaved it all off.

Lozano cleaned her scalp with an iodine solution, attached more measuring equipment to her frame, including an arc curved over her head, and covered the area with blue sterile plastic. After taking measurements and giving time for more local anaesthetic to kick in, Lozano cut the skin and pulled it back with a retractor, then started drilling a burr hole near the top of her skull, on the right side. It was the first of two holes, one on the right and the other on the left. She could hear the drilling and feel the pressure in her head. When they finished drilling, they burned the ends of broken blood vessels with an electrical current from a cautery pen, to keep them from bleeding. Then they cut open the dura, the sac holding the brain.

Lozano inserted a microelectrode probe through the first hole. As it passed through a so-called silent area, populated by neurons in the brain whose purpose neurologists don’t yet understand, popping sounds shot through the speaker system, and waves bounced up and down on the monitor. It was the noise of neurons sending signals. As the first probe arrived at area 25, it recorded a distinct firing pattern that confirmed Lozano was in the correct place. His team showed Prupas a series of images related to specific emotions. (She remembers being especially disturbed by a picture of dead birds.) They wanted to confirm their suspicion that area 25 acts up when patients are presented with sad or disturbing images.

After removing the probe, they inserted a bigger electrode, measuring 1.3 millimetres in diameter. Each electrode rod has four contact points on the end to stimulate different parts of the target area. Once it was in place, they sent an electric current through the first contact point at the end of the electrode on the right side. Mayberg was looking at Prupas, trying to gauge any change in her demeanour. She asked her a set of questions: Do you notice anything different? Can you rate your depression on a scale of one to 10? Is there anything you’d like to be doing right now? Nothing, Prupas answered. They tried the second, third and fourth contacts on the right side, each accompanied by the same set of questions. As Prupas kept giving the same answers, she started to panic, worried nothing was going to come of all this. Mayberg held her hand and talked her through it.

Then they switched to the left side. As soon as a current rushed through the first contact point, Prupas felt something. She looked up and noticed that the wall she thought was grey was actually a light lavender. And the doctors’ masks were different.

“I’m noticing your yellow masks,” she said.

“You hadn’t noticed that before?” asked Mayberg.

“Well I had, but they were just kind of, they looked kind of pale yellow. And now they’re looking like the hideous colour my husband painted on the bedroom walls.”

She answered Mayberg’s questions, telling her she felt lighter, and, if she had a choice, she’d like to be home cooking or out for a run. But she didn’t say anything about the compassion she noticed for the first time in the neurologist’s big, green eyes. She thought it would sound too hokey.

When one patient underwent DBS surgery for an eating disorder, he started to recall vivid memories from his youth. Another patient began to see bright colours and was surprised by the vibrant feathers of a bird’s wings

Then the colours faded. Lozano tried the next three contacts on the left side, but Prupas didn’t notice any change. The surgeons unhooked the current, leaving the electrodes in place, then covered the holes and stitched her skin back over top. They dismantled the frame and gave her a general anaesthetic. While she was unconscious, they inserted a box, about the size of a small cellphone and holding a 3.5-volt battery, under her skin, just below her right collarbone. They threaded a wire, also under her skin, from the top of her head, behind her ear and down her neck to her chest, connecting the electrodes in her brain to the battery pack. The entire procedure took four hours. She woke up several hours later in a hospital room with a massive headache and a sore neck and chest.

The next morning, she felt her head under the bandages and noticed the two plastic covers that protruded from her skull. “What’s with the deer knobs?” she asked Lozano when he came to check on her the next day. He explained that the plastic caps covered the holes left in her skull. “You should brush up on your spackling techniques,” she joked.

When her husband came to see her, she was in excruciating pain. Over the next couple of days, Mayberg and the group of neurosurgeons made adjustments to her settings and kept asking her the same list of questions from the surgery. The first couple of times, she was in the hospital bed with the blinds drawn, feeling depressed. After they came the third time, though, she got up, opened the blinds, had a shower and got dressed. When they came in an hour later, she was sitting up playing Sudoku.

Later that week, her husband brought their daughters—one nine and the other almost four—for a visit. They were told that Mommy had undergone surgery to make her better. The girls asked how she felt and then spent the rest of the visit sharing a Kit Kat bar and making the automatic bed go up and down.

Four days after the surgery, Prupas went home. She didn’t feel as sad, but over the next few months, she had to get her settings adjusted at the hospital several times. One day, she became so hyper she hardly slept for three days, cleaning out most of the cupboards in her house and, at one point, talking to her visiting 89-year-old father non-stop for seven hours. As he sat on the couch, she stood in her pyjamas telling him about the memories she had of her childhood and how she still loves going to hardware stores because that’s when she was able to spend time alone with him. She went back to see her doctors, and after a change in the stimulation level, the mania died down.

She had taken a leave of absence from work to get used to her new machinery. She started getting out of bed more and more, reconnecting with friends and spending time with her husband and daughters. Her world became a lot brighter. On a walk with her husband soon after the surgery, she said, “Oh, look at that bird! Look at the colours on its wings!”

“That’s just a simple wren,” he said, surprised. “I didn’t realize how little colour you’ve been seeing.”

The stakes are high when you’re cutting holes in people’s heads. Mayberg and Lozano’s original hypothesis—that slowing down activity in area 25 might make depressed patients less sad—seemed to hold, even if the small clinical trial wasn’t conclusive. Out of the 20 patients who underwent the surgery, 11 of them were significantly happier after one year. After her surgery, Prupas was scoring seven on the Hamilton scale. Imaging tests showed how, for patients who had improved, the areas in the frontal cortex had started to light up with activity.

