Hello I Want to Die Please Fix Me

by Anna Mehler Paperny

  (“Yeah, I know there are a lot of -otomies out there,” Dougherty says when I butcher all these terms yet again. “You’re doing great.” You can thank me when this comes up at your pub’s next trivia night.)

  As with almost every depression treatment right now, you don’t know whether burning holes in your brain will alleviate your depression until you try it.

  Mass General does two to six of these surgeries for depression a year. To be eligible you’ve got to have exhausted all other treatments, but Dougherty figures it’s hugely underused. Many patients and doctors aren’t aware it exists as an option. The sordid history of lobotomies doesn’t help, though he assures me again that “this couldn’t be more different than what was done in the past.” Sure, I guess. Although knowing the area surgeons target was originally chosen at random—even though they’re uber-precise about it now—is understandably freaky.

  * * *

  —

  SO THE GOLD standard for depression treatment is a combination of psychotherapy—whose clinical effectiveness is seldom regulated—and a handful of meds that have gotten more tolerable but no more effective in the five decades since their antecedents were discovered by accident. When that doesn’t work, the best fallback is a memory-thieving controlled cranial seizure that terrorized asylum patients seventy-odd years ago. The only once-popular treatments we’ve abandoned completely are insulin comas and the lobotomy. Even hyperthermia may be coming back into vogue.10 Therapeutic saunas for everyone.

  It’s worrying, destabilizing, irrationally guilt-inducing to know you’re running out of options for the thing ruining your life. On top of everything else I began to feel like a failure at treating my own depression. Was I taking these pills wrong in some way? Was I fundamentally metabolically flawed? It didn’t help that there seemed so little method to the madness of drug selection: I was on lithium, despite my lack of mania, then off it, then back on four years later; we tried half a dozen different serotonin, norepinephrine, dopamine reuptake inhibitors. Antipsychotics; an anxiolytic; an anticonvulsant. So many cognitive behavioural therapy thought records I could do them in my sleep. I did thought records for thoughts I hadn’t even had yet. I followed every directive, but despite myself lost hope in the prospect of a future free of paralytic despair.

  We keep smacking up against the limitations of existing options. Our approach to the brain, the methodology underlying every existing approved treatment for depression, has all the sophistication of apes poking a Space Odyssey monolith. Which leaves us fumbling in the dark to comprehend a disease that’s been on society’s radar for centuries, and to get people in the grips of one of the single biggest public health burdens in the world into treatment that works.

  14

  Brainiacs

  A pickled brain is cartoonishly brain-y. Like opening up someone’s chest to find a pulsing fuchsia emoji heart. It feels sea-creature slippery to the touch. Firmer, less spongy than you’d expect for a bodily organ. Its bloodless putty-coloured maze of bulgy folds and creases is mesmerizing but it’s clear the thing I’m holding is an inert facsimile of a human’s multi-billion-celled control centre.

  I don’t know anything about science or medicine but if I was going to learn everything I could about this enemy, my illness, I knew I would have to go to the brainiac epicentres. So I went to the National Institute of Mental Health (NIMH) Human Brain Collection Core in Bethesda, Maryland—one of the most major brain banks out there—to hold, with gloved hands, pieces of pickled brain and answer a fundamental question: What can you learn from a dead brain?

  The formalin solution reeks of sour yogurt and liquefied rubber. Don’t splash it on your clothes or skin. Latex gloves are mandatory. It’s getting rarer to pickle a brain this way: pickling degrades RNA, the ribonucleic acid you need to tease out epigenetic abnormalities. But formalin fixing is good for preserving cells’ physical integrity, if you’re into counting neurons’ starfish-armed dendrites to get a sense of the organ’s multitudinous connections. Flash-freezing a brain makes cell contents expand and burst through cell membranes the way forgetting your wine in the freezer makes it expand and burst through glass bottles. So sometimes you pickle and sometimes you freeze, depending what your plans are for this brain.

