Contains research objectives and reports on one research project.National Institutes of Health (Grant 5 ROl NB-04985-02)National Institutes of Health (Grant 5 RO1 NB-04897-03)U. S. Air Force (Research and Technology Division) under Contract AF33(615)-1747U. S. Air Force (Office of Scientific Research) under Grant AF-AFOSR-880-65National Science Foundation (Grant GP-2495)The Teagle Foundation, Inc.Bell Telephone Laboratories, Inc

Lettvin, Jerome Y.

McCulloch, Warren S.

Schnabel, C. P. G.

Wall, P. D.

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XXVIII. NEUROPHYSIOLOGYAcademic and Research StaffDr. W. S. McCulloch Dr. H. Hartman Dr. W. F. PickardDr. J. Y. Lettvin Dr. K. Kornacker Dr. C. P. J. SchnabelProf. P. D. Wall Dr. T. McLardy Dr. T. G. Smith, Jr.Prof. M. Blum Dr. A. Natapoff Dr. A. TaubProf. J. E. Brown Dr. S. A. Papert B. HowlandDr. R. M. Diaz Dr. Barbara C. G. Pickard W. H. PittsGraduate StudentsE. E. Fetz J. I. Simpson Barbara G. WickelgrenL. M. Mendell W. A. WrightRESEARCH OBJECTIVES AND SUMMARY OF RESEARCH1. Basic TheoryResearch on the functional organization of the reticular core of the central nervoussystem continues, in collaboration with Dr. William L. Kilmer of Michigan State Uni-versity.Our problem is to construct a theory for the reticular system which is compatiblewith known neuroanatomy and neurophysiology, and which will lead to testable hypothesesconcerning its operation.1, 2Our first and second approaches to this problem 3 were outlined in Quarterly Prog-ress Report No. 76 (page 313).We can report, at present, that we are embarked on a kind of iterative net statisticaldecision theory4 that is comprehensive, versatile, and penetrating enough to stand areasonable chance of success.5The computer modeling is being done at the Instrumentation Laboratory, M. I. T.,by members of Louis L. Sutro's group.W. S. McCullochReferencesI. W. S. McCulloch and W. L. Kilmer, "Introduction to the Problem of the ReticularFormation," in Automata Theory - Spring School 1964 (to be published by AcademicPress, Inc., New York).2. W. S. McCulloch, "What's in the Brain That Ink May Character?," Proceedings ofthe 1964 International Congress for Logic, Methodology and Philosophy of Science,Held in Jerusalem, August 26-September 2, 1964 (North-Holland Publishing Com-pany, Amsterdam, 1965).3. W. L. Kilmer, "On Dynamic Switching in One-Dimensional Logic Networks"(Information and Control, in press).This work is supported by the National Institutes of Health (Grants 5 ROlNB-04985-02 and 5 RO1 NB-04897-03), the U. S. Air Force (Research and TechnologyDivision) under Contract AF33(615)-1747, the U.S. Air Force (Office of ScientificResearch) under Grant AF-AFOSR-880-65, the National Science foundation (GrantGP-2495), and by grants from The Teagle Foundation, Inc., and Bell Telephone Labora-tories, Inc.QPR No. 80 249(XXVIII. NEUROPHYSIOLOGY)4. W. L. Kilmer, "Topics in the Theory of One-Dimensional Iterative Networks" (to bepublished in Information and Control).5. W. S. McCulloch, "Embodiments of Mind," in The Mind: Physical and BiologicalApproaches to Its Function (to be published by Michigan State University Press, EastLansing, Michigan).2. Project Plansa. Sensory ProcessesSmell. Five years have been spent on the olfactory system (with Dr. R. C. Gesteland,now at Northwestern University) and the results of this study are soon to appear. 1, 2Ithas been shown that the coding of smell is holistic, that every fiber in the olfactory nervehas a broad range of sensitivity rather than a particular sensitivity to a smell and is atwo-process system. These results have posed one of the most serious problems in theconcept of a smell system. We now feel quite certain that the transduction is due to anallosteric action in a surface protein, but that the allostery is much broader than is usu-ally conceived, and may be difficult to describe in terms of present theories of chemicalaction. It is a question that will underlie a great deal of research for several years.Vision. It is possible to show that the firing pattern of a dimming detector (off-fiber)in the optic nerve of a frog reflects primary transductive processes in the rods andcones sufficiently well to be used to measure those processes. It appears, by this modeof analysis, that there are at least three kinds of transduction involved in the frog, andone has been tentatively identified as measuring the amount of isorhodopsin. It will beabout a year before this method is utterly disabused or confidence may be placed in it.If it is valid, a new and significant tool in visual physiology has been found. The opera-tions once reported by this group on the frog's eye can now be specified in much greaterdetail. These are not as assumed, either in terms of origin or exact description. Thiswork, too, will take some time to complete.b. Membrane ProcessesDuring the past year and a half a number of predictions have been borne out quiteaccurately by experiment. It was supposed that La( 3 +) and Pr(3 + ) would act as super-Ca(2+) with respect to nerve membrane. This is, in fact, the case. It was also predictedthat Cs ought not to substitute either for K ( + ) or Na , and ought not