The Drugs That Changed Our Minds

by Lauren Slater

  Once in the operating theatre, Mario was given a local anaesthetic. His head had been shaved, his brain targeted to millimetre precision by MRIs. Attached to his head was a stereotactic frame to provide surgeons with precise coordinates and mapping imagery. He’d undergone extensive neuropsychological testing to determine where to put the implants and to provide a pre-operative baseline of functioning. Surgeons choose the brain targets on the basis of results of past lobotomies and cingulotomies, noting which lesions brought with them relief. The problem is, all sorts of lesions have attenuated anxiety and depression in desperate patients, lesions to the left or right, up or down, here or there. Without a single sweet spot, the possibilities are disturbingly numerous. No one in his right mind would get on a ship if the captain wasn’t sure where to steer. But of course that’s the point. Psychiatric patients who have this surgery are no longer truly in their right mind. They get on board because this is their last lifeboat.

  At Butler, where Mario’s procedure was done, the doctors put the implants in the anterior limb of the internal capsule. Other neurosurgeons in the past, however, have favoured the cingulate gyrus and still others the caudate nucleus. These are parts of the brain that reside in the limbic system, which is itself folded up under the frontal lobes. Helen Mayberg’s target, called Area 25, the subgenual cingulate, is in front of the anterior limb, the same target for Benjamin Greenberg, one of Mario’s psychiatrists, and for Don Malone of the Cleveland Clinic in Ohio. ‘We chose the anterior limb’, Malone told me, ‘because that’s where the electrodes fit the best’, a slightly unnerving comment, revealing as it does the somewhat arbitrary nature of the way these decisions sometimes get made.

  Success

  After surgery, a deep brain stimulation patient will be retested with core questions in mind. Have the symptoms improved, deteriorated, or stayed the same? Since these electrodes were implanted, how has cognitive functioning changed, if at all? As of 2017, about seventy people in the United States had received deep brain stimulation to treat obsessive-compulsive disorder. In a sample of twenty-six patients that Greenberg conducted with colleagues worldwide, 73 per cent had a reduction of at least 25 per cent of their score on the Yale-Brown Obsessive Compulsive Scale. Some of those experienced a complete remission of symptoms of severe anxiety. Despite the success rate, and Greenberg’s efforts to reach out to clinicians and recruit patients for the clinical trial, the number of people undergoing the procedure has not grown quickly. ‘In the real world’, Greenberg said, ‘the group of patients meeting appropriate selection criteria is truly small.’

  As for depression, the story is different. There have been about four times as many patients who have undergone deep brain stimulation for treatment-resistant depression, with Helen Mayberg of Emory University in Georgia participating in many of these surgeries. Mayberg’s earliest deep brain stimulation procedures, performed on six patients, took place in Toronto. Mayberg placed the electrodes in the white matter of Area 25, believing that this region played a critical role in modulating negative mood states. Supporting her hypothesis is the fact that SSRIs and other antidepressant medications appear to work by decreasing activity in Mayberg’s targeted area. All six of her patients reported ‘acute effects’ while in the operating theatre and under the influence of the current. Among the descriptions was a feeling of ‘lightness, a disappearance of the void’. The room in which the patients lay seemed suddenly brighter to them, their vision sharper. At home, family members noticed increased energy, a renewal of interest in activities that had before seemed impossible, and the ability to plan and to initiate, both of which become dulled by depression. At the one-month follow-up, two of the six implanted patients no longer met the criteria for depression; after two months, five of the six patients had improved. At the six-month follow-up, Mayberg found that a strong antidepressant reaction continued in four of her six implanted subjects, a two-thirds response rate which suggested that deep brain stimulation could be an effective intervention for severe treatment-resistant depression as well as obsessive-compulsive disorder, an ‘extremely encouraging’ result, according to Mayberg.