  I discover the bulgy folds are gyri; the grey creases, sulci. While in your skull, your brain’s encased in that protective vein-mottled swim cap of a dura, but you generally peel this off early in the dissection process.

  Sliding gloved fingers over gyri, peering at brain bits on a wheeled table, I felt like a mad scientist. I also felt hungry: coronal slices look like cauliflower cut stemwise.

  The most important parts of brain analysis are way less sexy-looking to the layperson. You break each pertinent flash-frozen section into tiny fragments—sometimes through pulverizing but often by sending it to precision labs that’ll isolate individual cells. “If your question is how this particular cell expresses its particular genes, [pulverizing] is not the best method,” Barbara Lipska warns me.1 Trust her: as the Human Brain Collection Core director, she knows. A small (but taller than me) and quietly fierce woman with short hair she wears under a kerchief-bandana—she is in remission for brain cancer, an against-the-odds battle she won and whose scars she’s written a book about—she ushers me through her lab and shows me how it’s done. You extract miniscule pieces and ship them out in tiny vials to researchers around the world. You use a microtome—like the world’s coldest, priciest, precisest prosciutto-slicer—to cut vanishingly thin translucent postage-stamp sections of brain you can then mount on a slide for staining or microscopy.

  One of the toughest jobs at a brain bank is the ask. Way before tissue hits pre-cooled metal, before the brain enters the lab to be cryoprotected, frozen, dissected, analyzed, someone needs to phone grieving families in the hours immediately after their loved one has died and ask them to donate their next-of-kin’s brain to science. I do a lot of awkward cold calls, but this one would be especially tough.

  I find Jonathan Sirovatka in his tiny office, retro by comparison to the bank of computers in the adjoining lab used to search and sort thousands of brain samples by dozens of variables. He’s introduced to me as an expert medical lab technician but he wields expertise in all parts of the brain acquisition process and has permutations of his script pinned to the wall and shelf space near the desk phone.

  Here, every morning, he talks to medical examiners—the trained professionals who perform postmortems. They call him or he calls them and they tell him what they’ve got.

  “The investigators read me the circumstances of death, the history of the person, and I make a snap judgment based upon what I hear, whether they’d be a good candidate. And most are not good candidates.”2

  You can’t accept just any brain for research. Any number of maladies and medical mishaps can render brains unusable. They are so heterogeneous even within diagnoses, labs do their best to limit as many confounding factors as they can.

  And of course, you want it fresh. Generally, you don’t want a brain from someone who’s been dead for seventy-two hours or more. But everyone decomposes differently.

  “Let’s say a person was shot in a Washington alley and was lying there for ten hours in the middle of the summer, a hundred degrees,” Barbara Lipska tells me as we sit in her office down the hall from super-cooled ice chests full of brains. “Another person is shot in the same alley in the winter and fell into the snow headfirst. Which brain would be better for us to do molecular studies? Obviously, the second one.”

  Between 10 and 20 percent of the cases that Jonathan Sirovatka gets from medical examiners meet those standards. Then comes the hard part. About three-quarters of people shut him down a couple of paragraphs into his script. Right around the bit about asking for the organ underpinning their deceased loved one’s consciousness.

  “Most families are in shock: it’s usually within twenty-four hours of the death,” he says. “I get all ranges of reactions. Most people—I�
�d say 85, 90 percent—are polite….But on occasion I get cursed at and yelled at and hung up on. ‘How dare you be calling me at this time?’ ‘I’m grieving.’ ‘You need to have respect: I’m trying to lay my loved one to rest and you’re asking for a piece of them? How dare you.’”

  He isn’t supposed to take a side. He can’t cajole people into contributing to what could be life-altering research for people they’ll never meet, who may not yet be born.

