The development of columnar systems in the mammalian visual cortex

TINS -July 1 982 tumor to tumor. It seems that chemotherapy may have to be based more on the permeability characteristics of an individual's tumor, rather than simply on its histological classification. To do this, methods must be developed that can measure regional variations of permeability in human tumors. Perhaps, in patients with tumors of low permeability, methods will be needed to enhance drug delivery, such as hyperosmotic disruption of the BBB (Ref. 16). Experimental models that bridge QAR methods in rats are needed to understand those factors that control permeability in human brain tumors. One such model may be the ASV-induced canine glioma model, which can be used for QAR, CT scanning ~° and PET scanning. Much remains to be done. The degree to which AIB permeability or iodinated contrast permeability can be used to predict chemotherapeutic drug delivery must be determined. The significance and clinical usefulness of ultrastructural studies of endothelial abnormalities in human tumors require systematic studies, not yet done. The fact that drug delivery is not solely dependent on capillary permeability, but also on the other variables listed earlier, such as blood flow, must not be forgotten. It may be necessary to determine both blood flow to and capillary permeability within individual tumors in order to predict drug delivery accurately, Moreover, accurate methods for the determination of brain tumor cell susceptibility to currently available chemotherapeutic drugs are needed. How much of the problem is drug delivery, and how much of the problem is lack of effective tumoricidal drugs are among the key questions to be answered.

Reading list 1 Blasberg, R. G. Gazendam, J., Paflak, C. S., Shapiro, W. S. and Fenstermacher, J. D, (1980) The Cerebral Microvasculatuee (Eisenberg, H. M. and Suddith, R. L., eds), pp. 307-319, Plenum, NY 2 Blasberg, R. G., Groothuis, D. R. and Moinar, P. (1981)Sem. Neurol. 1,203-221 3 Blasberg, R. G., Patlak, C. S. and Fenstermacber, I. D.J. CerebralBlood FlowMetab. (in press) 4 Blasberg, R. G., Paflak, C. S., Jehle, J. W. and Fenstennacber, J. D. (1978)Neurology 28,363 5 Brighunan, M. W. and Reese, T. S. (1969)J. Cell Biol. 40, 647-677 6 Butler, A. R., Horii, S. C., Kricbeff, 1. 1., Shannon, M. B. and Budzilovich, G. N. (1978) Radiology 129,433--439 7 Feastennacher, J. D., Blasberg. R. G. and Patlak, C. S. (1981) Pharraaco/. Ther. 14, 217-248 8 Groothuis, D. R., Fischer, J, M., Lapin, G., Bigner, D. D. and Vick, N. A. (1982) J, Neuropath, Exp. Neural. 41,164-185 9 Groothuis,D. R., Fiscber,J. M,, Pas~mak, J. F., Bigner, D. D. and Vick, N. A. (1981) J. Neuropath. Exp. Neurol. 40, 362 I0 Groothuis,D. R., Mikh~l, M. A., Fischer,J. M.,

235 Pasternak. J. F., Fouts, T., BigneL D. D. and Vick, N. A. (1981)J. ('omput. Assist. Tomogr. 5,538-543 11 Grc~thuis, D. R. and Vick, N, A. (1980) Radiation Damage to the Nervous" System (Gilbert. H. A. and Kagan, A. R.. eds), pp. 93-106, Raven Press, NY 12 Haudenschild. C. C. (1980)Adv. Microeirc. 9. 226--25l 13 Hayman, L. A., Evans. R. A. and Hinck. J. C. (1980) Radiology 136,677-684 14 Horowitz, M., Strong, J., Molnar, P., Blasberg, R., Schwade, J. and Fenstermacher. J. (1981) Pharmacologist 22, 176 15 Mikhaet, M. A. (1981)Sem. Neurol. I, 137-148 16 Neuwelt, E. A., Diehl, J. T., Vu, L. H.. Hill.

