The Drugs That Changed Our Minds

by Lauren Slater

  The good news is that if we may soon possess the ability to medicinally edit our histories, we also, simultaneously, may be able to do the opposite. While ZIP can nuke a memory, there’s a good chance that PKMzeta can enhance it, a possibility that is only becoming more necessary. Barring a cure for Alzheimer’s, by 2050 millions of people worldwide will suffer from this disease or some other age-related type of dementia. Neuroscientists are brainstorming ways to prompt cells to make more PKMzeta, the theory being that if the molecule is available to the brain in larger amounts, neuronal memory circuits might not decay. ‘It’s just an idea, at this stage,’ Sacktor admits, but one can hear the excitement in his voice – and in the field.

  The current drugs on the market for Alzheimer’s just treat its symptoms rather than blocking the actual mechanism for the disease. At best they can only slow the process of memory loss for six months to a year. It’s probably for this reason that the discovery of PKMzeta is so exciting. If scientists can figure out a way to make PKMzeta into a drug that causes the brain to produce more of the molecule, then we just might have, for the first time, a way of treating a devastating disease that haunts a huge population.

  And scientists are doing more than searching for drugs in this expedition into memory. Recently, a technique called deep brain stimulation (DBS) has shown promise in treating people with memory disorders like Alzheimer’s. Gwenn Smith, director of the geriatric psychiatry and neuropsychiatry division at Johns Hopkins, said that although the sample size of her study was only six, and it was designed mainly to establish safety, ‘we don’t have another treatment for [Alzheimer’s] at present that shows such promising effects on brain function.’

  Oddly, the idea of using DBS for memory disorders came about when scientists tried to use it to treat an obese man by implanting the electrode in the region of the brain thought to be associated with appetite suppression. The obese man did not get any thinner but, surprisingly, his memory expanded significantly, inspiring researchers to look towards electrical currents as well as chemicals in their search for dementia treatments. In a later study led by Andres M. Lozano, chair of the department of neurosurgery at the University of Toronto, an electrode was implanted in the brains of subjects suffering from Alzheimer’s. The electrode emits continuous electrical impulses to the brain, and PET scans show that in patients with mild forms of Alzheimer’s, there was a sustained increase in glucose metabolism. That finding was significant because a decrease in glucose metabolism accompanies Alzheimer’s disease, which means that the electrodes and the current they emit are able to turn around one of the primary symptoms of this devastating syndrome.

  Ours is of course not the first generation to be preoccupied with forgetting. In the sixteenth century, Jesuit missionary Matteo Ricci composed his Treatise on Mnemonic Arts, in which he explained the method of associating ideas with images and then locating those images in ‘rooms’, the result being a ‘memory palace’ that promised preservation of what is in fact ethereal human experience, made not of mortar but rather of gossamer. The memory palace is still used, especially by so-called memory champions, who train themselves to recall huge amounts of mostly arbitrary information (a sequence of cards, for instance) to compete in contests held around the world.

  But you don’t need to train for memory championships in order to help preserve your memory. Studies have shown that lesser efforts, including the much-touted crossword puzzle, can make a difference in helping us recall events. And more recent research suggests that continuing to learn new skills – playing an instrument, speaking a foreign language – into old age may be the best tonic for avoiding a misty mind. These new skills may help build new neuronal pathways in a brain that remains plastic until death. Learning keeps us curious – it’s not the other way around – and curious people are more likely to have strong social networks (after all, you want to share what you’ve learned), which may also help ward off age-related dementia.

  In the end – and of course there is an end, which we know only too well – we will succumb to the challenges of ageing, no matter how many of these advancements we make. It is this fact perhaps that drives the field of memory research, into which huge amounts of funding have lately been poured by a society that knows what lies in wait. There may very well come a time when purified molecules are made into medicines that can corral your fast-fading past and your problem-solving skills even as, on the other side of the line, ‘editing’ medicines can strike traumas from the mind. If or when this actually happens, we, as Homo sapiens, tool-building creatures for thousands of years, will have added significantly to our armamentarium. The question is whether we’ll have the wisdom and savvy to know how to use these tools well. Given that, since at least the Industrial Revolution, humankind has shown it has a very hard time being responsible with its own inventions, one might say the outlook is grim, even while the science shines at its most exciting edge.