  The next of kin has about two hours to decide. Sometimes less. If they say yes, they go through a recorded conversation confirming they’re making the donation decision freely, knowing they get no direct benefit and that all identifying information will be kept confidential. Then Jonathan Sirovatka drives in a government vehicle to the medical examiner’s office to transport the brain in a plastic bag inside an ice-laden insulated soft-sided cooler you’d use for a picnic or a six-pack. He’s never been pulled over or been in an accident but brings a document authorizing him to transport organs across state lines, just in case. The brain’s on NIMH’s campus ready for dissection six hours after that initial call to the medical examiner’s office. Sometimes sooner. And then you dissect.

  The instruments look deceptively simple: a scalpel; a long-ish rectangular knife; tongs used primarily for handling the colder-than-ice tray that holds specimen sections. They slice the brain into forty-five meticulously cut pieces, dab them with a tissue to remove most of the blood and take a series of organ mugshots from front, back, side angles. They note any abnormalities before the pieces go into forty-five marker-labelled, bar-coded resealable plastic bags like cascading sizes of Ziplocs that are then secreted in huge high-tech chest freezers kept somewhere between -74 and -80 degrees Celsius.

  It’s a little traumatizing at first, Sirovatka says. He was sixteen the first time he walked into a brain dissection and the supervisor said, “Come on over, look at this. We have a beautiful brain here.” There is such a thing as becoming blasé, he says. So straddling the emotional family side and the clinical dissection side helps him remember these masses of tissue were vital parts of human beings. Before he started making the donation-request phone calls, it was easier to forget the things he was dissecting had belonged to a person. “I was starting to have this disconnect. Now I’m speaking to the families….I was speaking to a father about his son and I was telling him about what he would be asked in the medical questionnaire and he said, ‘Yeah, we’re happy to do that, but there’s one thing you’re not going to get from any of the medical records that I want you to know: he was extremely loved.’”

  Melanie Bose needs no reminder of the personal side of brain donation: she convinced her dying dad to donate his.

  She was visiting him in Arizona when the issue came up. He was going to refuse, partly on religious grounds. She dug up rabbinic teachings that it’s justified to save another’s life. “And I also said, ‘Dad, you’re going to be dead. You’re not going to know about it.’” He laughed. He consented.3

  Melanie Bose isn’t tasked with convincing families to donate dead loved ones’ brains. She’s the one who does the detective work immediately afterward, calling relatives and friends and doctors to put together a detailed profile of a donor’s life and mental health in the weeks, months, years before death. The quality of medical records is variable. Health care providers are starting to enter the late-twentieth century but most of what Melanie Bose gets is still handwritten and sloppily copied. Their level of illegibility sometimes necessitates a magnifying glass. And lack of detail can be especially annoying. Hallucinations? Visual or auditory? Inside the head, or outside? Who were the voices, what were they saying?

  Things can get even more confusing if the individual’s psychiatric history includes a stack of conflicting medical records. If you saw four different psychiatrists over the course of your life and got four different diagnoses, it’s up to Melanie Bose and the psychiatrists she works with to figure out into which diagnostic category to place the brain. This is not a trivial thing: brain research relies on big cohorts—unipolar depression specimens versus bipolar depression specimens versus control specimens—whose clear-cut definitions bely their inherent fuzziness. These postmortem categorizations, retroactively assessing other people’s assessments of your symptoms, show how arbitrary—and often speculative—our psychiatric classifications can be.

  * * *

  —

  INDIVIDUAL HUMAN BRAINS are so wildly different from each other in so many ways—the relevance of which we’re ages away from fully understanding—that it’s still impossible to tell, looking at individual brains, which one had a mood disorder. Three brains of people diagnosed with the same disease will look completely different; three brains from people who’ve never experienced any mental illness will look completely different—how do you figure out what similarities the sick brains share that differentiate them from the well ones? In science, sample size matters: the people dedicating their waking hours to teasing out the phenotypic, neurobiological, epigenetic variations between different diagnostic categories of tissue rely on huge numbers to drown out the noise. You need analyses of hundreds or thousands of brains grouped by diagnosis and you need to use the sum of your findings to draw general conclusions. Doable, mostly. Or it would be, if the boundaries between categories weren’t so fuzzy. “The groups are so ill-defined….This is one of the problems: we don’t know how to categorize these illnesses,” Barbara Lipska, who so generously allowed me to explore her brain bank, bemoans. “And if you can’t, then what is left?”

