Brain and Mind

May 13 and 14, 2004
Roone Arledge Auditorium

May 13, 9 a.m.–12 p.m
Session I: Brain Structure

Lee C. Bollinger: Welcoming Remarks

"I want to take this occasion just to announce that Columbia will be launching—we are launching, as of this moment—an institute for neuroscience that will be part, eventually, of the major center for the study of the brain and behavior."

"The study of the brain and how it works is clearly central not only to the curing of disease, but also to the understandings that we bring to every, virtually every, area of life: social sciences, the professions, and the humanities. And it is Columbia's goal to try to bring as many scientific advances as we possibly can to this area, and also to integrate it with other areas of knowledge."

Gerald D. Fischbach: Neuroscience and Neuropathology—Converging Streams

"What you will hear today, this morning, this afternoon, and tomorrow, is a range of subjects of how we're approaching modern brain science, ranging from studies at the atomic level, reaching out toward chemistry and nanoscience about the structure of key molecules in the brain, through an understanding of how groups of nerve cells work together to form small circuits in the brain that we know now account for simple behaviors."

"These connections between the cells are far more complex than their number would imply because they change with experience. Not only are they laid down by genetic programs but they're influenced by everyday life, by what you are listening to right now."

"We now know more than twenty different diseases, congenital myasthenias, known as channelopathies, where muscle weakness occurs because of defects in the postsynaptic membrane and the presynaptic membrane . . . [W]e purified a protein, shown here diagrammatically, known as neuregulin, which when added to muscle fibers . . . caused these muscle cells to synthesize and accumulate many more acetylcholine receptors. And we believe this is a vital factor made in motor neurons that maintains the integrity of the postsynaptic membrane."

Roderick MacKinnon: Potassium Channels

"What's interesting is that across the tree of life, many molecules that are used in various circumstances are highly conserved, and it turns out that many of the ion channels, in fact most of the ion channels, are highly conserved across the tree of life. . . . [W]e can learn, in fact, about potassium channels that are in our own nervous system by looking at the structure of a potassium channel from a bacterium."

"The voltage-dependent channels, the voltage-dependent potassium and sodium and another kind, calcium channels, are life's transistors. And transistors are very important in electrical devices because they are conductors that conduct only at certain base voltages and not at others. . . . [N]ature has actually made transistors that are much, much better than the best transistors that material scientists can make."

"You look in the venom of these organisms and ask if these same very specific interactions work against the channels from the bacteria and from the prokaryotic organisms. And what you find is that they do. For example, inside the tail of the scorpion, it has venoms that bind with high affinity. They apparently evolved to inhibit eukaryotic ion channels in us, for example, and yet these things inhibit very specifically the ion channels, even in bacteria . . . They've maintained their structure over the eons of evolution."

Thomas M. Jessell: The Assembly of Neural Circuits in the Developing Brain

"One of the challenges in neural science is to understand the relationship between the organization of neural circuits and the emergence of behavior. And over the last fifty years or so, in large part through clinical studies, we've come to understand that circuits in different regions of the brain are assigned to different specific behavioral functions."

"In trying to understand the progression of circuit assembly, perhaps the important key, at least at a reductionist level, is the idea that the driving force for circuit assembly is the assignment or the allocation of neurons with particular identities."

"One can think of this developmental principle in two important steps: how extrinsic inductive signals control transcription-factor expression, [and] how these transcription factors direct the downstream expression of proteins that control neuronal circuits. And so I'm going to try and illustrate how these two principles shape motor neuron projections, shape sensory innervation into motor neurons, and control interneuron diversity that influences motor output."

Richard Axel: Scents and Sensibility: Towards a Molecular Logic of Perception

"All organisms have evolved a mechanism to recognize sensory information in the environment and transmit this information to the brain, where it then must be processed to create an internal representation, a map of the external world."

"Individual odors will activate a subset of receptors, which in turn will activate a subset of points in brain space such that the quality of an odor may be defined by unique spatial patterns of activity in the brain."

