The Memory Thief

The Secrets Behind How We Remember—A Medical Mystery

Lauren Aguirre

• Publisher: Pegasus Books
• Year: 2021
• ISBN:
  9781643136530
• Topic: Psicologia
• Subtopic: Scienze cognitive

FINALIST FOR THE 2022 PEN/E.O. WILSON LITERARY SCIENCE WRITING AWARD "Aguirre writes clearly, concisely, and often cinematically. The book succeeds in providing an accessible yet substantive look at memory science and offering glimpses of the often-challenging process of biomedical investigation."— Science Sometimes, it's not the discovery that's hard – it's convincing others that you're right. The Memory Thief chronicles an investigation into a rare and devastating amnesia first identified in a cluster of fentanyl overdose survivors. When a handful of doctors embark on a quest to find out exactly what happened to these marginalized victims, they encounter indifference and skepticism from the medical establishment.But after many blind alleys and occasional strokes of good luck, they go on to prove that opioids can damage the hippocampus, a tiny brain region responsible for forming new memories. This discovery may have implications for millions of people around the world.Through the prism of this fascinating story, Aguirre recounts the obstacles researchers so often confront when new ideas bump up against conventional wisdom. She explains the elegant tricks scientists use to tease out the fundamental mechanisms of memory. And finally, she reveals why researchers now believe that a treatment for Alzheimer's is within reach.

PART ONE BROKEN BRAINS

1 Case One

Massachusetts, October 2012

When neurologist Jed Barash was growing up in Orange, Connecticut, his father’s copy of the New England Journal of Medicine appeared in the mailbox every Thursday without fail. The arrival of the signature red-and-white NEJM marked the passing of Barash’s childhood as regularly as a metronome. Fifty-two weeks a year, 600,000 people around the world receive their copy of the world’s most prestigious medical journal. It’s considered essential reading for medical professionals, including Barash’s father, an anesthesiologist. The journal’s standards are exacting, the editorial process excruciating. To be published in its pages is a sign of professional success and a passport to credibility.

In the fall of 2012, the normally staid NEJM issue that appears in Barash’s mailbox includes an attention-grabbing title: CHOCOLATE CONSUMPTION, COGNITIVE FUNCTION, AND NOBEL LAUREATES. A Swiss-born author presents data revealing “a surprisingly powerful correlation between chocolate intake per capita and the number of Nobel laureates in various countries.” Switzerland tops the list. The burden of proof is high for such surprising claims. But this article is no more than a spoof designed to highlight a common mistake: jumping to the conclusion that when two things are associated, one causes the other. Some journalists miss the point and present the findings as proof that eating more chocolate makes you smarter. In this case it would be an inconsequential mistake. But when it comes to making decisions that affect human health, getting it wrong is dangerous. Figuring out the true relationship between two associated phenomena is something Barash will come face-to-face with in the months and years ahead.

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On the first Friday of October, Barash leans forward in his chair and stares at the MRI scan on his monitor. He’s looking at the brain of a young man admitted to the hospital last night, and the image is so strange and beautiful that he knows something has to be wrong.

“Whoa,” he says out loud to his empty office. “This is weird.”

Floating brightly against the darker background of the rest of the brain are two C-shaped structures tucked on either side of the central fluid-filled cavity. Together they make up the hippocampus—the place that holds the keys to memory—and the intense glow is a distress signal from many millions of cells. Some mysterious, marauding force has laid waste to just this tiny region, leaving the rest of the brain unharmed. Barash looks out his door to the still-quiet waiting room up on the seventh floor at Lahey Hospital & Medical Center in Burlington, Massachusetts, just outside Boston. Then he looks back at the monitor.

Last night’s phone call from nearby Winchester Hospital requesting permission to transfer this patient suddenly makes more sense. The distraught 22-year-old had recently overdosed. He was dragging one leg and repeatedly asking his mother if he was dying. Winchester is a smaller hospital that handles routine emergencies like a broken wrist or an appendicitis, but when patients with complex conditions or unexplained symptoms come in, the staff will often send them over to Lahey, a facility that has hundreds of specialists and more equipment. With the high-quality image in front of him, Barash can see what the Winchester staff could not, and it explains why the patient was acting strangely.