  Since 2015, NIMH has been focusing more on symptoms and behaviour. That means zeroing in on hallucinations, suicidality, mania, for example, instead of whatever disease category a cluster of symptoms fits into. But it’s tough to measure behavioural symptoms from dead brains.

  The molecular biology she practises didn’t even exist for brains until very recently: researchers mostly stuck to brains that were still alive so they could see what happened when you poked them or sliced apart big hunks of grey matter. Informed consent wasn’t much of a thing back then, so you had living human experiments like Patient H.M., the now-infamous man who lost his memory when a celebrated neurosurgeon with a lackadaisical approach to ethics hacked a chunk out of his hippocampus.4 And even then, it was tough to link action to consequence or do anything more than guess causation. The brain is too complicated.

  We’re only beginning to develop tools that allow us to inspect the brain at the level where biochemical differentiations are actually happening. RNA sequencing is one of them—it entails lining up long series of numbers and looking for patterns. Barbara Lipska and her team have been, among other things, sequencing RNA to see how the transcriptions of certain genes vary in different mental disorders.5 It’s “like a signature. It’s like a code,” she says. “It’s breaking a code.”

  I went to see her fellow code-breaker Maree Webster, who heads a brain research laboratory at the Stanley Medical Research Institute just a few kilometres away from NIMH, in Kensington, Maryland. Originally from Australia, she used to work at NIMH with Barbara Lipska; now she runs her own show, a 680-brain lab that got so full she had to stop accepting new specimens.

  In addition to conducting studies designed to replicate and verify what partners around the world are finding, Webster’s team is also researching human neurodevelopment, tracking what proteins play key roles in infant maturation and comparing development in various groups of brains in the hopes of pinpointing the places where people with mental illnesses diverge from healthy controls.

  It takes a lot of work, energy and money to keep hundreds of brains preserved indefinitely. Maree Webster’s lab has fifty-five hulking chest freezers. She sighs. “So rent and the electricity alone cost a fortune.”6 I get to watch a technician using frozen cordite to slice a translucent tissue-thin sample of striatum, a cluster of neurons and critical component of motor and reward systems, fragile as a pressed butterfly wing or a scrap of skin peeling off a bad burn. Elsewhere
in the lab the tiny tip of a minuscule tube is designed to dip hummingbird-like into a frozen tissue sample and emerge with microgram-sized fragments of brain.

  Both Barbara Lipska’s lab and Maree Webster’s send tissue to researchers all over the world. Tissue packages from Webster’s lab usually go by FedEx, in dry ice. The lab takes requests on the brain part and manner of preservation. A key condition: you have to send the results of your test back to her lab. Her staff have coded all the samples, and only they know which ones are control—specimens from people who had no mental illnesses—and which are not. This means Webster’s brain bank has all the data from all the studies done with all the tissue of all the brains in the bank.

  It’s a full-time job just ensuring everything makes it through customs okay.

  The striatum I get to watch being meticulously prosciutto-sliced is destined for Australia, about a two-day journey away. “Australia’s really a pain because they’re an island and they don’t want any biological things going in and out,” Maree Webster says. “Others are more worried about terrorism. I mean, Israel doesn’t like dry ice going in.” You can send brain tissue to picky countries, “but you have to go through a lot more rigmarole. They’ll take it as long as you do all the right paperwork.”

  Barbara Lipska knows better than to believe any brain-science hype—the breathless headlines trumpeting a discovery that will revolutionize the field. Even if it’s her own. “I’ve seen a lot of papers and studies that have been done very quickly and on very small numbers of subjects to just get published….I call it scientific pollution.” The replication everyone’s after is nearly impossible to achieve and just as hard to define, especially in psychiatric studies: there are too many squishy variables at play.