The Mind and the Brain (8 page)

So in February 1987 I launched a group therapy session for OCD patients, meeting every Thursday afternoon, in conjunction with an ongoing study of the disease’s underlying brain abnormalities that my colleagues and I at the UCLA School of Medicine had begun in 1985. One of the first patients in the group was a man who could not stop washing. His wife, driven to distraction by his compulsions, was on the verge of leaving him. Although the man felt incapable of resisting the urge to wash, at the same time he had clear insight into how pathological his behavior was. After nearly a year of group
therapy, with winter approaching, he said, “That’s it. I’ve had it. This winter I’m not doing washing compulsions. I’m not going through another winter with raw, red, cracked, chapped, painful hands. I’d rather be dead.” This was a level of resolve neither I nor anyone in the group had seen before. Over the next few weeks, he actually managed to pull it off. He held his washing to normal levels and made it through the winter without chapped hands.

That case was uppermost in my mind as we delved ever deeper into the study of OCD’s underlying neuroanatomy. Two years earlier we had studied depression, observing (as many other groups would later) that the brains of depressed patients are often marked by changes in cortical activity as detected on
positron emission tomography
(PET), the noninvasive imaging technique that measures metabolic activity in the brain. We had begun studying obsessions after observing that many patients with depression had intrusive, obsessional thoughts. The obvious question arose: What brain changes mark OCD itself? An advertisement that we placed in the local paper, asking, “Do you have repetitive thoughts, rituals you can’t control?” brought an overwhelming response. Over the next several years, we invited about fifty of those respondents to the UCLA Neuropsychiatric Institute to undergo a full assessment for possible OCD.

In an analysis of the PET scans of twenty-four patients, published in a series of papers in the late 1980s, we pinpointed several brain structures that seemed to be consistently involved in obsessive-compulsive disorder. Compared to the brains of normal controls, the brains of our OCD volunteers showed hypermetabolic activity in the orbital frontal cortex, which is tucked into the underside of the front of the brain above and behind the eyes (hence its name) as shown in Figure 1 on Chapter 2. The scans showed, too, a trend toward hyperactivity in the caudate nucleus. Another group had found that a closely related structure, the anterior cingulate gyrus, was also pumped up in the brains of OCD patients.

By 1990, five different studies by three different research teams
had all shown elevated metabolism in the orbital frontal cortex in patients with OCD, so this structure consumed our attention. We combed the literature for clues to what the orbital frontal cortex (OFC) does for a living in the normal human brain. Our first major clue came from studies by the behavioral physiologist E. T. Rolls at Oxford University in the late 1970s and early 1980s (studies whose results were later echoed by researchers elsewhere). In one key set of experiments, Rolls and his colleagues taught rhesus monkeys that every time they saw a blue signal on a monitor, licking a little tube in their cage would get them a sip of black currant juice, one of their favorite beverages. Licking the tube in the absence of the blue light would do nothing. Good Pavlovians all, the monkeys learned quickly to lick the tube when they saw blue. Through electrodes implanted in the brains of these alert animals, Rolls observed that the orbital frontal cortex now became active as soon as blue appeared.

Figure 1:
This side view of the brain shows some of its key structures, including those involved in OCD. In the “OCD circuit,” neurons that project from the orbital frontal cortex and the anterior cingulate gyrus to the caudate nucleus are overactive, generating the persistent sense that something is amiss.

Then Rolls switched signals on his little furry subjects: now green meant juice and blue meant salt water, which monkeys
(being no fools) despise. When the monkeys saw blue and licked the tube, but got brine instead of the juice they were expecting, cells in their orbital frontal cortex went ballistic, firing more intensely and in longer bursts than the cells did when the tube contained juice. Yet these cells did not respond when the monkeys sipped salt water outside the test situation. Instead, this group of cells fired only when the color previously associated with juice became associated with the delivery of something nonrewarding, or even of nothing at all. The mere absence of an expected reward, it seemed, was enough to trigger intense activity in these OFC cells. Apparently, cells in the orbital frontal cortex fire when something has gone awry, as when an actual experience (getting salt water) clashes with expectation (getting currant juice). The orbital frontal cortex, it seems, functions as an error detector, alerting you when something is amiss—if you’re a rhesus monkey, getting a mouthful of brine when you’re expecting currant nectar is the essence of amiss. Expectations and emotions join together here to produce a sort of neurological spellcheck.

If cells of the orbital frontal cortex do indeed function as rudimentary error detectors, then they should quiet down when expectation and reality are back in harmony. And that is what the Oxford group found. Once the monkeys learned to associate green with juice, OFC cells quieted down, firing in shorter and less intense bursts than they did when they detected an error in the world around them. From these experiments, it seemed clear to me that error-detection responses originating in the orbital frontal cortex could generate an internal sense that something is wrong, and that something needs to be corrected by a change in behavior. They could generate, that is, the very feeling that besets OCD patients. With this realization, I got a sense of real excitement, for this was our first solid clue about the physiological meaning of the PET data showing that OCD patients have a hyperactive orbital frontal cortex: their error-detection circuitry seems to be inappropriately stim
ulated. As a result, they are bombarded with signals that something is amiss—if not brine subbing for fruit juice, then an iron left plugged in, a germ unscrubbed. If the error-detection system is spotting things out of whack everywhere in a person’s environment, the result is like a computer’s spellcheck run amok, highlighting every word in a document. Intense and persistent firing in the orbital frontal cortex, it seemed, would cause an intense visceral sensation that something is wrong, and that action of some kind—be it alphabetizing cans or checking whether appliances are turned on—is needed to make things right again. In fact, the reason for the visceral sense of dread that OCD patients suffer is that the OFC (and related structures like the anterior cingulate gyrus) is wired directly into gut-control centers of the brain. Small wonder, then, that the ERROR! ERROR! message triggers such a stomach-churning panic. Monkeys quiet their error messages by correcting their responses: they stop sipping in response to that deceptive blue signal and try other options. What about OCD patients, I wondered? How can they quiet their faulty error-detection circuit?

