The burst aneurysm caused extensive damage to the left side of his orbitofrontal cortex, the structure just behind the eyebrows (hence “orbito”) which is responsible for higher-order cognitive functions such as planning and judgment, and to the caudate nucleus, which sits just beneath the cortex. Although long thought only to control voluntary movement, the caudate, which from the side looks like a squat question mark, turns out to have cognitive functions, too: it plots actions that will lead to goals, and tells the orbitofrontal cortex how much attention to pay to incoming sensory information. Because of the latter role, caudate malfunctions can tag a piece of information as being a cause for greater worry than it really is, resulting in obsessive-compulsive disorder, as I’ll discuss below.
In early 1997 the man underwent neurosurgery to repair the aneurysm and remove the buildup of cerebrospinal fluid in his brain. Within a couple of months he seemed to have mostly recovered, except for one striking change in behavior. One July day, he ventured out to a park for his first walk since his aneurysm burst, when a tiny object on the ground caught his eye: it was a bullet from a toy gun. He picked it up. Then he picked up another toy bullet. Whenever he returned to the park—indeed, whenever he went outside—he felt an overwhelming compulsion to search for toy bullets. Nothing else particularly interested him—not coins, not papers, not anything that might have value, only the tiny round pellets, the size of a pencil eraser, which he searched for by walking with his eyes cast downward, combing streets and park paths for hours in even the rainiest, most dismal weather. In the two years before he came to the attention of neurologists and psychiatrists at Samsung Medical Center in Seoul, he had collected more than five thousand bullets. He kept them in bottles, neurologist Duk Na and colleagues reported in 2001 in the journal Neurology, and never felt any desire to take them out or handle them, or to collect anything else.
Damage to the orbitofrontal cortex in other patients triggered different forms of compulsive collecting. A forty-nine-year-old Frenchman treated at the Salpêtrière Hospital in Paris for a brain tumor in 1995 was found, in a CT scan, to have two large cavities in his frontal cortex, and within two years he felt driven to search out discarded household appliances. He wandered his hometown, Salpêtrière neurologist Emmanuelle Volle and her colleagues reported in Neurology in 2002, compelled to search out telephones, washing machines, television sets, vacuum cleaners, refrigerators, and videocassette recorders (this was, after all, the 1990s). He went about this methodically and efficiently, setting out twice a month as if for an appointment with destiny. The man stored the first thirty-five television sets in his living room and, when it could not hold any more, filled his daughter’s room, then hallways, a bathroom, three cellars, and, finally, ventilation shafts with his scavenged treasures. Apart from a compulsion to collect appliances, the man showed no cognitive deficits, though he did have trouble mustering enthusiasm for anything else.
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These Korean and French patients were on the losing side of experiments of nature that left big holes in their brain, triggering bizarre compulsions. From this, we might be tempted to conclude that damage to the frontal regions and/or caudate is the cause of compulsions. Were it only so simple.
Neuroscientists are far from nailing down the brain basis for compulsive behaviors. What they have is a hodgepodge of ways compulsions can seize the brain. More than anything, the research is showing that there are many, many ways for a brain to feel irresistibly, compulsively, driven to a behavior. Remember, for instance, the multiple psychological reasons why people hoard, including deep emotional attachment to objectively worthless items and impaired decision-making that leaves the hoarder unable to identify what can go and what should stay. Since all mental activities, including feelings and thoughts, reflect brain activity, each psychological trait must have a neurobiological basis.
Yet that basis has been maddeningly elusive. For years, psychiatry has been pummeled for failing to find objective diagnostic criteria for the hundreds of ills it identified. There is nothing like a blood pressure cuff or, more realistically, a neuroimaging test. Psychiatrists and neurobiologists have made a valiant effort to remedy that, putting seemingly every mentally tortured soul into an MRI tube to measure brain activity and identify what went wrong, but the effort has largely failed. That state of affairs so troubled psychiatrist Thomas Insel, then director of the National Institute of Mental Health, that in 2013 he slammed psychiatry’s diagnostic manual for “its lack of validity” and for failing to base diagnoses on objective laboratory tests. “Patients with mental disorders,” he wrote on his NIMH blog, “deserve better.”
