The Accidental Mind

Oslo, 1964.  A malaise had settled over the community of neurobiologists investigating the biological substrates of memory.  Obviously, memories can last for the lifetime of an animal.  Thus it was expected that experience should produce long-lasting changes in neuronal function to underlie the memory trace. The best guess for the aspect of neuronal function changed by experience was synaptic transmission. Synaptic transmission is the fundamental mode of rapid communication between neurons and so is central to information processing in the brain. The dominant hypothesis was that particular patterns of neuronal stimulation delivered to neurons with electrodes (thereby mimicking actual experience in the world) would produce long-lasting changes in the strength of synaptic transmission.  The problem at the root of the malaise:  no evidence whatsoever for this postulated mechanism.   The longest-lasting changes that had been recorded persisted for only a minute or two— a time scale that was totally insufficient for memory storage. 

In 1964, Terje Lomo was a doctor in the Norwegian navy, soon to be discharged.  On leave in Oslo to look for a job, he bumped into the neurophysiologist Per Andersen, walking down the street.  After an animated conversation about synapses and neurons, he agreed to join Andersen’s laboratory as a Ph.D. student.  At that time, recordings of synaptic function in the brain were, for a variety of technical reasons, very difficult.  Most recordings of neuron-to-neuron synapses had been performed in the spinal cord (these yielded the aforementioned brief facilitation). Andersen had developed techniques to record synaptic transmission in a brain region called the hippocampus, buried deep within the temporal lobe of anesthetized rabbits.  Lomo took up these techniques and began to probe the properties of hippocampal synapses.  In 1965, he had the first hints that repeated stimulation (120 pulses at 12 pulses/second), could cause synapses to persistently increase their strength.  However, it was not until the Fall of 1968, when Lomo was joined by Tim Bliss, a visiting British scientist with an interest in memory storage, that things really took off.  In their first experiment together they used a design in which a single test pulse was delivered to measure the synaptic strength.  After recording a series of stable baseline responses, a “conditioning stimulus” consisting of 300 pulses at 20 pulses/second was delivered.  Following several repetitions of this conditioning stimulus, the response to the test pulse was larger, reflecting an increase in synaptic strength.  Most importantly, this increase persisted, not for a minute or two, but for many hours—as long as the recording could be maintained.  That day in 1968 marked the first real glimpse of a memory storage mechanism in the brain and began the modern era of memory research, in which memory is analyzed at a cellular and molecular level.

Lomo and Bliss called their new phenomenon long-lasting potentiation or LLP.  However, as often happens in science, this name didn't stick, and it is now known as long-term synaptic potentiation or LTP (Bliss once remarked that the expression “LLP” didn't catch on because it made the speaker sound as if he were in need of urgent assistance).   Starting in 1970’s, LTP created tremendous excitement among memory researchers not only because of its duration, but also because of it relation to a well-known neurological case. 

H.M. was a  patient who underwent surgery to control otherwise intractable epilepsy. The surgery, which involved bilateral resection of his hippocampus and some surrounding tissue, cured the epilepsy, but left him with two profound memory impairments:  he could no longer recall facts and events for a period of 1 – 2 years prior to the surgery, and, even stranger, he could no longer form any new memories for facts and events.  Thus, the hippocampus was already implicated in memory storage.  At that time, the idea was that LTP (and its later-discovered mirror twin, long-term synaptic depression or LTD) were rare phenomena, that would only be found at a few specialized synapses in the brain with particular roles in memory storage.  That has not turned out to be the case at all: LTP and LTD are nearly ubiquitous properties of synapses and can be found everywhere from the spinal cord to the most recently evolved portions of the frontal cortex, and almost every brain region in between.  Even the most ancient parts of our brain, that we share with fish and lizards, regions that control basic functions like spinal reflexes, breathing, temperature control and the sleep/wake cycle, have the LTP and LTD and hence the capacity to be modified by experience.

Montréal, 1954.  

Fortunately, Peter Milner and James Olds didn’t have perfect aim with their electrodes. While postdoctoral fellows at McGill University under the direction of the renowned psychologist Donald Hebb, Olds and Milner were conducting experiments which involved implanting electrodes deep into the brains of rats.  The implanting surgery was done under anesthesia and the electrodes, two of them, half a millimeter apart, were then cemented to the skull. After a few days to recover from the surgery, the rats were fine.  Long, flexible wires were attached to the electrodes at one end and to a electrical stimulator at the other, to allow for discrete activation of the specific brain region where the tips of the electrodes had come to rest.  One particular Fall day, Olds and Milner were testing a rat in which they had attempted to target a structure called the midbrain reticular system.  Located at the midline of the brain, at the point where the base of the brain tapers to form the brainstem, this region had previously been shown by another lab to control sleeping and waking cycles.  But in this surgery, the electrode had gone astray and it wound up, still at the midline, but in somewhat more forward position in the brain, a region called the medial forebrain bundle.