S. A., Michael. A. J. and Frenkel. E. P. (1981) Ann. Int. Med. 94,449-454 17 Ostertag, C. B., Mundinger, F. and Weigel, K. (1981) Med. Hyg. 39, 1994-2008

18 Sokoloff, L. (1981) Neurosci. Res. Prog. Bull. 19, 159--210 19 Vick, N. A. (1980)Brain Metastasis (Weiss, L., Gilbert, H. A. and Posner, J. B., eds) pp. 115-133, G. K. H',dl & Co., Boston 20 Yen, C.-K. and Budinger, T. F. (1981)J. (~m-

put. Assist. Tomogr. 5,792-799 D. R. Groothuis and N. A. Vick are at Northwestern University Medical ,School, Department of

Neurology, Evanston Hospital, 2650, Ridge Avenue, Evanston, H 60201, U.S.A.

The development of columnar systems in the mammalian visual cortex The role of innate and environmental factors N. V. Swindale The mechanisms for forming ocular dominance and orientation columns m the visual cortex o f cats and monkeys are innate, but their outcome is flexible. I f daring development, the cells in one set o f columns are not visually stimulated, the more active columns expand and partially obliterate the unstimulated ones. l f ull forms o f visual experience are absent, many aspects o f normal cortical development are slowed down or halted. Widely varying opinions have been expressed about the relative importance of innate and environmental factors in the development of the visual cortex. At one time it was believed that few kinds of stimulus specificity, other than direction selectivity, and a rough degree of binocular correspondence of receptive field positions, could ever emerge without the aid of visual expetience"~; while recently, LeVay, Wiesel and HubeP" have claimed that "visual experience seems not to play a major role in the development of the mammalian visual system'. The situation is not helped by the existence of a variety of conflicting experimental results, and this makes it difficuh to argue for, or against, any firm conclusions. In mitigation, it can be claimed that many issues are clearer now than they were a few years ago 2. Many of the experimental conflicts of the past are now regarded as resolved, although difficulties of interpretation still remain. One drawback of physiological techniques is that they record the behaviour of only a small proportion of cells in a small area of tissue, and in this respect the advent of anatomical techf

niques, such as transneuronal autoradiography, and the 2-deoxyghicose method, has proved a great advantage. These reveal the patterns of ocular dominance and orientation columns directly, and allow large areas of tissue to be studied (Fig. 1). Provided the methods are used carefully, and with adequate controls, the results obtained are intrinsically reliable, and provide a valuable complement to the data obtained by physiological methods. All of the experiments that will be described here have been done on the cat and monkey, and most of them are concerned with the properties of ocular dominance and orientation selectivity. These were the first to be discovered by Hubel and WieseF 8, and have proved easiest to study. both physiologically and anatomically. Other properties, such as disparity selectivityn,4°, contrast sensitivity and spatial frequency tuning have tended to be neglected, though the development of these seems equally dependent on vision, and equally important in determining visual performance. Three sorts of experiment will be consiElsevlcr Biomedical

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alter birth; kittens begin to use theirs in the second and third weeks of life• Studies of the cortex at these times show the visual cortex to be immature in many respects, and more so in the cat than in the monkey. Ocular dominance columns, as revealed by transneuronal autoradiography, are incompletely formed in monkeys:~:~(Fig. 2a) and absent in kittens "~, the afferents from each eye being spread throughout layer IV of the cortex, instead of occupying segregated patches or stripes, as they do in animals more than about 5 weeks old :~'~'~:~ Oriemadon selectivity is present in visually inexperienced monkeys ~7, and the preferred orientations form columnar sequences that are nearly as well organized as those in adults (Fig. 2b), Despite this, more cells than in adults are visually unresponsive, or poorly tuned for orientation~'~.'~7~ contrast sensitivity and cutoff spatial frequency are also substantially lower than in aduh,,, I:'. In visually inexperienced kittens, the cortex is even less mature: many more cells than normal lack orientation selectivity 4.~2-~.2~,:~,4~ (Fig, 3a); those that do possess it seem to form rough columnar sequences in some areas and not in others s,~e,4~ Recent experiments with 2-deoxyglucose have failed to show orientation columns in 3-week old kittens, but given normal vision they develop rapidly and are nearly fully formed at 5 weeks of age (Thompson, Kossut and Blakemore, personal communication)• This is in agreement with physiological data on the normal time course of development of adult levels of orientation selectivity v~-~ (Fig. 3). Other cellular properties are immature by adult standards: cells are less responsive 2"~,4'~,orientation tuning curves are often abnormally broad ~2 J7,~,; there may be little selectivity for disparity ~" and. as in the monkey, cells have poorer contrast sensitivity and lower acuity f,~r sine wave gratings of optimum orientation '~:'.