"Different odors elicit different patterns of activity, and that these patterns of activity can be read out as specific behaviors. The implication is that the nervous system, in the case of olfaction, dissects and deconstructs the odor into its structural components such that a given odor is represented by multiple spatially invariant loci of activation."

"There is not likely to be a single master area to which all signals ultimately report in any sensory system. Moreover if there were, who would look at it, who would read its spatial image? Rather, the sensory representation, I would argue, is likely to be distributive, and how this distributive ensemble is read and ultimately elicits appropriate behavioral or cognitive responses is what Vernon Mountcastle has described as 'the big in-between, the ghost in the machine.'"

Eric Kandel: The Storage and Persistence of Memory

"Learning experiences produce long-term changes by altering gene expression. So insofar as you remember anything in these lectures . . . it's because gene expression is being altered in your brain. . . . And the reason that alteration is important is because it gives rise to the growth of new synaptic connections."

"Despite the fact that explicit memory storage and implicit memory storage are radically different in terms of the neural systems that use them, and the nature of those neural systems, the storage mechanism per se shares core features in common. In each case a signaling system that involves, importantly, the cyclic AMP-dependent protein kinase activates genes, they give rise to the growth of new synaptic connections, and a modulatory system is importantly recruited to trigger the long-term process."

"The study of the prion in a completely different context, in the study of memory storage, has revealed a new class of properties about prions that was never previously anticipated. And that is that a physiological signal can regulate the conversion, and that the form that is the self-propagating form is not a killer form, but it is the good, healthy, functional form of the protein that allows the memory to be carried forward in time."

May 13, 1:30 p.m.–5 p.m.
Session II: Brain Function and Disease

Moderator: Richard Mayeux: Introductory Remarks

"The burden of brain disease—and by that I mean all neurologic, psychiatric, and neurosurgical diseases—is high, one in seven people have a disorder of the brain. . . . Studies of most brain and nervous-system disorders, such as these in twins, suggest that at least 50 percent of the societal burden is likely to be genetically influenced. But most of these common neuropsychiatric disorders are genetically complex."

"I think what you're going to hear this afternoon should give you hope, the hope that someday devastating diseases of the brain and nervous system will be detected earlier in life, perhaps even before birth, and effectively treated before the onset of disability, [and] the hope that our neurologic and psychiatric hospitals can become centers for prevention of disease rather than for the treatment of chronic and progressive disorders."

Judith L. Rapoport: Brain Development in Healthy, Hyperactive, and Psychotic Children

"Prospective studies give a unique sensitivity which we've never had before, that different brain regions develop at different times, and that there's some regional difference in heritability."

"Interestingly the area that by the end of adolescence in fact looks the healthiest still, . . . the dorsolateral prefrontal cortex, is the one that in adults people make the most fuss about, but that isn't where it started. And this was really an arresting sight."

"There's this progressive back-to-front wave of loss. It may be an exaggeration of the normal developmental pattern, and I would love speculations from geneticist colleagues in the audience. It is associated with candidate gene risk but may have a restitutive function, and that we are very interested in."

Huda Y. Zoghbi: Rett Syndrome and MeCP2: Steady Development

"A handful of families even for a disease that's sporadic would allow one to identify the genetic basis eventually, and those families can be very precious and valuable and should be pursued."

"If you have the typical random pattern, as we see in classic cases of Rett Syndrome, where half of the cells have the mutant allele that's enough to give that classic Rett Syndrome. But if the patients are fortunate where they happen to have the majority, maybe 85 percent, 90 percent of their cells expressing the X chromosome with the healthy allele they'll have mild mental retardation or autism. . . ."

"Another thing we've noticed about these [Rett] mice is that, while we notice they have tremors and they have all their neurologic problems, anytime we try to handle them they appear extremely anxious, they're very tremulous, very nervous. So we wanted to evaluate do they really have anxiety-like behavior, and we've done a variety of tests all of which converge to show that they do have anxiety-like behavior."

"What's the molecular basis of this anxiety? Could drugs that reduce anxiety help this phenotype? Would it be if we treat these animals before they become symptomatic and decrease the anxiety they might go through the course of their illness, improve their outcome? So such studies are ongoing in the animals in the hope if we find a benefit we can at least treat one symptom that makes the life better for the patients."