  9

  Deep Brain Stimulation

  Who Holds the Clicker?

  Prosthetics for the Brain

  Mario Della Grotta was thirty-six years old when he first spoke with me, in 2005. He had a buzz cut and a tattoo of a rose on his right bicep, and wore a gold chain around a neck as thick as a thigh. He was the kind of guy you might picture in a pub in a working-class neighbourhood, a cigarette wedged in the corner of his mouth and a shot glass full of something amber. He seemed, at first appearance, like someone who swaggered his way through the world, but that wasn’t true of Mario. Until four years earlier, his attempts to ward off panic meant that rituals could consume eighteen hours of every day. He couldn’t stop counting and checking. Fearful of dirt, he would shower again and again. He searched for symmetries. Had he remembered to lock the car door? Had he counted things up correctly? His formal diagnosis was obsessive-compulsive disorder, which the French, with a phrase that aptly gets to the existential core of worry, call folie du doute, a clenched demonic doubting that overrides evidence, empiricism and plain common sense. For Mario, his entire life had been crammed into a single serrated question mark.

  For fourteen years he had suffered anxiety so profound and so impervious to other treatments that finally his psychiatrists, at Butler Hospital in Providence, Rhode Island, suggested psychosurgery, or what, in the current medical climate, has often been labelled more neutrally as neurosurgery for psychiatric disorders, to avoid the stigmatisation associated with lobotomies and, their newer version, cingulotomies. Older forms of psychosurgery have been used to treat anxiety disorders like obsessive-compulsive disorder and its close cousin, depression, since the mid-1930s. Back then, any benefits people derived from the knife were perilously balanced against the flattening of feeling and the blanching of personality that accompanied the reduction in psychiatric ailments. This, however, may no longer be true. Tiny implants for the brain, originally developed in the 1990s to treat movement disorders in Parkinson’s patients, are now being used on some of the most intractable but common psychiatric problems: anxiety and depression. Even two decades after they were first introduced, these neural pacemakers are still highly experimental and available only to patients who have been failed by every other treatment. Nevertheless, they suggest a time in the not-too-distant future when there may be options other than drugs available to serious sufferers of both disorders.

  Unlike psychosurgeries of the past, this new procedure does not necessitate the destruction of neural tissue, the cutting of whole nerve tracts between here and there, like the taking down of phone lines. In place of that older method, surgeons are installing what amount to prosthetics for the brain: implanted electrodes. When correctly programmed, these electrodes – usually eight in total, four per hemisphere – emit a constant electrical current that, theoretically, jams pesky brain circuits, the ones that say you’re worthless, you’re worthless, you’re worthless or oh no, oh no, oh no.

  This was an idea that made sense to Mario. His experience of the illness was one terrible loop the loop. He said ye
s to the surgery, in part because he knew that if he didn’t like the neural implants, he could simply have them switched off. And so Mario became one of the first American psychiatric patients to undergo this procedure.

  Psychosurgery’s Earliest Pioneers

  Neural implants are not new; they are merely being revived. The first researcher to confirm that brain function, and by extension dysfunction, could be localised was the French neurologist Pierre Paul Broca, in 1861. Autopsying a patient who could say only one word – ‘tan’ – Broca identified organic damage to what he theorised was the speech centre. But it took seventy-five years, and a Portuguese neurologist by the name of Egas Moniz, to take Broca’s theory of speech localisation and apply it to madness. Moniz, who would win a Nobel Prize for his invention of lobotomy, went through the halls of Lisbon’s insane asylums looking for patients suitable for the frontal-lobe surgery, which Moniz’s surgical colleagues performed, first via ether injections, with the alcohol essentially burning away the brain, and later with a leucotome, a device shaped like an ice pick, with a retractable wire to whisk out grey matter. It was a procedure for which Moniz had originally gotten the idea after a neurology conference in London, when he observed a chimpanzee that had been made docile by having its frontal lobes removed.