In 1997, some clever studies expanded the job description of the orbital frontal cortex and its neighbor, the anterior cingulate, to account even more fully for this inchoate sense of dread. Researchers led by Antoine Bechara and Antonio Damasio at the University of Iowa had volunteers play a sort of gambling game, using four decks of cards and $2,000 in play money. On each card was written a dollar amount either won or lost. All the cards in the first and second decks brought either a large payoff or a large loss, $100 either way, simulating the state of affairs that any savvy investor understands: the greater the risk, the greater the reward. Cards in decks 3 and 4 produced losses and wins of $50—small risk, small reward. But the decks were stacked: the cards were arranged so that those in decks 3 and 4 yielded, on balance, a positive payoff. That is, players who chose from decks 3 and 4 would, over time, come out ahead. The losses in decks 1 and 2 were not only twice as large, moreover, but
more common, so that after a few rounds players found themselves deep in the hole. A player who chose from the first two decks more than the second two would lose his (virtual) shirt.

Normal volunteers start the game by sampling from each of the four decks. After playing a while, they began to generate what are called anticipatory skin conductance responses when they are about to select a card from the losing decks. (Skin conductance responses, assessed by a simple electronic device on the surface of the skin, gauge when sweat glands are active. Sweat glands are controlled by the autonomic nervous system, whose level of activity is a standard measure of arousal and anxiety—and thus the basis for lie detectors.) This skin response occurred even when the player could not verbalize why decks 1 and 2 made him nervous; nevertheless, he began to avoid those decks. Patients with damage to the inferior (or
ventral
, meaning the “underside of”) prefrontal cortex, however, played the game differently. They neither generated skin conductance responses in anticipation of drawing from the risky decks, nor shied away from these decks. They were instead drawn to the high-risk decks like high-rollers to the $500 baccarat table and never learned to avoid them.

Bechara and Damasio suggest that, since normal volunteers avoided the bad decks even before they had conceptualized the reason but after their skin response showed anxiety about those decks, something in the brain was acting as a sort of intuition generator. Remarkably, the normal players who were never able to figure out, or at least articulate, why two of the decks were chronic losers still began to avoid them. Intuition, or gut feeling, turned out to be a more dependable guide than reason. It was also more potent than reason: half the subjects with damage to the inferior prefrontal cortex (which includes the orbital frontal cortex) eventually figured out why, in the long run, decks 1 and 2 led to net losses and 3 and 4 led to net wins. Even so, amazingly, they still kept choosing from the bad decks.

Decision making, then, clearly has not just a rational but also an
emotional component. Damage to the inferior prefrontal cortex seems to rob patients of key equipment for accessing intuition. This finding is particularly important, I realized, because it mirrors the situation in OCD patients, who have the opposite malfunction of the very same brain area. OCD patients, who have an
overactive
inferior prefrontal cortex, get an excessive, intrusive feeling that something is wrong, even when they know that nothing is. In patients in the gambling study, these areas were damaged and therefore
underactive
; these patients failed to sense that something was wrong even when they knew, rationally, that something was. The normal subjects in the gambling study felt something was wrong when it was wrong, even if they didn’t know why. This all constitutes powerful evidence that the orbital frontal cortex is involved in generating the intuitive feeling “Something is wrong here.”

A second overactive region we detected on the PET scans of the brains of OCD patients was the
striatum
. This structure is composed of two major information-receiving structures, the
caudate nucleus
and the
putamen
, which nestle beside each other deep in the core of the brain just in front of the ears. The entire striatum acts as a sort of automatic transmission: the putamen acts as the gear shift for motor activity, and the caudate nucleus serves a similar function for thought and emotion. The striatum as a whole receives neuronal inputs from so many other regions of the brain that it rivals, for sheer complexity, the central switching station for the busiest telecom center imaginable, with signals arriving and departing in a buzz of perpetual activity. All areas of the cortex send neural projections to the striatum; so do parts of the thalamus and the brainstem, as shown in Figure 2 on Chapter 2.

But what particularly intrigued me was the fascinating traffic pattern connecting the striatum and the cortex. One set of neuronal projections into the striatum originates in the prefrontal cortex, especially in regions associated with planning and executing such complex behaviors as the manipulation of mental images. Small clusters of projections formed by these prefrontal arrivals are called
matrisomes
. The matrisomes are typically found near distinct microscopic patches that stipple the striatum; they are called
striosomes
. The striosomes, too, receive some input from the prefrontal cortex, in particular the areas most intimately associated with emotional expression: the orbital frontal cortex and anterior cingulate cortex. These are the very cortical structures that PET scans have shown to be overactive in OCD. But the primary inputs to these striosomes are the polar opposites of the thoughtful, rational prefrontal cortex: the striosomes are also bombarded with messages from the limbic system. The limbic system comprises the structures that play a critical role in the brain’s emotional responses, particularly fear and dread. It is the limbic system’s core structure, the amygdala, that seems to generate fear and dread. And it is the amygdala that projects most robustly into the striosomes’ distinctive patches.