  Her study was expanded to a total of twenty patients, all of whom had treatment-resistant depression and who were followed by researchers for a one-year period. In this larger study, 60 per cent of patients responded to deep brain stimulation after a six-month period, and 55 per cent of patients were responders at one year. After three years of chronic stimulation, researchers found a 60 per cent response rate and a 50 per cent remission rate. Encouraged once more by her results, Mayberg continued to implant people with severe treatment-resistant depression. Beginning in 2008 she broadened her sample to include those suffering from bipolar II depression as well, and initially implanted thirty such patients.

  Area 25

  Mayberg has been studying the brain for decades, trying to find the circuit or circuits responsible for depression. She started by looking at the brains of depressed Parkinson’s patients using PET scans and from there went on to people without Parkinson’s but with severe depression. She has homed in on what she calls Area 25, a region in the brain that shows enhanced activity when a person is depressed, along with a decrease of activity in the frontal and limbic regions, brain areas that allow us to reason, emote, remember and learn. When Mayberg studied people whose depression improved on an antidepressant, she found that their depressed frontal-lobe activity rose while the activity in Area 25 dropped. She researched non-depressed subjects who were asked to think about sad memories while undergoing a brain scan. Her results were incredibly consistent. Non-depressed subjects ruminating on depressing thoughts had a decrease of activity in their frontal lobes and an increase of activity in that pesky little Area 25, which clearly plays a significant role in whether or not we find joy in our day-to-day existence. Mayberg believes that in treatment-resistant patients, activity in Area 25 stays high and activity in the frontal lobes stays low despite our usual array of medicines and shock. ‘If we couldn’t talk depression down, couldn’t drug it down, couldn’t shock it down,’ she said, ‘then I believed we could go directly to Area 25 of the brain and tune it down.’ Given the fact that she is placing electrodes in a region of the brain she has been studying for decades, Mayberg does not consider herself a risk taker. She has done, so far, more than two hundred implantations, with ever-increasing precision and, therefore, a higher rate of clinical success.

  Recently she has turned her attention towards precisely how deep brain stimulation achieves its outcomes. She is not a localist when it comes to thinking about the brain. She does not believe, for instance, that overactivity in Area 25 is simply and solely responsible for our down days. ‘I never thought depression was just about Area 25,’ she said. ‘It’s always been about communication between multiple brain regions.’ Mayberg’s sense of Area 25 is that it’s like a ‘junction box’ for the parts of the brain that work together to mitigate the effects of negative mood and depression.

  In addition to the more than two hundred implantations in which she has participated, she knows of ninety other implantations that have focused on Area 25 and roughly eighty that have focused on different brain regions. One, which Mayberg was not a part of, involved a middle-aged Dutch patient who, in 2013, had endured twenty-two years of psychiatric treatment before deciding to try deep brain stimulation for his addiction to heroin. He underwent the surgery at the University of Amsterdam, where researchers drilled holes on either side of his skull and inserted long probes with electrodes attached at their ends. The researchers positioned the electrodes in his nucleus accumbens, a region of the brain thought to be responsible for addictions and their associated cravings. After the electrodes were placed, connecting wires were run to battery packs embedded in his chest. When the electrodes were turned on, they emitted constant current, with the goal of disrupting the brain circuit that researchers hypothesise is involved in addiction. In the beginning the electrodes actually appeared to increase the patient’s crav
ing for heroin – he practically doubled his dose – but once researchers were able to adjust the electrodes and the timing of the pulses they emitted, the man experienced a real diminishment of his cravings, and his use of heroin, while it did not stop entirely, dwindled to nearly nothing.

  The Dangers

  In addition to the now roughly 150,000 people who have been treated with deep brain stimulation for movement disorders, as of 2017 more than five hundred people around the world had received experimental implants to treat various psychiatric disorders. On the one hand, one could argue that a mere five hundred people worldwide in the last fifteen or so years does not indicate a treatment that’s very promising for being used with any frequency, especially when one considers how much people have to go through beforehand simply to be eligible for the procedure. However safe psychosurgery is, then, some may feel that it does not present a real, viable alternative to psychotropic drugs, at least not for very many people. On the other hand, we would do well to remember that fully 30 per cent of depressed patients do not respond to any antidepressant treatment whatsoever. That’s an awful lot of people. That translates into not only millions of pounds in lost productivity in a society but also, at its most extreme, a tragic number of suicides. Seen in this light, deep brain stimulation for psychiatric disorders achieves a real relevancy. While it is not common right now, with more research it could become so. It offers an alternative, and with that a slice of hope, to those whose suffering continues unabated.