In ten years of medical training, Barash has reviewed thousands of scans—brains shrunken from Alzheimer’s disease, brains dotted with tiny broken blood vessels, brains with tumors in different sizes, shapes, and locations. In every case, no matter what the damage looked like, it was pretty clear what was going on. But what Barash sees on the screen in front of him is strange and alien, belonging to no category he can imagine. It looks like someone took a page out of his medical school neuroanatomy textbook and deliberately highlighted the brain’s memory center.

He reexamines the MRI, scrolling up from the base of the skull through the familiar soft gray brain structures until the hippocampus comes back into view. It seems certain that this patient will fail the memory tests they’ll give him today, and the damage has triggered Barash’s interest in strange cases and rare brain diseases. He believes more in chance than in destiny, but still, he thinks, it’s almost as if his years of study and obsession have guided him directly to this moment, sitting in this office, looking at this startling image.

The care of this patient is now with his colleague, Yuval Zabar, a neurologist Barash admires for his intellectual curiosity and ability to run through every diagnosis that could possibly explain a patient’s symptoms. It’s Friday, the final day of a week being on call, and Barash is allowed to leave for the weekend at noon to make up for the last seven nights of fragmented sleep. But instead of heading for home, Barash turns off the monitor, pulls on his white doctor’s coat, and heads down to 6 West to join the neurology team on their daily rounds. He has to see the patient for himself.

Between the patient, his mother and grandmother, and the doctors, there are more than half a dozen people in the cramped hospital room. Barash chooses an out-of-the-way corner from which to watch the examination. This is his preferred mode, to observe rather than be observed, and it doesn’t bother him that he wouldn’t stand out in a crowd. Born, raised, and educated in New England, 33-year-old Barash is solidly built and stands just shy of six feet, with a broad forehead, short brown hair, and a face that would look incomplete without his glasses.

James Maxwell Meehan, boyish and handsome enough to play the leading role in a romantic comedy, is sitting up in bed looking puzzled. On the whiteboard on one wall someone has written the following:

“Max, you are at Lahey Hospital in Burlington.”

“You overdosed the night before last.”

“You are having trouble with your memory.”

Max’s mother, Laura, explains that Max keeps asking her, his sister, and his friend the same questions, so they’ve written the answers on the whiteboard so he would stop.

A resident-in-training begins the examination by interviewing Laura and Max to find out what brought him into the hospital. A few nights earlier, Max went to one of his favorite bars in Boston’s Back Bay, where he danced and drank for hours. Back at his boyfriend’s apartment, he injected what he thought was pure heroin and passed out. It wasn’t such an unusual night for Max, but according to his boyfriend, when Max woke up the next morning on the couch he complained that his left leg felt numb, and when he tried to stand up he fell over. A few minutes later, when he decided to stand up again, he fell over. Maybe his leg had fallen asleep, he figured. After another little while, he couldn’t say how long, he realized it was morning and he ought to get up. But then he noticed that his leg didn’t seem to be working. It occurred to him that maybe he’d slept too long on one side and pinched a nerve. Nothing made sense. Every few minutes, the realization that his leg felt paralyzed seemed like a horrible new discovery. Max started sobbing. It’s not unusual for people who have overdosed to be confused and disoriented afterward, but Max found himself in a kind of limbo, a never-ending present.

“It’s just very odd,” his mother says. “He’s fine. He’s himself, he still has the same sense of humor. We even showed him that Ain’t Nobody Got Time For That video on YouTube to distract him, and he laughed like he always does at silly things. But then we showed it to him again, and he laughed like it was the first time.”

Zabar, an experienced neurologist in his mid-forties, takes over the examination from the resident. Zabar’s thick head of hair is showing the first signs of gray, and he has the harried attitude of a man aware that his phone or pager is likely to buzz again within the next five minutes. Most patients appreciate the care he takes to explain things clearly and the way he doesn’t sugarcoat bad news.

“Max, I’m going to ask you to remember a few simple words.” Zabar looks him squarely in the eye to make sure Max is paying attention. “The words are purple, velvet, honesty.”