The OCD Circuit
Psychiatrists tried, god knows. The greatest progress has been made in identifying the brain basis for obsessive-compulsive disorder, so much so that OCD has become an exemplar for turning a psychiatric disorder into a neurological one. The first steps came in the late 1980s, when psychiatrists and neuroscientists at the University of California, Los Angeles, ran a newspaper ad inviting people with compulsions to volunteer for a brain imaging study. Hundreds responded, and after a standard psychological evaluation two dozen were given brain scans using the technology of the time, positron emission tomography, or PET. What leaped out was a consistent pattern of elevated activity in three regions: the orbitofrontal cortex, the nearby anterior cingulate, and the striatum deep in the brain’s interior just forward of the ears.
The orbitofrontal cortex has a plethora of functions. It weighs complex decisions, especially those involving risk, and is also responsible for ruminations and worries. For purposes of OCD, its key job is that of error detector: it compares actual events to expected events, noting, for instance, when a reward that the brain has learned to anticipate does not arrive. Neurons in the orbitofrontal cortex fire when something goes wrong, when experience clashes with expectation, or when something seems amiss, such as a slightly askew picture on a wall, uneven piles of books, cans not sorted by label, or any of the myriad of other niggling imperfections that send someone with OCD into a panic. The result is an intrusive, insistent, gut-level feeling that something is wrong. The elevated orbitofrontal activity in people with OCD seems to be the reason they perceive errors the rest of us are blind to.
The anterior cingulate houses a slightly different kind of error-detection machinery. It fires when you make a mistake or when you make a choice that you know, subconsciously or intuitively, is wrong in some way. A common example is when, in the popular psychology test called the Stroop task, you name the color ink that a color word is written in when the two are discordant (such as green written in red ink). The anterior cingulate typically detects errors that you make, not things that are off in the world outside the brain.
The striatum receives signals from and sends signals to so many other regions that it’s the neural equivalent of one of those 1940s telephone switchboards, blooming with wires, but raised to the nth power. It has been implicated in voluntary movement, learning, memory, and goal-directed behavior, but the key for OCD is that one of its components, called the caudate nucleus, sends inhibitory axons to many other brain structures. It is one of the brain’s “quiet down” centers. (The caudate was damaged in the unfortunate gentleman who developed the bullet-collecting compulsion.) The more active the caudate, the more traffic flows along these axons, and the stronger the shhhhh. When the caudate is abnormally active, then, the inhibitory message goes from a sedate hush to a powerful shut up. One of the structures that gets nearly silenced has the job of itself inhibiting activity in yet a third structure down the line. (If you’re a toe-bone-connected-to-the-foot-bone fan, we’re up to the ankle bone.) When the silencer is silenced, the gunshot sounds at full volume—and when the inhibiting structure is blocked due to overactivity in the caudate, activity in the next structure, a switching station called the thalamus, has no brakes on it. Result: heightened thalamic activity. The thalamus acts as kindling to the cingulate and its neighbor, the orbitofrontal cortex, with the
result that both of those structures are also overactive. Which is precisely what neuroimaging of people with OCD shows. Remember that overactivity in the orbitofrontal and anterior cingulate means hyped-up error detection.
Together, the orbitofrontal cortex/anterior cingulate/caudate circuit—or, in the common shorthand, a cortical-striatal circuit—is known as the “worry circuit” or “OCD circuit.” “It’s basically the circuit that tells you something bad is about to happen—like you’ll get contaminated, covered with germs—and you have to do something about it,” said UCSD’s Sanjaya Saxena. “The pattern of activity in OCD is very consistent from patient to patient. There is elevated activity in the orbitofrontal cortex, the caudate nucleus, thalamus, and anterior cingulate. And when you get better, activity decreases in all these areas.”