Fig. i. Parterre of ocular dominance columns" ta), and orientuti,,n colunuls tbJ, ul adult monkeys, Iambsa photornontage o f a series o f autoradiographs made from secti, ms cut tangential to layer IV o f the visual cottea'. The comrulateral eye had been iajected with radioactive label, and the ocular dominance columns fi~r The visually deprived cortex The above studies show that many adult that eye sho w up as bright accumulations of silver grain.s. C_olut ntis for the other eye oc~'upy the complementary pattern o f gaps between the labelled regions. ~cate har . I ram, tReproducedlrom LeVay. Wiesel and properties are at least qualitatively present HuheP~.) (b} A bright field autoradiograph prepared from a single tangential section through the monkey soon after birth in both cats and monkeys, visual cortex, showing the pattern o f darker regions o f increased ['% ']2-deoxvglaco~e uptake caused by and clearly these have an innate basis. On seeing moving vertical stripes. Most of the section passes through layer~ V and V I; the ~ hire o val to the left o f the other hand it is reasonable to claim that the photograph is unlabelled white matWr. (Reproducedfrom Hubel, Wiesel and '¢,l~kef'~ )

dered. The first sort tries to establish what properties of cortical cells are innate in the strict sense, that is, present at birth. As these experiments show that many properties are not present at this stage, but emerge over a period of weeks, a second type of experiment has been done to find out whether this process of maturation can occur in the absence of visual experience. Since this evidence suggests that the mat-

aration is dependent on vision, the aim of a third type of experiment is to discover whether selective deprivation of different kinds of visual stimuli can alter the rates or types of stimulus specificity that emerge normally. I will review the experimental results in this order. The visually iaexperie,eed cortex Monkeys use their eyes immediately

visual experience must be involved in any process of maturation that is slowed down, halted or reversed by visual deprivation. Physiological studies of the visual cortex of dark-reared or binocularly lid-sutured kittens, are hampered by an overall loss of responsiveness of cortical cells (which itself indicates a dependence of responsiveness on vision), and this may obscure an underlying increase in stimulus specificity. Nevertheless there is agreement among many investigators that the cortex does not

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mature normally. In the first of such studies, on kittens dark-reared to the age of 2½-4,~ months, Wiesel and Hube156reported that only 41% of recorded cells had receptive fields that were normal by adult standards. However, later studies in animals of 4-10 weeks of age have produced widely varying estimates. Some authors have claimed that there ,is almost no adult specificity18.~; others have demonstrated intermediate levels of about 10--40% of adult type cells ~.12, while one report suggests that over 90% of cells possess a degree of stimulus selectivity 45. This latter estimate can probably be reconciled with the intermediate ones if a distinction is made between orientation-biased and orientation-selective cells (see legend to Fig. 3), and it is probably fair to claim that the normal increase in the proportion of cells with adult levels of orientation selectivity is at least halted, if not reversed by visual deprivation. In monkeys, Blakemore and VitalDurand '3 likewise conclude that total visual deprivation prevents the normal increase in the proportion of orientation-selective cells, as well as maintaining contrast sensitivity and cutoff spatial frequency at the immediate post-natal level. Not all development halts in the dark however. Anatomical studies on the monkey's ocular dominance stripes show that they continue to form in the absence of visual experience ~", though whether at a normal rate is not known. In dark-reared kittens, segregation proceeds to a stage where slight periodic fluctuations in the density of inputs are detectable in some parts of area 17 but not in others (Fig. 4)5L These fluc-