Zabar pauses between each word to give Max time to register.

“Can you repeat those words back to me now?” he asks kindly.

“Purple. Velvet… honesty,” says Max.

“Good.”

Zabar gives Max a piece of paper with three figures on it—a triangle inside a circle, a skinny rectangle capped with a semicircle that looks like a mushroom, and the letter L. Below each shape is a word—pride, hunger, station.

“I want you to copy these three shapes and three words just as you see them.” Zabar needs to make sure Max is paying attention and can follow directions.

Max copies them correctly, but when Zabar gives him a blank sheet of paper and asks him to re-create the shapes and words, he can’t remember them.

“Okay. Now, can you tell me the three words I asked you to remember earlier?”

“Purple…” Max stops.

“Anything else?”

“That’s all I remember.”

Barash picks up on Laura’s growing anxiety. She’s trying to get a read on the room, but the resident, intern, and medical student are all focused on Zabar, who, wearing a poker face, presses on. He hides a pen, a crumpled piece of paper, and a cup around the room while Max watches. Several minutes later, when he asks Max to point them out, Max doesn’t even know what he’s talking about. Barash finally catches Laura’s eye and tries to give her a comforting look. From the damage to the hippocampus that they’d seen on the MRI scan, the official diagnosis confirms what was almost a foregone conclusion: anterograde amnesia. Max still knows who he is and remembers everything that happened to him before he overdosed. But he can’t form a single new memory. Every moment of the last few days has disappeared.

Zabar regularly sees patients with memory problems, and they’re often elderly. Some have had strokes or brain tumors, but most suffer from dementia. Max’s memory loss reminds Zabar of people with advanced Alzheimer’s disease, but aside from the fact that he’s much too young for that, his brain scan doesn’t match the diagnosis. In Alzheimer’s, some brain regions, including the hippocampus, tend to be smaller than usual, a sign of slow, insidious destruction. But in his twenty years as a neurologist, Zabar has never seen a case like this one. Aside from the damaged hippocampus, blood flow in the rest of his brain is normal. The only significant health problem Max has is drug use, both legal and illegal: tobacco, alcohol, marijuana, cocaine, ecstasy, LSD, and heroin. The standard urine toxicology screen run on any overdose patient detects opioids, corroborating Max’s account that he had injected heroin. After leaving Max’s room, Barash and Zabar stop in the hallway to talk over the case for a few minutes. Even though it seems likely that the drug or a contaminant is in some way responsible, neither one of them can fathom why only the hippocampus is injured.

Barash heads back to his office to hang up his white doctor’s coat and check his e-mail one last time before heading home. Aside from colorful socks, he dresses traditionally, favoring button-down shirts with the sleeves rolled up, a tie, chinos, and comfortable shoes. He’s two months into his first job as a full-fledged attending neurologist. Since he’s new and there’s no space left in the main neurology pod on 7 West, he’s been assigned a tiny windowless office that was recently vacated by the chaplain. It’s right off the waiting room, where a loud printer just outside the door ejects copies throughout the day. Visitors often assume he’s a secretary and step into his office to ask for directions.

Driving home to Lexington from the hospital that afternoon, Barash is so wrapped up in puzzling over the mystery and reliving the events of the day that he barely registers the familiar suburban landmarks along the way—the mall, the movie complex, the gas station. He imagines how he’ll describe the case to his wife, Gillian Galen, how he met a patient who couldn’t remember more than the previous few minutes, a guy who can’t go home and tell someone the story of his own day.

Dr. Galen, slender, green-eyed, and levelheaded, is a psychologist and an excellent observer of human nature. She understands the mind—and Barash—well enough to understand his fascination. They discuss it in their standing-room-only kitchen as they share a pizza and he drinks his Friday-night ginger bourbon fizz.

“His MRI was just insanely weird,” Barash says.

“Weird how?”

“Like something completely scorched his hippocampus.”

“Both sides?”

“Both sides, and he was toast. Like, two days after an overdose he should be fine, but he was confused. And he wasn’t confused in the classic sense of confusion. He literally was just not… he wasn’t able to move forward in time. He was stuck. He kept going back to the same thing, telling his mom the same thing, asking Zabar the same question within a few minutes. It’s a classic amnestic syndrome.” Barash stops to imagine. He’s used to seeing people with advanced Alzheimer’s whose memories are as bad as Max’s, but what would it be like to be so young and just wake up that way one morning?

