This is a copy of a letter written to Dr. Greek long ago (July 2003) in response to his request for a written contribution from me. Everything I say in this letter is the honest truth of what I think now, as I did then, with regard to cognitive neuroscience in the non-human primate. At the foot of the letter I add a glossary of terms unfamiliar to other readers.
Dear Dr. Greek,
Thank you for your letter of July 8 inviting me to contribute a chapter to your new book on the scientific evaluation of the animal model in science and medicine. It seems a highly worthwhile and timely project. Unfortunately, because of my–deserved or undeserved–reputation, to which you kindly refer, I am unable to contribute the chapter that you solicit. I have a very active research program, a splendid group of graduate and undergraduate students to teach, and an apparently never-ending list of meetings and writing commitments. In a word, I’m swamped.
However, because I think the issue is legitimate and important, and you are interested in hearing both sides of the controversy, I cannot refrain from addressing it here with a few words, although only sketchily. Of course, I presume you see me, correctly, on the side of those who believe that the animal model is extremely useful, at least for some aspects of neuroscience. Indeed, I firmly believe that, with regard to the cerebral cortex, there is no adequate substitute for the non-human primate model (no set of algorithms, no computer simulations, no inferences from human imaging or scalp electrophysiology). The value of the primate model, in what pertains to cognitive functions and the role of the cortex in the human, rests in the homology between the cortex of the non-human primate and that of the human.
That homology is structural as well as functional. As you probably know, the cytoarchitectonic structures of the two cortices are very similar, almost indistinguishable from each other. Functionally, the homology is just as striking. Here I am referring to the physiological mechanisms and principles of operation of the principal cognitive functions (perception, attention, memory, intelligence); not language, of course, which is exclusive patrimony of our species. Certainly, human cognition is immensely richer than monkey cognition, but the same essential network structure and dynamics can be recognized in the cortex of the two species. I do not need to explain to you the implications of the similarities in cortical structure and function for the pathogenesis, etiology, diagnosis, and treatment of certain nervous and mental disorders, even though some of those implications may not be direct or immediate (“lifesaving”).
To be sure, we have to be aware of the limits of the homology and of the important and undeniable inter-species differences. We have to also avoid the simplistic, indeed silly, assumption that homology is reducible to genetic identity. In the cortex, as in genetics, relationship is what really matters. Relationship–between cortical cell assemblies or between genes–is what ultimately defines the cognitive structure (percept, memory, etc.) or the phenotype. In the 21st century, as I see it, both cognitive neuroscience and genetics will finally make the much-needed Copernican shift from the sterile down-spiral of reductionism into molecules to the more holistic view of how biological systems operate (I recommend to you Hayek’s Sensory Order, U. Chicago, 1952 and my Cortex and Mind, Oxford, 2003, sorry I have no extra copy at hand to give you). For that crucial shift, the primate cortical network model is going to be pivotal.
For many years, in my laboratory, we have been working on the neuronal foundation of memory and the role of the cortex, especially the prefrontal cortex, in it. It is difficult research, with its problems and limitations, like any research in complex systems. It is also quite rewarding and productive. Again, to a person like you I do not have to explain, because you will readily understand, that we study neural activity at the cellular level because we are interested in cortical systems and networks and in the functional relationships between neurons and between cortical areas. Much of the knowledge we acquire in the monkey is undoubtedly transferable to the human. Some of it is not. On the whole, our work is not only consistent with, but also supports, the network model of cortical function. Nowadays it gives me considerable satisfaction to see that model slowly but surely penetrating current thinking in cognitive neuroscience.
However, precisely because of the homology, indeed the unquestionable similarities, between human and monkey in cortex and cognition, we face some special problems. In your letter you state that you are not interested in ethical or philosophical questions. Yet, in our field, some of these questions are inextricable from scientific questions. In the first place, on scientific grounds alone, we cannot tolerate that our monkeys experience stress or pain. You know how detrimental both stress and pain can be for cognitive functions. Stress and pain, even minimal, can be serious obstacles to the attainment of our scientific aims, especially when we have to use behavioral tests for cognitive assessment. We have to avoid them in our monkeys at all costs. This is something that people in the animal rights movement do not seem–or want–to understand, even though I have no trouble understanding some of their ethical concerns. (In fact, years ago, when we had a miserable regulatory climate, I was gladly one of their best allies.)
Then, of course, there are the very legitimate ethical and philosophical questions of experimenting on animals that are very much like us but lack one of our cognitive functions, namely (no pun intended), language; they cannot tell us what pleases or displeases them, even though they are fully sentient. Fortunately, of course, they have emotional “language.” (I am sure you know it but, in case you don’t, I highly recommend to you Darwin’s wonderful book on emotional expression in man and animals, reedited by Eckman). Thus, by vocal, facial and bodily signs, monkeys can indeed tell us how they feel. (After almost half a century of working with macaques, I think I can proudly add “monkey language” to the list of the other six that I can understand reasonably well!)
So, the challenge in the study of primate cognitive neuroscience is to apply a judicious combination of scientific, ethical, and philosophical precepts. The ideal balance is difficult to achieve, but the basic principles are simple enough: (1) Impeccable scientific rationale toward practical and meaningful goals; (2) Minimum number of animals to attain those goals; (3) Exquisite care of the animals; and (4) Exhaustive analysis of the data to obtain maximum yield of information and to avoid duplication.
I’ll finish by going back to the scientific aspects, which are those that interest you. Right now, we are investigating the coupling, in higher cognitive functions, between neural activity–as reflected by neuronal discharge and local field potentials–and hemodynamic change, something that cannot be done in the human. The results of this exciting research, in my view, may have enormous implications for our understanding of the biophysics of functional imaging methods in the human and the dynamics of cortical networks.
Although I cannot write the article that you graciously invited me to write (it almost seems that this long letter ought to do!), you are naturally welcome to visit my website, where you can find the details of my use of the monkey model in cognitive neuroscience. That would undoubtedly give you a better perspective of my views on the issue than I have been able to convey in these lines.
I wish you success with your book, which I look forward to reading after it appears in print. I hope you will, indeed, cover both sides of a very important controversy.
Yours sincerely,
Joaquín M. Fuster, M.D., Ph.D.
Professor, UCLA School of Medicine
Glossary
Cognitive Neuroscience. The neuroscience of knowledge and memory, that is, of what we know and remember (more).
Cytoarchitecture. Structural geometry of cells and fibers in the brain.
Etiology. The cause(s) of disease (more).
Genes. Chemical substances inside cells that encode the hereditary characters of the organism (more).
Hemodynamic change. Change in blood flow in nerve tissue as a result of its nervous activation. It is an indirect measure of brain activity currently used in hospitals, clinics, and laboratories. Extremely useful in cognitive neuroscience to assess the cerebral foundation of higher cognitive functions, such as memory.
Homology. Equivalence of anatomical and physiological brain features across animal species.
Neural networks. Assemblies of interlinked cortical neurons (brain cells) that by their patterns of connectivity encode memories and actions.
Pathogenesis. The anatomical and physiological foundations of disease.
Phenotype. The physical manifestation of the developed hereditary traits (more).
Prefrontal cortex. The anterior cortex of the frontal lobe, essential for organizing behavior. It plays a vital role in all the executive functions (working memory, decision-making, planning, etc.) that serve behavior organization (more).
Reductionism. The scientific search of ever-smaller physical elements (down to particular chemical molecules) in attempts to understand cause and effect in higher functions (for example, cognitive functions).
Speaking of Research 