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Fig. 3. The change in the proportions o f orientation selective fOr.), orientation biased (O.B.) and non-oriented cells (N.O.) as a function o f age in (a) normal kittens and (b)dark-reared kitttens. The number o f cells on which each measurement h~based is sho wn at the top o f each bar. A cell was classified as Or. if the ratio ofits best response (at its preferred orientation) to its weakest (asually at the orthogonal orientation) was 1O: I or greater,- as O.B. if this ratio was less than l O: l bat greater than 2 : 1, and as N. O. if the ratio was less than 2:1. The results suggest that visual deprivation halts the normal process o f maturation o f orientation selectivity. Note that if the distinction between Or. and O.B. categories is ignored, an experimenter might conelude, as Sherk and Sto'ker did 4~, that lew,ls o f selectivity in dark-reared kittens are similar to those o f normal animals. (Reproduced ti'om BondsL )

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238 tuations may have their origin in the spontaneous activity of retinal ganglion cells, for if this is blocked by the continuous application of tetrodotoxin to both eyes, segregation fails completely4~. This suggests that the dividing line between the innate and environmental contributions to the normal development of ocular dominance columns in the cat may be narrow. Selective visual deprivation Several important conclusions can be drawn from the results discussed above. There is no doubt that the basic mechanisms for the development of columns of orientation selective cells, and of ocular dominance, must be innate in both monkeys and cats. Thus, any theory that attempts to account for orientation selectivity and columnar organization purely on the basis of visual experience (as many do) must be regarded as inadequate. Nevertheless. the results show that the contribution of visual experience to development cannot he ignored, and this raises more specific questions about how visual experience might act. There are two possibilities. One is that innate mechanisms will, over a period of time, confer a particular stimulus specificity on a given cell, but that visual experience can only alter the rate at which this predetermined specificity is assigned. This would be a type of developmental gating akin to that which might be excited by undernutrition, or thyroid hormone deficiency for example. The other possibility is that of a more active role where experience can alter both the type, as well as the rate of emergence of stimulus specificity during development. So far as ocular dominance is concerned, the latter hypothesis seems to be correct, for as is well known, the outcome of the normal process of segregation of geniculate inputs a

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into non-ovcrlapping domains within layer IV can be altered in both monkeys and cats, by closing one eye while the columns are in the process of formation:~.44. Columns representing the closed eye shrink, while those fi'om the normal eye expand. Physiological experiments show that as a result of this, and possibly of changes in intracortical circuitry as well, nearly all cells"~*.'~5except those in regions whcre input from the closed eye remains'~:u~'~'44become responsive only to the eye that had been open. Thus some cells - those at the boundaries between the columns -- have had their stimulus specificity altered. Other manipulations of the visual environment can also produce properties in cells that are different from those they would otherwise have had. Anything that prevents both eyes from seeing similar patterns of light in the two retinas (e.g. inducing a squint, alternately covering each eye, or dimming one retinal image by 1-2 log units) leads most cells to lose an input from one or the other eye and become monocular~+~6.2s+3°.In the case of squint, the ocular dominance columns appear to develop normally43, suggesting that these procedures mainly affect the organization of intracortical circuits.

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~ of orlena~iaa ptekrem-e It is less clear whether the outcome of tl~ process of assigning categories of preferred orientation to cells can be redirected by visual experience, though the evidence points in this direction. The experiment analogous to depriving one eye of vision, in this case, is to deprive both eyes of all but a narrow range of oriented contours. This has usually been done by putting kittens in a striped drum, or by letting them wear goggles that focus Imtterns of bars directly onto the retinas. Another technique has been to use b c

Fig. 4. Dark field autoradiograph o] a /,u,azomat section through the visual cortex o f a 16-week-rdd. dark-reared kitten. The ipsilateral eye hc~ bee.,+ injected with radioactive label, and only slight fluctualions in the density o f inputs from thi~ eye can he seen in layer IV.