“That’s so sad. Will he get better?” Gillian asks.

“We have no idea. Never seen anyone like him before,” Barash says, “but it’s not gonna be sunshine and rainbows.”

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One week after the overdose, on Max’s twenty-third birthday, he returns to Lahey. As they do in most major teaching hospitals, the neurology team has weekly grand rounds, when doctors present interesting cases. The entire department can attend, including nurses, physician assistants, medical students, interns, and residents, and everyone is encouraged to weigh in. Zabar has decided to present Max’s case.

Barash takes a seat among fifty or so other people crowded into the windowless, poorly lit neuroscience conference room. Paintings of distinguished neurologists and neurosurgeons line the wood-paneled walls. Max is seated at the head of the aisle with several rows of chairs on either side for the audience. Zabar stands at a podium and gives a brief overview of Max’s case. Then, with Max’s permission, he examines him, running through cognitive tests like the ones he’d given him in his hospital room a week earlier. He also tells Max a simple story, which he comes back to now and then, asking Max to repeat it at greater and greater time intervals. Max is cooperative, but his memory remains profoundly impaired. He is, in the words of neurologists, “densely amnestic.”

When the exam is over, Max leaves, and Zabar displays his MRI on the screen behind him. The image captures the moment of acute damage, when some uncountable number of neurons would have only recently died, trapping water that would normally have been pumped across the cell membrane. Zabar dives into the case review.

“The thing that is really striking to me,” says Zabar, “is that this signal is so bright that it looks like a stroke, but this person is so young. He has no risk factors for stroke. He’s not immunosuppressed, and there’s no evidence of any other infection like HIV, Epstein-Barr virus, or herpes.”

One of the stroke specialists in the audience takes advantage of a break in Zabar’s rapid-fire delivery.

“I have never seen a scan like this. I mean, it does look like a stroke. The intensity is there, but I’ve never seen a stroke that just took out the hippocampi bilaterally and not surrounding…”

Barash asks the question hanging in the room. “Yeah, why would it just be the hippocampus on both sides?” No one answers, so he continues in his quiet, rumbly voice. “It’s so perfect, it’s so localized. Whatever happened, there was clearly an affinity for just that area.” Usually grand rounds end with a clear understanding of the diagnosis or, if not, ideas to explore further. But today the discussion goes long and the meeting ends with a conundrum; what happened inside Max’s brain?

If anyone at Lahey has the expertise to figure it out, it would be head neuroradiologist Juan Small. He’s written four books on radiology and is known for his ability to sort through every possible explanation for an abnormal brain scan. And he’s careful about drawing inferences. Small couldn’t attend the grand rounds presentation, but word’s gotten out about a highly unusual case, and he keeps a list of them to help medical students learn how to make difficult diagnoses. Now he sits in his darkened basement office and calls up Max’s imaging data on his large monitor.

Small selects the view that shows Max’s brain from the base of the skull through to the crown of his head. Slowly, he scrolls up through the soft gray landscape. The familiar contours of the eye sockets begin to appear. Everything looks as it should until two islands of white emerge, complete, perfect, and intensely bright. I don’t know what this is, he thinks. He’s used to seeing tiny white dots in the hippocampus, each one representing dead neurons. They are the telltale signs of a stroke. But he has never seen the entire territory laid waste, and he reviews some ten thousand scans a year. Small scrolls back and forth a few more times, confirming the scope of the damage. I don’t know what this is, he thinks again. And not only that I don’t think anybody knows what this is. Max’s brain scan is in a category all its own. Small adds it to his list, although he won’t have an answer when his students ask for the correct diagnosis.

Back in his tiny office after grand rounds, Barash turns his focus to preparing for a full slate of afternoon patients. The complete lack of daylight deprives him of any sense of time. The office is spare, with a desk, two chairs for visitors, a file of scientific papers he’ll probably never have time to read, and the computer monitor. Diplomas and three picture...