  In 1936, shortly after the first lobotomies were performed in Lisbon, the procedure arrived in the United States, where it was adapted with all-American vigour, so much so that by the late 1950s, more than twenty thousand patients had had lobotomies and the surgery was being used to ‘cure’ everything from mental retardation to homosexuality to criminal insanity. Its most fervent promoter, Walter Freeman, eventually performed surgeries on multiple patients in an assembly-line fashion. Post-surgery, it was common for lobotomy recipients to be perpetually placid, carbon copies of themselves, faint and fuzzy.

  Not many years after Moniz and his protégés began sawing through skulls, Robert Heath, among the first researchers to experiment with the use of implants in the treatment of psychiatric cases, was studying an alternate form of psychosurgery – deep brain stimulation, or DBS – at the Tulane University School of Medicine in Louisiana. Heath took patients culled from the back wards of the state’s mental hospitals, slit open their skulls and dropped electrodes down deep inside them. He implanted more than a hundred electrodes in patients over a period of six years back in the 1950s, when psychosurgery was still an industry. With the use of a hand-held stimulator, Heath discovered that electrodes placed in the hippocampus, the thalamus or the tegmentum could produce states of rage or fear, while electrodes placed in the brain’s septal area and part of the amygdala could produce feelings of pleasure. Heath ‘treated’ a homosexual man (identified as B-19) by firing electrodes into his pleasure centre while having him watch films of heterosexual encounters, and within seventeen days B-19 was a newly made man, proving it to Heath by sleeping with a female prostitute Heath himself had hired for this demonstration.

  Whether the experiments were ethical or unethical, the motivations noble or ignoble, neural implants were significant right from the start, not only because they provided hope for the clinically distressed, but also because, by confirming Broca’s theory of localisation, they began to change the way we collectively thought of the brain. Though he was misguided in some ways, Heath and researchers like him demonstrated that you could prod a tiny piece of cortical tissue and get a specific response, a taste of prune in the mouth, say, or a smear of yellow in the air. This was a major paradigm shift. In earlier centuries people had believed that thoughts and emotions were carried through the head via hollow tunnels, but now the brain became a series of discrete segments, real estate, if you will, some of it swampy, some of it stately, but all of it perhaps subject to human renovation.

  Unlike lobotomies, those renovations were adjustable and did not have to be permanent. In a public demonstration at a bullring in Spain, another researcher, Yale’s José Delgado, provoked an implanted bull with a matador’s red cape. The enraged animal raced towards him, head down, stopping only at the very last second, when Delgado, with the push of a button, fired the implant and the bull, its aggression eradicated, loped away. The potential uses and abuses of neural implants were obvious: you could control people, and perhaps you could effectively wipe out violence.

  By the late 1960s, implants appealed to those in the medical and law enforcement communities who believed that urban riots were born not of poverty or oppression but of ‘violent tendencies’ that could be monitored or altered. The US Law Enforcement Assistance Administration handed out large sums to researchers studying implants and other behaviour modification techniques. Under one such grant proposal, in 1972 Louis Jolyon West of University of California, Los Angeles (UCLA) was to form the Center for the Study and Reduction of Violence and conduct research at various state prisons. The plan was to take inmates, implant them and then monitor their brain activity after discharge. When a Washington Post reporter investigated this scheme, he discovered a precedent: in 1968 officials at California’s Vacaville Prison performed electrode surgery on three inmates (including a minor) with the assistance of military doctors.

  A series of Senate hearings in the mid-1970s brought these and other government forays into behaviour modification to the public’s attention, and the public was more than a little perturbed at the notion of mind control as a viable solution to social injustice or crime. Meanwhile, the CIA was rumoured to be experimenting with implants to break down prisoners of war and discredit rebellious citizens (Heath admitted he’d been approached by the agency), and Michael Crichton’s novel The Terminal Man, in which the main character receives implants to control his epilepsy and turns psychotic, became a bestseller. All this, concomitant with the rise of the antipsychiatry movement, ensured that neural implants fell into disrepute.