  Unfortunately, while many times the news is good, there are also plenty of patients who have experienced adverse events: suicidal thoughts and feelings, completely unmotivated homicidal rage, or its opposite, extreme apathy, or sleep disorders, a worsening of depression, sudden panic attacks. One patient who participated in the Broaden Trial for Deep Brain Stimulation at UCLA experienced such severe side effects he nearly lost his life. Watching television one night, he suddenly got up and poured boiling water all over himself, acting as if he were an automaton. Another time he felt compelled to slash his body with a knife, laughing hysterically as the wounds dripped blood. This patient, who asked that his name not be used, had the device removed but feels that his brain has been irreparably harmed in the process. ‘I wrote an email to [Emory University], saying, “You’re involved in studies of DBS effects. So, study me. There are people falling off the boat and you’re not circling back to rescue them. Circle back and see what’s going wrong.” I didn’t hear back.’

  Doctors are understandably anxious to separate deep brain stimulation from psychosurgeries of the past, when ice pick-like instruments were thrust up through the eye sockets, and blades swished through the brain. While the finer points of brain functionality are still hazy, the surgery itself is conducted with far more precision and technological finesse than Moniz or Heath could ever have hoped for. Yet some facts remain the same. There is a gruesome quality to any brain surgery. The drill is huge; its twisted bit grinds through bone, making two burr holes on either side of the skull.

  The drilling into Mario’s skull was over in a few minutes. Surgeons then took a couple of hours to get the implants in place. As is the practice with brain surgery, Mario remained awake throughout and he was repeatedly questioned: ‘Are you okay? Are you alert?’ His head was held in place by a steel halo that screwed into his skull bone in six places. The surgeon threaded two wires just 1.27 millimetres thick through the burr holes on which the tiny platinum-iridium electrodes were strung. Picture it as ice fishing. There is the smooth bald lake, the hole opening up, dark water brimming around the aperture and then the slow lowering of the line, the searching, searching, for where the fish live.

  Mario felt none of this because the brain itself, the seat of all sensation, has no sensory nerves. Next the surgeons implanted two 5 × 7.5-centimetre (2 × 3-inch) battery packs beneath each of Mario’s clavicles and ran wires from the packs (the batteries of which have to be replaced every few months) up under the skin of his neck to the implants. The packs, controlled by a remote programming device, power the electrodes when the doctor flips the switch and adjusts the current. Mario lay there, waiting.

  He would have to wait a while. Psychiatrists do not turn the electrodes on right after surgery. That happens later, when the swelling in the head has gone down, when the bruised brain has had a chance to heal itself and the burr holes have been sealed with new skin. At that time Greenberg would pass a programmer over Mario’s chest, and the wires would leap to life.

  Poised for a Comeback

  With the re-emergence of neural implants, the only malleable and reversible form of psychosurgery, and the development of high-tech imaging devices and stereotactic equipment that allow for impressive precision, psychosurgery is poised to make a comeback, to step out of the pall cast by the early lobotomisers into a circle of respectability and, more importantly, possibility. Now a patient can potentially reap the very real benefits bestowed by psychosurgery without having to undergo the dulling personality changes associated with broad frontal-lobe ablation and the irreversibility of a lesion. If this seems a far-fetched notion, it’s good to remember that, at one time, so did the first open-heart surgeries and organ transplants, procedures that are now performed daily.