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239

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the experimental animals have received 100-200 h of such experience spread over a period of weeks. Provided the restriction in exposure is effective, experimenters are agreed that, of those cortical cells with a well-defined orientation preference, a far greater proportion than normal is tuned to the experienced orientation 7,9.n.ts,~,~.~9. A gating model would explain these effects by supposing that cells already tuned, or pre-tuned to the experienced orientation had retained or acquired a normal degree of selectivity or responsiveness, while unstimulated cells had become, or remained, either unresponsive or broadly tuned for orientation. Typically, about a third to a half of the normal range of orientation preferences is present in a stripe-reared kitten, and thus a gating theory would predict that about a half to two-thirds of cortical cells should be non-oriented or visually unresponsive. The proportion of such cells reported to o c c u r i s usually much lower than this (25% in Blasdelet al. ~s and 8% in Biakemnre7) though Stryker et al. 49 give a much higher estimate of 34% of nonoriented cells and 20% visually unresponsive. It can always be argued however that the percentage of visually unresponsive cells recorded is likely to depend very much on the experimenter's desire to record them. An analogy with ocular dominance colunms would suggest that visually experienced orientation columns might expand in a stripe-reared animal, while uastimulated ones would contract, and Singer, Freeman and RauscheckeP~ and Flood and Coleman 24 have recently used the deoxyglucose technique in an attempt to demonstrate such changes directly. The strategy used by both groups was to compare the pattern of deoxyglucose labelling in the left and right cortical hemispheres of a stripereared kitten after stimulating one visual hemifield with stripes of the experienced orientation, and the other hemifield with stripes of the orthogonal orientation. The major difference between the two hemispheres as revealed by Singer et al. (it is not clear whether Flood and Coleman got the same result) is in the overall levels of deoxyglucose uptake, which are about five times higher in the adequately stimulated hemisphere than in the inadequately stimulated one (Fig. 6). This demonstrates that there have been orientation-dependent changes in responsiveness, as a gating theory would predict, and as a secondary consequence this complicates attempts to compare column widths in the two hemispheres. Flood and Coleman, and Singer et al. all show that, neglecting any overall difference in labelling intensity, the areas in which deoxyglucose uptake exceeds the back-

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F'~g.6. Factors which complicate the interpretation o f the structure of orientation columns in deoxyglucose experiments: (a) The situation in normal cortex: preferred orientation changes, on average, linearly with distance, and the orientation-tuning curves of cells are, on average, 60° wide at their base. The curves show the average increase in neural activity, and thus levels of deoxyglucose uptake, produced by stimulating the cortex with either horizontal or vertical bars. The shape and width o f these curves is a reflection of the shape o f the average oriemation turning curve. (b) The corresponding patterns of deoxyglucose uptake produced in a horizontally stripe reared cortex, predicted according to a gating theory of the effects of stripe rearing. The spatial structure of the orientation columns remains unchanged, but the height of the orientation tuning curve is greatest for horizontally selective cells, and least for vertically selective cells. Note that, as the height of the tuning curve decreases with distance from horizontal, this will tend to lower the shoulders, and narro w the width o f the left hand curve, and conversely broaden the right hand curve. (c) The patterns of deoxyglucose uptake predicted if the experienced columns broaden in width, and inexperienced ones narrow, assuming that all orientation tuning curves remain unaltered in both height and width. 7"he experimental resalt$ shown in Fig. 6 suggest that what happens in a stripe reared kitten is a combination o] both (b) and (c).