The brain glitch responsible for OCD stands out for several reasons, including that it was the first to be deciphered. But another reason is that it involves patterns of activity, not the “chemical imbalances” that the public—thank you, direct-to-consumer pharmaceutical ads—has been brainwashed into believing are the cause of mental disorders. This isn’t a book about what a train wreck that idea has been, leading to the proliferation of prescriptions for drugs that supposedly correct those imbalances but whose benefits are very, very slight or nonexistent, and turning most psychiatrists into just diagnosticians and drug dispensers more than therapists who seek to work through a patient’s problems via psychotherapy. For our purposes, what matters is that it is empirically wrong: abnormalities in the brain’s wiring, not neurochemical imbalances, underlie most mental illness. And OCD was the first to show that.
The worry circuit exists in healthy brains as well. “You know that feeling you get when you step off a sidewalk to cross the street and suddenly a car that you didn’t see is bearing down on you?” the IOCD Foundation’s Jeff Szymanski asked me. “It’s the same circuit that’s telling people with OCD that something is dangerously wrong.” Some brains are born with a low threshold for feeling that (their OCD circuit fires at the least provocation), while others develop that low threshold. “So you protect yourself, or get out of there, or do anything you can to defuse the danger—or the sense of danger,” Szymanski said. That reinforces the sense that you were in danger, validating the anxiety, and telling the brain that the threat was probably real. The OCD circuit becomes even more active, sending “Danger! Danger!” at the slightest provocation. The brain also learns that giving in to the warning by executing a compulsive behavior relieves anxiety. Score one for Pavlov (more on whom below).
Identifying the OCD circuit represented a significant step toward understanding the brain basis for the disorder. Overactivity there is not so unambiguous as to be diagnostic, however: neuroimaging cannot reliably detect OCD. The characteristic worry-circuit activity jumps out when scientists look at hundreds of brain scans; if you average the activity in one hundred normal brains and then in one hundred OCD brains, you’ll find this telltale difference. But a particular OCD brain might or might not show this pattern, Yale psychiatrist Marc Potenza told me: “We’re not at the point where we can make a psychiatric diagnosis with brain imaging.” Height offers an analogy. If you average the heights of one hundred men, and compare that to the average heights of one hundred women, the former will be greater. But any particular woman might be taller than the average man, and any particular man might be shorter than the average woman.
Whenever a brain exhibits some abnormality or quirk, the question arises: Where did that come from? There are only two possibilities: it was present at birth, and is thus the result of brain-development genes inherited from mom and dad or of some event in the womb; or it emerged after birth, and is the result of something the person experienced. Compulsions can be caused by both nature and nurture.
Family studies have shown that OCD is five to seven times more frequent in first-degree relatives of patients than in unrelated people, suggesting a genetic component: if a close relative has the disorder you are more likely to as well, but “more likely” does not mean “definitely.” That reflects the fact that there is no such thing as an “OCD gene” that, like those for Tay-Sachs and sickle-cell disease, produces the disorder in everyone who inherits it from both parents. Instead, in complicated psychiatric conditions, multiple genes play a role. In 2012, for instance, scientists at Massachusetts General Hospital ran the first genome-wide association study of OCD. Enlisting 1,465 people with OCD, more than 5,500 unaffected controls, and 400 trios consisting of an OCD patient and both parents, they analyzed some 480,000 gene variants and got hits in two places. One, the MGH team reported in Molecular Psychiatry, was near a gene called BTBD3, which seems to be involved in brain wiring (it directs the output fibers of one neuron to the input fiber of another). The other hit was to a gene called DLGAP1, which is involved in choreographing the formation of synapses. In mice, which have a version of this human gene, deleting it produces OCD-ish symptoms. That suggests a healthy working version of DLGAP1 is necessary for normal brain development, while an absent or aberrant version of the gene somehow leads to the circuitry underlying OCD.