  But psychosurgery’s potential comeback, its growing social acceptance, is not due only to the new flexibility of its treatments. It’s also likely rooted in our growing collective realisation of the limitations of drugs and our frank disenchantment with the companies that make them. Both in the United States and the UK, we spend a huge fortune every year on psychiatric medications, even though we now know that SSRIs come with serious warnings and offer no relief at all to 30 per cent of users. We know that the companies producing these drugs claim that their high cost to consumers is justified by the research and development that is necessary, and yet, as we’ve seen, few if any truly original drugs have been introduced in the past few decades. Most so-called new drugs are what the industry designates ‘me too’ drugs, slight variations on the successful drugs already on the market, with an eye towards adapting them into one that can become a profit centre. What’s more, we’ve learned that drug companies sometimes selectively publish only the studies with favourable results, a serious lie by omission. We also know how drug companies court doctors at conferences by paying for posh hotel rooms and other high-end goodies. We have seen companies push their sales reps to sell medications – Pfizer’s gabapentin sold under the brand name Neurontin comes to mind – for uses that are almost entirely untested. How can you trust a tablet if you can’t trust its progenitor?

  When psychosurgery first came into vogue in North America, Walter Freeman and his cohort performed assembly-1ine lobotomies, going from clinic to clinic plucking patients who kicked and screamed their way to the operating table, sometimes even renting out hotel rooms for the procedure. There were no internal review boards, no ethics committees and no solid scientific studies backing the work itself. Most importantly, there was no concern with patient consent. Rather there were simply fervent testimonials from patients like Harry Drucker, who claimed, in 1938, ‘Psychosurgery cured me.’ And it did cure some people, or at least tweaked their lives for the better, but the cost was sometimes huge, and the damage to human dignity could be appalling. Some psychosurgery patients were made incontinent by the procedure, or worse, they lost what Moniz called their ‘vital spark’.

  Contemporary psychosurgeons fervently want to sidestep the excesses of the early lobotomisers such as Freeman, and have exerted tremendous efforts to separate themselves from their shady forebears. Much as today’s proponents of psychedelic drugs are aware of the importance of public perception, psychosurgeons are conscious of the need to project a polished image so as not to be viewed in a dark or suspicious light. It is true, on the one hand, that it is impossible to use animal testing to gauge whether deep brain stimulation can effectively treat depression and anxiety, which means the only guinea pigs available are people like Mario. But in order for Ma
rio to be eligible for neural implants, he not only had to have tried and exhausted every available pharmacological option at either optimal or above-optimal doses, but also had to have undergone at least twenty hours of behaviour therapy and submitted to multiple rounds of ECT. He had to understand the risks and implications of the procedure and provide his consent. His case was reviewed by three different review boards. The US Food and Drug Administration, which regulates medical devices, gave its blessing to this experiment. ‘We don’t want to repeat the mistakes of the past,’ said Greenberg, who in particular seemed haunted by the circus sideshow history of lobotomies. ‘We want to be sure this therapy is not only not used indiscriminately, but that it is reserved for the group of people who have failed trials of everything else.’

  Why so much precaution? After all, when you take a drug, you are arguably altering your brain in ways at least as profound as, if not more than, with neural implants. And when you take combinations of drugs, as many mentally ill people do, you put yourself at risk for medication-induced Parkinson’s and a raft of other serious outcomes. ‘That’s true,’ Greenberg told me. ‘Look, I agree with you.’ But his agreement didn’t cancel out his caution. For him, the past did not feel far away.

  Getting in Tune

  After three weeks, Mario went back to Greenberg’s office. The men sat facing each other, Greenberg with the programmer on his lap. He snapped open the laptop-like device and, using a hand-held controller, activated the implants. Mario remembered the exact moment they went on. ‘I felt a strange sadness go all through me,’ he said, and recalled Greenberg’s fingers tapping on the keyboard, adjusting the current, pulse duration and frequency. After a few taps, the sadness went away. ‘With DBS the thing has a certain immediacy to it,’ said Steven Rasmussen, Mario’s other former psychiatrist. ‘You can change behaviour very, very rapidly. On the flip side of it there’s a danger too. This really is a kind of mind control.’