ground in less responsive columns are about 50% greater in the adequately stimulated hemisphere, compared to the other one. They argue from this that cells in columns adjacent to those of the experienced ones must have shifted their orientation tuning curves along the orientation axis towards the experienced orientation. However, this ignores several possible complications. In a normal cortex stimulated with bars of a single orientation, the regions of elevated deoxyglucose uptake will be a reflection of the shape of the orientation tuning curve (Fig. 7). This normally has a width at its base of about 60 °, and as a consequence about a third of the total area of visual cortex shows an elevation in deoxyglucose uptake in such an experiment. However, the orientation tuning curves in stripe-reared kittens are not normal. For example, Stryker et al.4~ show that many cells have abnormally broad orientation tuning curves. If this broadening was present in the curves of cells in columns adjacent to the experienced ones, this alone, without any shift along the orientation axis, would lead to an apparent expansion of the columns. It could also be argued that reducing the heights of the tuning curves of the inexperienced cells might make them narrower (the so-called 'iceberg effect'~9), and that this might also narrow the apparent width of a

less responsive set of orientation columns. On the other hand, Blasdel et al. lS suggest that it is mainly the tuning curves of the inexperienced cells which broaden, and this would tend to broaden the inexperienced columns rather than the experienced ones. The results o f S i n g e r e t a l . also provide evidence that it is the orientation tuning curves of the inexperienced cells which broaden, because these cells show a greater absolute rate of deoxyglucose uptake when stimulated with an orientation orthogonal to their optimal one, than do experienced neurons when similarly stimulated with the wrong orientation. Perhaps the least problematic way of interpreting the deoxyglucose results, however, since it avoids the potential complications introduced by changes in the orientation tuning curves, is to look at the density of labelling in regions of cortex that are intermediate in distance between the peaks and troughs of label. If the orientation column structure has remained unchanged after rearing in an environment of horizontal or vertical stripes, such regions of cortex should contain cells selective, if at all, to oblique orientations. These cells should respond equally well to horizontal and vertical orientations, and thus the absolute levels of deoxyglucose uptake in these intermediate regions should be the same in both hemispheres. However, comparison

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240 of deoxyglucose autoradiographs from left and right hemispheres of the same animal, exposed for equal lengths of time (Fig. 61, shows that rates of uptake in these intermediate regions are much higher when stimulated with the experienced orientation than with the inexperienced one, and the conclusion that cells in these regions have shifted their orientation preferences towards the experienced one seems inescapable. Little can be said with certainty about the mechanisms by which visual experience is likely to act in these experiments, though there are some very definite pointers towards the involvement of Hebb synapses. Overall levels of activity in the optic nerve seem not to be important in establishing which eye gains control of conical cells in monocular deprivation experiments, nor do gross temporal variations in discharge frequency seem to matted'. Instead it seems to be the existence of local spatial and temporal correlations of the sort that will make conical neurons respond that is significant4~,*L Thus, the innate predisposition of conical cells to respond to such patterns is likely to be an important, though not an over-riding factor in determining the sort of specificity that emerges in development.

Analogies between ocular dominance and orientation columns The analogy between the behaviour of ocular dominance and orientation columns seems to be one that is worth pursuing. In both cases there is an innate mechanism for producing the columns, but its outcome is flexible, and can be altered in the absence of the stimulus that would make the cells in one set of columns respond. In both cases this period of flexibility is limited to the time when the columns are in the process of formation, a relationship that is highlighted by the additional observation that in both cases the columns seem to form first in layer IV, and that plasticity comes to an end in this layer before other oneS J°A2't4'ae'4e. Though the pattern of stripes and patches formed by the ocular dominance columns may seem to have little in common with the smooth cyclic progressions of orientation preference across the conical surface, mathematically similar rules can be used to describe their formationS°,sL It may also be possible to extend the analogies in behaviour to other columnar systems, such as that for direction preference "8,~". This can be altered by rearing either in a stroboscopically illuminated environment. which abolishes direction selectivity altogether~.~,a7; or in an environment where one direction of movement is prevalent, which biases selectivity towards the experienced direction 20,22,54.