A third OCD-related gene entered the picture in 2014, when researchers at Johns Hopkins University scanned the genomes of more than 1,400 people with OCD and more than 1,000 close relatives. They found that DNA variants near a gene called protein tyrosine phosphokinase (PTPRD) were more likely to be found in people with OCD and their relatives than in people without the disorder, they reported in Molecular Psychiatry. In lab animals, the PTRPD gene has been shown to regulate a number of cellular activities, including growth and differentiation. In particular, it promotes the growth of axons and dendrites, which carry signals into and out of neurons; anything going awry with those processes could lay the foundation for aberrant wiring that becomes an OCD circuit. But while these genetic studies are steps forward, they fall far short of convincing explanations: many OCD patients do not have the aberrant genes, and many people with the aberrant genes do not have OCD. All the genes do is increase one’s risk of developing OCD.
Environmental factors that make children more likely to develop a compulsion are even murkier. One idea is that people become compulsive when they feel the world is an unpredictable and threatening place and their compulsive behavior is the one thing they have control over (even though they don’t). Some psychologists have speculated that parental obsession with germs can be imparted to kids, but it’s equally likely that children will react to that message by a perversely opposite behavior, reveling in all the dirt and grime they can find. Beyond that, the causes are anyone’s guess.
A Hoarder’s Cortex
One reason hoarding was classified as a standalone diagnosis in the DSM-5, rather than remaining a form of OCD, is that the patterns of brain activity in the two disorders are distinct. That is, the brains of people with pure hoarding disorder show none of the telltale overactivity in the cortical-striatal “worry circuit” found in the brains of people with OCD. The neurology fits with the psychology: hoarders don’t ruminate excessively, they don’t suffer from perpetual feelings that something is amiss. They’re basically fine until and unless someone disturbs their packed-to-the-rafters world.
An early clue to the brain basis of pure hoarding came from Phineas Gage, whose brain became world famous. Even if you have heard his story, stick with me; this is the seldom-told part.
A railroad foreman, Gage was overseeing a crew clearing a track bed in order to lay rail near Cavendish, Vermont, in 1848, when an explosion shot a forty-four-inch tamping iron straight into his skull under the left cheekbone and clear through his brain. Spearing his frontal lobes, it exited the top of his head and landed thirty yards away. Miraculously, although Gage seemed shaken, he was able to walk to an oxcart that took him back to his boardinghouse, where a local physician tended to his wounds, replacing dislodged skull fragments. After recovering from his acute injuries, the formerly even-tempered and soft-spoken Gage became prone to unprovoked and pro
fanity-filled rages, and turned “pertinaciously obstinate” and “capricious,” Dr. J. M. Harlow wrote in 1868, “impatient of restraint of advice when it conflicts with his desires.”
Generations of neuroscientists tell the story of Phineas Gage because his was the most dramatic experiment of nature (or railroad crew) to link damage to a region of the brain with a precise emotional and psychological outcome: the prefrontal region impaled by the tamping iron is the locus of emotional control, reason, planning, and similar high-order cognitive function. But scientists who study hoarding dug up a less-known consequence of his accident: Phineas developed a “great fondness” for souvenirs, according to Harlow.
That would hardly be enough to link frontal lobe damage to hoarding, but a 2005 study of eighty-six brain-damaged patients suggested that Phineas was no anomaly. Before they sustained brain damage, the patients had no history of psychiatric disease or unusual collecting behavior, let alone hoarding. But when neuroscientists probed more deeply, it turned out that thirteen of the eighty-six “exhibited abnormal collecting, characterized by massive and disruptive accumulation of useless objects,” Antonio Damasio, then at the University of Iowa, and his colleagues wrote in the journal Brain. In particular, the patients accumulated newspapers, magazines, junk mail, catalogues, appliances and appliance parts, food, clothing, broken furniture and furniture parts, televisions, scrap metal, car parts, grocery bags, food containers, empty bottles, and cardboard boxes. “In all cases, the abnormality of collecting behaviour was severe and persisted despite attempted interventions,” the scientists wrote.
All the hoarders had damage to the frontal cortex reminiscent of the Korean toy-bullet hoarder and the French appliance hoarder. It was not surprising, then, that most also had deficits in functions controlled by the frontal cortex: their memory and organizing skills were below normal, supporting Randy Frost’s observation that executive function deficits such as not being able to figure out how to even start making a dent in the mountains of stuff underlie many cases of hoarding.
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