Lozano and Mayberg were pleased. With severely depressed patients, 55 per cent wasn’t a bad outcome. They published their results in the scientific journals Neuron and Biological Psychiatry, and the psychiatric community took notice. It wasn’t as if this surgery was going to overturn the pharmaceutical industry or put an end to talk therapy, but it showed an understanding of how the brain’s circuits are organized, and that neurosurgery could have a demonstrable effect on mental illness. “If you can’t talk it down, drug it down, shock it down,” says Mayberg, “then directly tune it.”

There’s one problem: nobody knows what “it” is, exactly. Despite our pharmacological, psychotherapeutic, and now targeted electrical war on depression, scientists still don’t agree on what causes it and whether it’s something we should even be trying to eliminate. While much of the thinking around depression is focused on brain chemistry or dysfunctional circuits, it’s difficult to distinguish the brain image of a depressed patient from someone who is just plain sad. That makes it hard to prove that all the symptoms used to diagnose depression—sadness, insomnia, lethargy, despair—are caused by a single disease. There’s no question that depression is “in your head”; the conundrum is what has control over that head. Enthusiasts of talk therapies argue (and have shown, in many cases) that we can regulate our brains using logic, and think our way out of despair. Some believe depression can even be useful, a healthy response to serious problems that we need to work through.

Proponents of antidepressants and electroconvulsive therapy believe that talk therapy alone isn’t sufficient. They argue we need to recognize that depression can be an extremely painful and damaging illness, and we should be doing everything to help relieve those suffering from it. Yes, everyone gets sad, but not everyone gets stuck in a pit of despair for years on end, for no apparent reason and with no way out. Not everyone stops getting out of bed for months or years, stops spending time with family and friends, and plans ways of killing themselves.

It’s not just sadness that’s the problem; it’s the inability to snap out of it. It’s like being forced to listen to the same song on repeat at full blast and having no power to turn it off. The idea behind DBS is to help dial down the sadness when nothing else is capable of reaching the volume control. “It doesn’t remove people’s ability to get sad,” says Mayberg. “It’s just that when they do, they don’t get stuck.”

People suffering from severe treatment-resistant depression will desperately grasp for any possible cure. In Lozano and Mayberg’s first DBS study on patients with depression, patient number three, while being interviewed as a candidate, promised she wouldn’t commit suicide before the experiment was over. She was one of the successful cases and insists the surgery has given her life back, but her desperation speaks to the vulnerability of the patients undergoing the procedure.

Lozano has seen many desperate patients. He says some of them would not consider death to be a bad outcome of the surgery—anything is better than their ceaseless misery. But he thinks this is all the more reason to push ahead and attempt to relieve them of depression, while being careful to make sure they’re well aware of the risks.

With each successful DBS surgery, Lozano and his team have become more convinced the electrical current is quieting the neurons in area 25. He also believes the current has an effect on the cognitive areas in the frontal lobe, which become more active as area 25 calms down. They aren’t sure about the link to heightened perception—why Prupas and several other patients started seeing more colour is on the long list of unknowns.

Thirty-seven depressed patients have now been set up with the DBS device at Toronto Western. Of course, the success of the studies could be due to patients’ sheer conviction that the surgery must be helping—i.e., DBS acting as a placebo. To prove otherwise, Lozano has received the go-ahead to test 40 more patients, this time in a double-blind study. He is also a consultant for a larger double-blind DBS study on 200 patients in the U.S. For these experiments, some of the stimulators are not turned on for the first six months, but neither the patients nor the supervising doctors know which ones. The results are expected to come out in 2012. Though she still consults on the studies at Toronto Western, Mayberg has moved to Emory University in Atlanta, where she is researching why some patients respond to the treatment and others don’t.

Although researchers claim that the effect of DBS is reversed by simply turning the current off, there is a possibility it could result in permanent long-term changes to cognition and personality

Since the technique has been shown to work for Parkinson’s patients and seems promising as a treatment for depression, Lozano is eager to explore new ways to make use of it. He will soon be releasing the results of a study on early-onset Alzheimer’s disease with six patients. (When a patient getting DBS surgery for an eating disorder started recalling vivid memories in the operating room, Lozano’s team had to speculate that the procedure could also have a positive effect on memory.) Not only does Lozano think the technology has the potential to help suffering patients, he’s also convinced it will give us a better grasp of what is going on in the complex networks of our brains.

In September 2007, a year and a half after her surgery, Prupas went back to work. She had more energy and was no longer having trouble getting out of bed in the mornings; she often woke up before her alarm. And she no longer felt like an imposter when she’d show up to work in a good mood.

It was hard to get used to her equipment; she can feel the wires running along her neck, the deer knobs on her head and battery pack bulging from her chest. She practises tae kwon do with her youngest daughter and has to be careful to avoid direct contact, in case her wires are wrenched. When she’s shopping at the mall, her battery pack sometimes sets off store alarms as she walks in.

Last May, she had a setback when her father died at age 92. The same week, Prupas’s cousin died of leukemia. She was devastated and took a week off work. She returned to the office during the summer, but months passed and she wasn’t feeling any better. She was terrified that her depression was back to stay.

When the psychiatrist in charge of monitoring her stimulator checked the settings, he said things didn’t seem right. He fiddled around with the hand-held programming device, then went to get another one.

“Oh!” he said. “I think your battery’s dead.” It was supposed to last from three to five years.

A month later, she went in for surgery to have the battery replaced. The stimulator started up again and she held her breath, waiting for the world’s colours to return.