P l ~ ' t i c i t y a n d associative memory Since columnar forms of organization prevail in many, and perhaps all, cortical areas, the dependence of columnar structure in the visual cortex on patterns of stimulation that will activate all the constituent cells has significant implications for more general theories of conical function. A property of superimposed, but independent systems of columns, is that they would allow the representation of many different combinations of a large number of features. This property has an obvious relevance to theories of associative memory, which demand the establishment of just those sets of associations between features that are present in the natural world. In this light, the work on plasticity of columns in the visual cortex takes on a special significance. Although so far, the plastic changes that have been demonstrated have been in response to deprivation of large classes of stimuli, there is every reason to expect that the absence from the world of more limited combinations of features would also lead to changes in columnar structure. To take a somewhat hypothetical example, the absence of leftward moving vertical edges in the right eye would be expected to lead to shrinkage or absence in the visual cortex of regions where vertical orientation columns, right eye columns and leftward movement columns intersect. A number of experiments suggests that just such an interaction takes place between orientation and ocular dominance columns 2~'274~'42. The columnar plasticity first discovered by Hubel and Wiesel in the visual cortex may therefore be an example of how the brain avoids representing some of the associations that might, but in fact never, or rarely occur in the world.

Reading list I Bard, J. B. L. ( 1981 )J. Theor. Biol. 93.363--385 2 Barlow, H. B 1t975)Nature (London) 258. 19%204 3 Bartow. H. B., Blakemore, C. and Petligrew, J. D. (19671J. Physiol. (London) 193,327-342 4 Barlow, H. B and Pettigrew, J. D. 11971)J. Physiol. (London) 218, 98-100P 5 Blakemore. C. (1970)J. Physiol. (London) 209, 155-178 6 Blakemore. C. (1976)J. PhysioL (London) 261, 423-444 7 Blakemore, C. 119771 Philos. 7)'arts. R. Soc. London, Ser. B 278, 425~.34 8 Blakemore. C. (1978) in The Handbook of Sen-

sory Phyvioiogy. Vol. VIII: Perception. pp. 376-436, Spdngar-Verlag 9 Blakemore. C. and Cooper. G. F. (1970) Nature II.ondon) 228. 477-478 10 Blakemore, C.. Garey, L. J. and Vital-Durand, F. (1978)J. PhysioL (London) 283,223--262 11 Blakemore, C., Movshon, J. A. and Van Sluyters, R . C. (1978)Exp. Brain Res. 31,561-572 12 Bl',~emore, C. and Van Sluyters. R. C. (1975) .I. Physiol. (London) 248. 663-716

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13 Blakemore, ('. and VataI-Durand, i r IqSl ) ~,,,,, Neurosci. Abill. 7. 14o 14 Blakemore. C.. Vital-Durand, F. and (,arty. 1 J (1981) Proc. R S,J~ London, %- B 2!i. 399-423 15 Blasdel, G. G.. Mitchell, D. E., Mmr. D. ',&. and Pettigrew, J D 119771 J. Phy~tol iLondon) 265. 6154136 16 Blasdel. G. G and Petligrev.. J [) 119791 J. Neurophvsiol. 42, 1692-1710 17 Bonds. A B. (19791 in Developmental Neurobiology of Vision (Freeman. R. D.. ed. ). NATO Advanced Study Institute Series, Series A, Lifie Sciences, Vol 27. pp. 31-41. New York.

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N. and Hubel,

D.

H.

(1965)

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N. V. Swindale is M R C Research Associate at the Kenneth Craik Laboratory, Department o f Physiology, Cambridge CB2 3E(;, U.K.

Inheritance of major psychiatric disorders E. S. Gershon and J. I. Nurnberger, Jr In the numerous twin studies of affective illness and chronic schizophrenia that have been performed in the last half century, the concordance of monozygotic (identical) twins has consistently been much higher than for dizygotic (fraternal) twins~'2L Furthermore, it is quite unusual to find affective illness in one twin and schizophrenia in the other. For both types of disorder, the incidence of psychiatric illness amongst biological relatives of adopted patients is higher than for adoptive relatives. Furthermore, the diagnoses in the biological relatives are similar to those of the patient. These findings suggest that schizophrenia and affective illness represent distinct classes of disorders which are transmitted genetically, though the possibility remains that non-genetic influences such as infection with a slow virus, acting prior to the age of adoption (i.e. during infancy) could mimic genetic transmission. The major affective disorders a'aditionally include bipolar (manic-depressive) illness, where there are episodes of both mania and depression or of mania only, and unipolar (depressive) illness, where there are episodes of depression only. Based on family study data, schizoaffective disorder with free intervals is properly classified with the affective disorders. The adoption studies of schizophrenia ~ suggest that chronic schizophrenia and borderline schizophrenia are transmitted together, but that acute (remitting) schizophrenia is unrelated to chronic schizophrenia. Beyond these generally agreed upon findings lie several major genetic questions which remain unresolved. In particular, the mode of transmission and the nature of the transmitted deficit are not established.