Michael Rutter: Neurodevelopmental Disorders

"The disorders involve, in all cases, some degree of specific or general cognitive impairment, and there is a tendency for overlap among these different neurodevelopmental disorders. They have things in common, but they also have some quite striking differences. In all cases the genetic influences are quite strong, but there is evidence that environmental factors are also contributory."

"One of the things that came out of the first small-scale twin study that Susan Folstein and I did was that, although there was concordant for autism, there was also an association with what we came to call the broader phenotype. . . . [B]ack in the seventies, then, this was the first indication that we needed to think in terms of the genetic liability for autism as going well beyond autism as it was conceptualized at that time."

"In theory of mind, normal individuals' mentalizing processes associated with activation of both the prefrontal and the temporal areas, whereas in individuals with autism that is less so, there is some of that. But what is more striking is reduced connectivity between the extrastriate regions and the superior temporal sulcus. . . . [I]t appears that it's not so much that there are various areas that are malfunctioning, but that in some way it's the connectivity across areas that is the striking feature."

"With the exception of ADHD, what is striking is that drugs have proved remarkably lacking in benefit. There are some drugs that in some children make some difference, but if you compare it with ADHD or depression or schizophrenia or bipolar disorder one has to say, here we have what all of us think are systems disorder, and yet we find nothing of any great interest in drugs that affect neurotransmitters. Well maybe we're looking at the wrong neurotransmitters. But it is still a puzzle."

Nora D. Volkow: Drug Addiction: The Brain in Disarray

"For the past ten years of neuroscience research, it has become clear that the dopamine system which is targeted by drugs is not per se relevant, perhaps to hedonic pleasure, as we call it, but actually signals something that is more indispensable for survival and motivation, and that it signals the saliency of a particular stimulant. And pleasure is one of the characteristics that make the stimulus salient."

"While as a group cocaine abusers do have lower levels of dopamine D2 receptors, and this in turn may tell me something about propensity for taking drugs and addiction, it certainly is also telling me that it is not sufficient to account for addiction, because if it were sufficient to account for addiction then how do you happen to explain a cocaine abuser with levels that are normal or a normal control with levels that are lower?"

"Indeed, in animals, overexpression of dopamine D2 receptors dramatically reduces alcohol intake, and does provide evidence that high levels of dopamine D2 receptors indeed may be protective, not just in general of not taking drugs, but protecting you against taking high doses of a drug, which is ultimately what leads to addiction. . . ."

"Certainly dopamine D2 receptors per se are not accounting to addiction, not at all, but they may be modulating and regulating your propensity to become addicted or severely addicted depending on whether you have the genes or you have the environmental interventions that may then lead to the addictive process. And that's how I basically right now view the process of the dopamine D2 receptors."

May 14, 9 a.m.–12 p.m.
Session III: Biology of Mind

David Cohen: Introductory Remarks

"As Eric Kandel and I were commenting to each other yesterday, a session of this nature is something that we could have only fantasized about when we began in the brain sciences some forty years ago, yet the questions that will be discussed today are the kinds of questions that initially attracted many of us to the brain sciences, even though the prospects of any kind of experimental answers at the time were exceedingly dim. That we're here today in a session of this sort really is testimony to the explosive development of brain research over the past four decades."

Nancy Kanwisher: fMRI Investigations of Human Extrastriate Cortex: People, Places, and Things

"The face area, what it's doing for us is both detecting and identifying faces, and it plays little role in detecting or identifying other kinds of stimuli."

"We've shown that the activity in these regions is very strongly modulated by visual attention. So if you have exactly the same retinal information hitting your eyes from a stimulus, if you choose to pay more attention to faces than places you can essentially crank up and down the dials on your own visual system."

"Maybe natural selection has produced special-purpose machinery that's hardwired into the brain, and maybe that's why those things land in systematic locations in the temporal lobe. But here's another equally plausible story: Each of us individuals looks at these stimuli very frequently in daily life throughout our lives, and we know that the cortex is very shaped by experience, as several of the preceding lecturers have described. And so maybe the visual cortex just kind of does statistics on the input, and says, I'm seeing a lot of these and those and those, and let's allocate big chunks of cortex to the things we see a lot."