to pass nervemembrane. This is also the case. Finally, nerve membrane was expected to be asym-metrical in structure, and this has been demonstrated (by Dr. S. Frenk of this labora-tory) using La(MnO 4 ) 3 as a stain in electron microscopy. The present work is withartificial membranes, phospholipid paucimolecular layers, which exhibit a surprisinglylow impedance and very large streaming potentials and streaming currents. The aim isto make such membranes with nonlinear properties of interesting sorts.c. InstrumentationA new device has been developed that is very helpful in looking at neural signals. Itis a CLOOGE (acronym for Continuous Log Of On-Going Events). It presents sequentialpulse intervals on linear, logarithmic or reciprocal scale extending over four decades,and includes certain additional processing that makes the output extremely easy to fol-low.New low-cost high-gain amplifiers and special headstages for general use have alsobeen designed. In fact, several low-cost, but accurate, data-processing devices areQPR No. 80 250(XXVIII. NEUROPHYSIOLOGY)being planned. These will permit on-line data reduction in analog; thus, the fairly expen-sive and still inefficient methods for use with digital computers will be bypast.J. Y. LettvinReferences1. R. C. Gesteland, J. Y. Lettvin, and W. H. Pitts, "Chemical Transmission in theNose of the Frog" (to appear in the Journal of Physiology).2. J. Y. Lettvin and R. C. Gesteland, "Speculations on Smell" (Cold Spring HarborSymposia on Quantitative Biology, in press).3. Present and Proposed ResearchDuring the past year we have pushed forward on the investigation of the propertiesof dorsal horn cells and have begun to exploit a number of the consequences of thisresearch.1-7 There are three horizontal laminae in the dorsal horn of the spinal cord.These laminae can be identified both by anatomical and physiological properties. Theyare laminae 4,. 5, and 6 of Rexed. In lamina 4, the most dorsal, there are cells thatreceive only cutaneous afferents. We have shown, now, that most of them receive fromthe full spectrum of peripheral fibres. There is a gate control that influences the pas-sage of arriving impulses from the periphery as they pass onto these cells. The gateis closed by activity in large-diameter peripheral fibres and by descending impulsesfrom brain stem. The gate is opened by activity in small-diameter peripheral fibres.We have also given evidence that impulses can be generated in the dendrites of thesecells. This suggests a much greater potentiality for analysis by nerve cells than pre-vious models in which it was believed that only a single trigger point of origin of nerveimpulses existed.In lamina 5, we find cells with a special anatomy which receive cutaneous informa-tion collected by the cells of lamina 4. They are under the control of impulses descendingboth from the brain stem and from the peripheral tract. These cells show a new prop-erty that we have named "novelty detection." They fail to respond to the later stimuli ina train of repeated stimuli. We have been able to locate the place where this blockingof repeated input volleys occurs.In lamina 6, the most ventral lamina in the dorsal horn, cells receive both from skinand from muscle. This convergence of inputs of different modalities is under control.In the decerebrate animal, the cells are dominated by the input from muscle and joints.In the spinal animal, where descending impulses from the brain stem have been elimi-nated, these cells are dominated by their cutaneous input. This process of switchingis a new property of nerve cells which has not previously been described.In the past year we have made very rapid advances in the discovery of a controlmechanism that influences the effect on the central nervous system of entering nerveimpulses. We had discovered some time ago that it was possible to decrease the effec-tiveness of entering nerve impulses by decreasing their size before they reached thefirst central cells. It was shown that a slow potential could be detected which measuredthe intensity of this "presynaptic inhibition." Next, we were able to assign the genera-tion of this presynaptic inhibition to the activity of some very small cells whose functionhad not previously been known. These are the cells in substantia gelatinosa.The next stage was the discovery that the set of the presynaptic control mechanismwas in continuous action and was influenced by the position of the limbs, pressure on theskin, and by descending impulses from the head. If this system was in steady action,we wondered if the very fine slowly conducting peripheral fibres were playing a part inthis tonic long-acting mechanism. We developed a technique for isolating the impulsesQPR No. 80 251(XXVIII. NEUROPHYSIOLOGY)in small fibres from those in large. We found that the small and large fibres were actingin opposition, the large fibres tending to close the gate, and the small to open it. Theposition of the control mechanism therefore depends, among other things, on the relativeactivity in large and small fibres. Thus far, this is the only function discovered forsmall fibres. This control mechanism, which can be moved