T.

J. Neurophysiol. 28, 1029-1040

psychiatric diagnosis, and expresses the probability of each type of diagnoses (including normal) in their relatives. Vulnerability is graded, with schizoaffective illness as the most severe form of illness (highest proportion of total ill relatives) followed by bipolar and unipolar disorder. These analytical models consider affective illness or schizophrenia as having a single genetic diathesis, and do not consider the possibility of genetic heterogeneity, in which several deficits (possibly localized on different chromosomes) can each produce similar clinical manifestations. Heterogeneity of this kind can be detected by two methods; by identifying the pathophysiological deficit(s) directly, or by identifying a genetic linkage between a known chromosomal marker and the susceptibility gene(s). In either method it is Mode of transmission possible to consider families individually, For both types of disorder, genetic anal- and thus to demonstrate a mode of inheriyses of pedigree data have not fitted models tance even if it only applies in a fraction of of single-locus (autosomal or X-chromo- cases. some) inheritance consistently'.2L Two gene locations (loci) are linked if A multifactorial (polygenic) inheritance they are close together on the same chromomodel did fit the NIMH family affective some. When the locus is polymorphic, i.e. disorders study data ~4 and several other may be occupied by more than one allele, family studies of affective disorders have the specific alleles may be traced through a been reviewed elsewhere 12. In this model, pedigree, and linkage to illness is present if 'vulnerability' to illness is calculated from one allele is transmitted along with the illthe model parameters as a linear combina- ness. When linkage of a marker to an illness tion of genetic and random (non-familial) is demonstrated in pedigrees, this constienvironmental factors. The vulnerability of tutes proof that a single locus close to the a class of individuals is defined by their marker locus contains an allele which pre-

disposes to the illness. Note that the illness linkage is to the marker locus, not to any particular one of the alleles capable of occupying the locus; if the illness was disproportionately associated with one allele at the marker locus, this would be association. not linkage. Unlike linkage analysis, which applies only to single loci, tracing a pathophysiological deficit such as an enzyme abnormality through a pedigree can be done even when the deficit has a complex or unknown mode of inheritance. If the deficit contributes to the susceptibility for the illness, it will tend to appear only in the ill persons from within the pedigree. On the other hand, if having the deficit does not contribute to the probability of being ill, then it can be concluded that the deficit is unrelated to the illness. Chromosomal linkage markers have been studied in several pedigree series in affective disorders. Linkage of affective disorders to the X-chromosome markers Xg blood group and red/green color blindness has been reported in pedigrees of bipolar patients, as reviewed elsewhere2L The same illness locus could not be linked to both X-chromosome markers, because they are at different ends of the X-chromosome, so the two initial reported linkages were not consistent with linkage to the same illness locus. In a large series of pedigrees we were unable to confirm the original reports of linkage to either locus is. 17. Unlike other investigators ~,19, we do not consider X-linked affective disorder to be an established fact. A similar situation exists for HLA antigens as markers. Some (inconsistent) associations with affective disorders have been observed, and this inconsistency is thought to indicate that there is no general association. We have been able to rule out linkage in a pedigree series 2~, but two recent reports claim linkage is present in some pedigrees 24,2~. At NIMH. Goldin et al. (unpublished observations) have studied 21 other common linkage markers, consisting of red cell antigens and enzymes and serum proteins, and found that none of the studied markers were linked to affective disorders. It has been hypothesized that depression may be associated with a deficit, and mania

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