"I think the answer in many cases will be no, there aren't highly selected bits of brain allocated to high-level cognitive functions, there are general purpose bits that do a lot of cognition for us."

William T. Newsome: Decision Making and the Neural Representation of Value

"There are internal representations within the brain of value, the likely value, of certain outcomes and certain actions that we all take, and these internal representations of value influence decisions just as much as does the sensory input, and sometimes more so."

"We've successfully trained this animal to do what Herrnstein said they would do to get an optimal solution to this exploration-exploitation problem, which is to match the ratio of their responses to the ratio of the rewards that they're experiencing."

"Now what that means is that the computation of value has to be local in time. If the animal were estimating over this entire period here, trying to get his estimate of the likelihood of getting a reward, he would not change this quickly, he'd keep cruising past this inflection point and he would only change very slowly out here, okay? So this animal in order to compute value must be paying attention to the most recent trials that he's experienced."

"What does the neuron do during that interval when he's trying to decide? . . . We got a lot of activity when the monkey's choosing the target in the response field, as we would expect. We've got low activity when he's choosing outside the response field. And this activity titrates out nicely by value."

Christof Koch: Towards the Neuronal Basis of Consciousness

"There seem to be mechanisms in the brain that prevent two very similar things from being the focus of attention at any given point in time, you can only be conscious of one thing, and then of course you can rapidly switch your attention and your consciousness to something else. And so that ultimately, that's expressed by neurons that compete for each other."

"We surmise that the neurons that underlie the consciousness, or the NCC, the neural correlates of consciousness, that they have to have direct access to the planning stages of the brain, which by and large are in the frontal part of the brain."

"What that tells us there are discrete stages in the visual system, in the visual hierarchy, and that at one stage you have the neuronal correlate of these after effects, for example, the afterimage that's probably in the retina, or [an] orientation-dependent after-effect in V1, and that visual consciousness has to arise at a higher stage. So again that's important because it tells you it's not just one holistic thing, but that there are discrete processing stages and consciousness seems to arise at or beyond a particular processing stage in the brain."

"If we distract the animal it seems to interfere specifically with trace but not with delay conditioning. And if we remove a part of the brain, ACC, that in humans is involved in something similar, you can again eliminate trace conditioning without interfering with delay conditioning or context-dependent conditioning."

John R. Searle: Consciousness, Causation and Reduction

"We are conscious, we have intentionality, we have free will, we have rationality, we have language, we have society, we have ethics, we have a self-conception which we're pretty reluctant to give up on, we're pretty fond of that self-conception. Now here's the question: How do we reconcile what we know about the world—so to speak, the basic facts—with that self-conception?"

"We have this tradition that says consciousness isn't really part of the material world, and we have a vocabulary that distinguishes between materialism, on the one hand, that says there isn't anything in the universe that isn't material, and dualism, on the other hand, that says no, we really live in two worlds, the mental world and the physical world. Now, I think both of those views are false."

"We should think of perception not as creating consciousness but a modifying a preexisting conscious field. Think of the conscious field that these guys have and then think of the perceptual inputs as creating the NCC, not for consciousness as such but for that particular percept, that particular modification of the conscious field."

"If we can overcome certain traditional errors, if we can overcome the mistake of supposing that we live in two different realms, then we can accept consciousness on its own terms, and begin to investigate, and now the investigation is well underway, how exactly it works in the brain."

Nancy Wexler: Concluding Remarks

"We have at Columbia all of this kind of interdisciplinary conversation going on. We have more patients just across the street and up the way, we have more scientists, and have more interaction, and we have spectacular meetings like this where everybody can hang out and talk to each other, and I think that's really how we're going to advance the next 250 years."

"It would be horrendous if all of the kind of phenomenal wealth we heard about the last two days cannot be translated for the benefit of people who are suffering. And we need economics, we need persuasion, we need politics, and we need everybody here today to try to reverse this trend and make these drugs more accessible."

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