The rat was placed in a large box with corners labeled A, B, C, and D and was allowed to explore freely.  But, whenever the rat went to corner A, the experimenter pressed a button to deliver a brief, mild electrical shock through the implanted electrodes.  After a few jolts, the rat kept returning to corner A and finally fell asleep in a different location.  The next day, however, the rat seemed even more interested in corner A. Olds and Milner were excited: they believed that they has found a brain region that, when stimulated, provoked curiosity.  However, further experiments on this same rat soon proved that not to be the case.  By this time, the rat had a acquired a habit of returning often to corner A to be stimulated.  The experimenters then tried to coax the rat away from corner A: they would give a shock every time the rat made a step in the direction of corner B.  This worked all too well—within 5 minutes, the rat was in corner B.  Further investigation revealed that this rat could be directed to any location within the box with well-timed brain shocks—brief ones to guide the rat to the target location and more sustained ones once there.

Many years earlier, the psychologist B.F. Skinner had devised the operant conditioning chamber or “Skinner Box” in which a lever press by an animal triggered either a reinforcing stimulus such as delivery of food or water, or a punishing stimulus like a painful footshock.  Olds and Milner soon adapted the chamber so that a lever press would deliver direct brain stimulation through the implanted electrodes.  What resulted was perhaps the most dramatic experiment in the history of behavioral neuroscience—rats would press the lever as many as 7,000 times per hour to stimulate their brains.  They weren’t stimulating a “curiosity center” at all-- this was a reward circuit, the activation of which was much more powerful than any natural stimulus.  A series of amazing experiments revealed that rats preferred reward circuit stimulation to food (even when they were hungry) and water (even when they were thirsty).   Self-stimulating male rats would ignore a female in heat and would repeatedly cross footshock-delivering flood grids to reach the lever.  Female rats would abandon their newborn nursing pups to continually press the lever.  Some rats would self-stimulate 2,000 times per hour for 24 hours, to the exclusion of all other activities.  They had to be unhooked from the apparatus to prevent starvation!

Further work was done to systematically vary the placement of the electrode tips and thereby map the reward circuits of the brain. These experiments revealed that stimulation of the upper surface of the brain, the neocortex, where sensory and motor processing reside, produced no reward—the rats continued to press the lever at chance levels.  However, deep in the brain, there was not just a single discrete location underlying reward.  Rather, a group of interconnected structures, all located at the base of the brain and distributed along the midline comprised the reward circuit. These included a variety of locations with names like the ventral tegmental area, amygdala, medial forebrain bundle and septum as well as portions of the thalamus and hypothalamus.  Not all of these areas were equally rewarding.  Stimulation in some parts of this “medial forebrain reward circuit” could support self stimulation rates of 7,000 times/hour while others only elicited 200 times/hour.

It’s hard to imagine now, but at the time, the notion that motivational or reward mechanisms could be localized to certain brain regions or circuits was highly controversial.  The dominant theory, which had held sway for many years, was that excitation of the brain was always punishing and that learning and the development of behavior could be explained solely by punishment avoidance.   This was called the “drive-reduction hypothesis.”  In Olds’ characterization of this theory, “…pain supplies the push and learning based on pain reduction supplies the direction.”  There was no need for reward: it was all stick, no carrot. The pioneering experiments of Olds and Milner clearly demolished the punishment-only model in favor of a more comprehensive, hedonistic view that “behavior is pulled forward by pleasure as well as pushed forward by pain” (Olds, 1958).  In this way, brain pleasure/reward circuits were revealed as important determinants of behavior.

The afternoon rains have ended leaving the air briefly free of smog and allowing that distinctive Thai perfume, frangipani with a faint note of sewage, to waft over the shiny streets.  It’s the early evening.  I hail a tuk-tuk, a 3-wheel motorcycle taxi, and hop aboard.  My young driver has an entrepreneurial smile as his turns around.

“So….you want girl?”

“No.”

“I see.” 

Long pause, eyebrows slowly raised. “You want boy!”

“Uh, no.”

Longer pause. Sound of engine sputtering at idle.  “You want ladyboy?”

“No.”

“I got cheap cigarettes…Johnnie Walker...”

“No thanks.”

Voice lowered. “You want ganja?”

“No.”

“Coke?”

“No”

“Ya baa (methamphetamine tablets)?”

“Nope.”

A whisper now. “Heroin?”

“No.”

Voice raised back to normal.  “I can take you to cockfight.  You can gamble!”

“I’ll pass.”

Just a little bit irritated now.  “So, farang, what you want?”

“Prik noo,” I respond.  “Those little mouse shit peppers.  I want some good, spicy dinner.”

As we tear through the streets to the restaurant, blasting through puddles, I’m left wondering-  aside from various shades of illegality, what do these offers have in common?  What is it, exactly, that makes a vice? 

For those of you who just can't get enough of me running my mouth on the topic of brain evolution, here's a podcast from the American Physiological Society aka The Home Team.  It's episode 12 of the "Life Lines" series and it also features kewl nooz on athletic blood doping and fetal alcohol syndrome.

Phil Hogan, writing in The Observer (UK), says he's made it up to Chapter 5 in The Accidental Mind and offers this useful summary of the book so far...