either to exaggerate ordiminish the effect of arriving sensory nerve impulses, has many implications for under-standing sensory discrimination, and in particular the mechanism for generating pain.Anesthetics, for example, close the gate. Furthermore, a number of pathological statesof the skin sensory system may be correlated with different settings of this control sys-tem. New concepts are appearing of the analysis of sensory events in context with simul-taneous and preceding events.In other work in this laboratory, we have proceeded with the analysis of skin sensa-tion by examining third-order neurons along the pathway. We have also developed sometestable theories about the method used by the nervous system in signalling the locationof a stimulus. This work has involved work on normal amphibia and those with varioustransplanted eyes, legs, and skin.A new theory of pain mechanisms has been developed. 8 The activity of second-,third-, and fourth-order nerve cells in the cutaneous and proprioceptive pathways isbeing studied in animals in many different states of control.Several aspects of the research reported above will be developed.(a) Studies of pain control in man. We have already begun to test a prediction fromour pain theory which suggests that continuous activity in large fibres should raise thethreshold for induced pain. We shall use normal men and cases of trigeminal neuralgia,causalgia, and other types of intractable pain. Initial results are extremely promising.(b) Spinal-cord organization in rat. We have shown that it is extremely profitableto study the activity of dorsal cells in cat cord with the animal in several different states.We intend to repeat these studies in rat with the intention of examining single cells duringunrestricted movement.(c) Descending control of spinal cord dorsal horn cells. We shall study in detail theeffect of descending pyramidal volleys on the effects of arriving afferent volleys and onthe firing of cells in laminae 4, 5, and 6.(d) Effect of repeated stimulation. It is known that there are novelty detection cellsin dorsal horn, and that motoneurons fail to respond to the later members of a long trainof slowly repeated stimuli. We shall define the properties of this adaptation of a ventral-root reflex and probe within the cord to determine which cells adapt out in the chain frominput to output.(e) Behavior of cells in ventral horn. We have described the lamination of dorsalhorn and will advance to a study of lamina 7, which contains cells of a very high degreeof complexity.(f) Origin of the way in which muscles in a reflex response direct the response tothe location of the stimulus. We shall study by a series of new methods the linkagebetween skin stimulation and motor neuron response in the frog skin wiping reflex.(g) Limulus eye. Studies of the coupling between light received in the eye and thegeneration of a local response and the coupling between cells in the ommatidium willcontinue.P. D. WallReferences1. L. M. Mendell and P. D. Wall, "Cord Cells Responding to Peripheral UnmyelinatedFibres," Nature 206, 97 (1965).2. P. D. Wall, "Impulses Originating in the Region of Dendrites," J. Physiol. 180, 116(1965).QPR No. 80 252(XXVIII. NEUROPHYSIOLOGY)3. B. B. Boycott, J. Y. Lettvin, H. Maturana, and P. D. Wall, "Octopus Optic Responses,"Exptl. Neurol. 12, 247 (1965).4. P. D. Wall and R. Melzack, "A Duplex Theory of the Mechanism of Cutaneous Sen-sation," Proc. 23rd International Congress on Physiological Science, Vol. 4, p. 234,1965.5. A. Taub and P. Bishop, "The Spino-Cervical Tract: Dorsal Column Linkage, Con-duction Velocity, Primary Afferent Spectrum," Exptl. Neurol. 13, 1 (1965).6. P. D. Wall, "Organisation and Reorganisation of Dorsal Horn" (to appear in Journalof Physiology).7. L. M. Mendell, "The Response of Dorsal Horn Cells to Peripheral Cutaneous Unmy-elinated Fibres" (to appear in Experimental Neurology).8. R. Melzack and P. D. Wall, "A New Theory of Pain Mechanisms" (to appear inScience)..A. NUMBER OF MODES OF OSCILLATION OF A NET OF N NEURONSGiven a set of N neurons. The state of the net at time t is determined by the stateof all neurons at time t. There are two possible states for each neuron at time t (firingor nonfiring). The total number of possible states of the net is 2NWhen the net oscillates it runs through a number of states in a repetitive way. Amode of oscillation of the net is determined by the states into which the net.gets duringone period, and the order of these states but one. If we select k states out of ZN , thereare (k-l)! ways of ordering (k-1) of these states.Selecting k states is possible in (kN) ways. So the number of modes of oscillationof the net, in getting into k different states is(k-l)! ( 2 N)Summing this expression for all possible k gives the total number of modes of thenet:N  N(k-i)! (N) = Z (k-i)! (zN)k= 2 k= 1If we want to be able to generate any of these modes by putting a constant binary inputon a number of input lines, then this number ought to be at least the least whole numberthat is larger than or equal toNlog 2  (k-l)! 2kN)k= 1C. P. G. SchnabelQPR No. 80 253

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