  The Sweet Spot

  Implants were resurrected, however, in 1987, when a French neurosurgeon, Alim-Louis Benabid, operating on a Parkinson’s patient, discovered that if he touched the patient’s thalamus with an electrical probe, the patient’s shaking stopped. A decade later, neural implants were approved by the US Food and Drug Administration (FDA) for treating tremors, dystonia and some forms of pain, and 150,000 patients worldwide have since been implanted for movement disorders.

  But something else was being observed as well in those implanted Parkinson’s patients. Many experienced positive mood changes, or felt their worries go away. It appeared the circuits that controlled their physical shaking were somehow connected to mental quaking as well. Remember how iproniazid, the precursor of the MAOIs, turned out to make tubercular patients happier and more energised in addition to curing their tuberculosis? ‘It’s how a lot of medicine happens,’ neurosurgeon Jeff Arle of the Lahey Clinic in Burlington, Massachusetts, told me. ‘It’s by extrapolating backwards. Someone then has to have the chutzpah to say, “Gee, maybe we ought to try this for certain psychiatric problems.” You believe it’s worth the risk. You don’t know until you try it.’

  By the mid-1990s a small international group of psychiatrists, neurologists and neurosurgeons was considering using the implants for the treatment of mental illness. One of their primary questions is ‘Where, precisely, in a psychiatric patient would one put the electrodes?’ While Heath and Delgado had demonstrated that you can crudely trigger generalised states of affect – like terror and rage – by stimulating areas of the limbic system, no one had so far found those millimetre-sized snarls of circuitry where researchers hoped the more nuanced forms of mental health, or illness, resided. ‘We want more than anything’, said Helen Mayberg, a leading deep brain stimulation for depression researcher at Emory University, ‘to find that sweet spot, and go there.’

  If finding the exact loci of depression or obsession proves to be problematic, couldn’t scientists simply override people’s psychic pain by stimulating their pleasure centres? That would be too crude, neuroscientists believe, akin to getting patients high. Harold Sackheim, of the New York Sta
te Psychiatric Institute, added, ‘If you can get relief without invasive surgery’ – this procedure does come with a small chance of haemorrhage or infection – ‘you might want to pursue that other avenue first.’

  And just what is that other avenue? Tablets, of course. And we have pursued that avenue. For all our consumption, though, the risk of suicide associated with antidepressants is now considered serious enough for adolescents that the US government has mandated black box warnings on labels (like those on cigarette packets) alerting doctors and patients to the dangers. Equally compelling are data that suggests antidepressants leave a staggering number of users without any relief at all. ‘We have searched and searched for the Holy Grail’, said depression researcher William Burke of the University of Nebraska Medical Center, ‘and we have never found it.’ And that’s true. In its tracking of the remission of symptoms for people suffering from depressive disorders, the US National Institute of Mental Health reports rates of 31 per cent after fourteen weeks and 65 per cent at six months. But according to John Halpern, even of the 65 per cent who are helped, only 30 per cent of those, meaning fewer than 20 per cent of patients taking the drugs, feel robust relief. The rest get some symptom relief and limp along. Doctors advise the limpers to switch or combine drugs, but between 10 and 20 per cent of patients never improve no matter what medicines they take.

  Mario, who’d tried some forty different combinations of medications, knew this all too well. He wanted a shot at the ordinary, a lawn he might mow just once a week. The ability to endure the mess and touch of children. He decided the implants were well worth the risk.

  The Surgery

  On a Monday in early February 2001, as Mario woke up next to his pregnant wife, neurosurgeons at Butler Hospital in Rhode Island were getting ready for his operation. A week or so before, in preparation for his surgery, Mario had gone to a tattoo artist and had the Chinese sign for ‘child’ inked into his wrist. ‘If I didn’t make it, if I never got to see my daughter be born, then at least I would have this tattoo,’ he told me. ‘Child. With it on my skin, I knew I could go to the grave with some meaning.’