"Now, where was I? Ah, the book, The Accidental Mind by David J Linden. It's brilliant, I'm sure, though the more I read the less I know. I gather from his general thesis that brains are not as brilliantly engineered as we like to think. We might have a hundred billion cells going at it round the clock but they're constantly misfiring or getting the wrong end of the stick. Brains are more Heath Robinson than Bill Gates, having evolved over the aeons simply by growing new pipes and cables on top of the crappy old ones. 

And while ordinary electrical signals happily travel down copper wire at almost the speed of light (669 million mph), brain signals go as fast as a Ford Fiesta. Not only that, but you have to imagine a Ford Fiesta with stuff falling out of the boot. And - this is the best bit - to get from one cell to the next you have to jump out of your Ford Fiesta and swim with your message across a synaptic channel of neurological gloop before getting in another hopeless Ford Fiesta at the other side, air hissing out of tyres, wing mirrors hanging off. That's how high tech it is. It's a wonder we can find our way to the bus stop."

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Apparently, The Accidental Mind has won the Silver Medal in the "Science" category at the 2008 Independent Publisher Book Awards.  I didn't even know I was entered and only learned about the award through the dubious practice of self-googling (which is prohibited in many of the world's religious traditions).

On Monday, I unlocked the door to my office and found the place totally trashed.  My scanner was smashed to bits, books were strewn everywhere, my desk and chair were crushed.  My first thought was, "Damn.  Those creationists who've been sending me all the death threats since The Accidental Mind was published managed to get in here."  Then, I realized that all the mayhem resulted from a single action- the huge wall-mounted cabinets full of books had broken loose and had come crashing down (one would have neatly bisected my cranium, had I been sitting at my desk.) Examination of the cabinets revealed that, back in 2002, the contractors had failed to secure the cabinets to the studs, relying solely upon flimsy drywall anchors, thereby saving themselves about 30 min of labor and 50 cents worth of screws.

From the promotional material for Gary Marcus' new book Kluge:

"Are we noble in reason? Perfect, in God's image? Far from it, says New York University psychologist Gary Marcus. In this lucid and revealing book, Marcus argues that the mind is not an elegantly designed organ but rather a "kluge," a clumsy, cobbled-together contraption. He unveils a fundamentally new way of looking at the human mind -- think duct tape, not supercomputer -- that sheds light on some of the most mysterious aspects of human nature."

Damn, that's clever.  I wish I had thought of that.   From Chapter 1 of The Accidental Mind:

"It is the widely assumed that since the mind is in the brain, and this is a great achievement, that the design and function of the brain must then be elegant and efficient.  In short, it is imagined by many that the brain is well-engineered. Nothing could be further from the truth. The brain is, to use one of my favorite words, a kludge (pronounced ‘klooj’), a design that is inefficient, inelegant and unfathomable, but which nevertheless works.  More evocatively, in the words of the military historian Jackson Granholm, a kludge is “an ill-assorted collection of poorly matching parts, forming a distressing whole”. What I hope to show here is that at every level of brain organization, from regions and circuits to cells and molecules, the brain is an inelegant and inefficient agglomeration of stuff, which nonetheless works surprisingly well.  The brain is not an optimized generic problem solving machine.  It was not designed at once, by a genius inventor, on a blank piece of paper.  Rather, it is a very peculiar edifice which reflects millions of years of evolutionary history.  In many cases, the brain has adopted solutions to particular problems in the distant past which have remained over time and have been recycled for other uses or have severely constrained the possibilities for further change.  What’s important about this point as applied to the brain is not merely that it challenges the notion of optimized design.  Rather, appreciation of the quirky engineering of the brain can provide insights into some of the deepest and most particularly human aspects of experience, both in day-to-day behavior and in cases of injury and disease."

So, I had a good laugh today, when reading a review of Marcus' book in Nature by Sandra Aamodt which included the following.

"In Kluge, psychologist Gary Marcus presents a lively tour of the shortcomings of human minds and concludes that evolution has left us with something of a mess. In an argument reminiscent of David Linden's The Accidental Mind, Marcus makes his case by describing cognitive difficulties, including false beliefs, linguistic ambiguity, impulsiveness and mental illness."

Yeah.  Sumbitch eatin' mah lunch. 

"Closure is a greasy little word which, moreover, describes a nonexistent condition.  The truth, Venus, is that nobody ever gets over anything."

--Martin Amis, House of Meetings

The Times of London reports that British neurosurgeon Henry Marsh has been visiting Kiev in the Ukraine, twice a year, in order to assist and train a Ukrainian colleague.  In London, Marsh would use an expensive  (30,000 pound) specialized medical drill to create holes on the skull.  But, due to lack of funds in Kiev, he and his colleague have made do with a handheld Bosch drill favored by home hobbyists.  Cost: 30 pounds.  If this cheapskate solution becomes known in the USA, I'm afraid that the insurance companies will reimburse for nothing else.

From Germany comes the latest in backpacker cuisine, the cheeseburger in a can.  A steal at 3.95 euros.

To paraphrase Michael Pollan...

"Eat beef.  Processed in a factory.  With lots of packaging."

Update:  they also sell dehydrated wine.  I swear.  I couldn't make this up if I tried.

In my family, when we get our teeth into a joke, we don't like to let go until it's good and dead.