Action potential propagation and conduction velocity — new perspectives and questions

Trends in NeuroSciences May 1983

Mechanisms of cell synchronization in epileptiform activity Researchers have long considered the potential roles of electrotonic synapses and ephaptic interactions in the central nervous system (CNS). They are obvious candidates for producing the synchronization of neuronal populations which characterizes epileptiform discharge. Are these primary mechanisms or do they simply modulate other, more powerful, forces? Can chemical synaptic connectivity alone account for spontaneous, rhythmic, synchronized discharge? Current research into basic mechanisms underlying epileptogenesis provides some interesting observations relevant to these questions. The considerable research activity dealing with epileptic activity in the mammalian CNS has, over the last decade, concentrated primarily on mechanisms underlying neuronal hyperexcitability and single cell burst discharge a.~2.~8. These investigations have resulted in significant insights into epileptogenesis, but have largely ignored one of the characteristic-defining features of epileptiform discharge - the synchronous activity of a large neuronal population. Although researchers have long been interested in the question of how a population of cortical neurons becomes synchronized4.~, only recently have techniques been developed which encourage direct experimental, as well as theoretical, approaches to the problem of synchrony during epileptiform activity. The three most likely processes that could lead to synchronous discharge during epileptogenesis appear to be: (1) chemical synaptic activity; (2) electrotonic synaptic effects; and (3) non-synaptic (ephaptic) interactions. Contemporary research clearly identifies chemical synaptic pathways as the prevalent means by which neurons interact with each other; these avenues for synchronization have thus been implicitly assumed to mediate cell synchrony, and have often been shown experimentally to be vital to the development and maintenance of synchronous activity. Rhythmic population discharge in normal brain, such as spindling activity and theta rhythms, typically involves a common drive from an afferent source which affects

many postsynaptic cells and/or a local circuitry which provides a strong phasing influence. Do such mechanisms explain epileptiform synchrony? Is the chemical synapse both necessary and sufficient for epileptogenesis? Studies have shown that blockade of normal chemical synaptic activity results in a loss of epileptic activity, at least in some experimental models 1~. However, two recent publications have shown that seizure-like discharge can be generated

under special conditions where no chemical synaptic activity is present. Taylor and Dudek is and Jefferys and Haas 7 have bathed hippocampal slices in low calcium-high magnesium solutions (to block PSPs), and demonstrated rhythmic synchronized bursting activity in the CA1 pyramidal cell population. Single cell transmembrane potentials associated with population burst activity (calculated by subtracting the extracellular field record from the intracellular record) showed significant depolarizing components attributable to the population discharge is (Fig. 1). The authors suggest that such electrical field effects (or 'ephaptic' interactions) contributed to the recruitment and synchronization of the population by depolarizing marginally active neurons. Even small ephaptic effects might trigger discharge, since neurons were already somewhat depolarized in the low-calcium medium 7. Polarization of cortex, such as occurs transiently during epileptiform discharge, can be produced experimentally by applied direct curCm~t~ued on ~

158

Action potential propagation and conduction velocity- new perspectives and questions Recent studies on axonal structure and function have elucidated some of the constraints which determine conduction velocity in nerve fibers. They have also suggested new modes of action potential propagation, and have raised important questions about impulse conduction. Axonal conduction velocity is monotonically related to diameter. However, diameter-conduction velocity relationships are quite different in myelinated and nonmyelinated fibers. An important question, which has been examined by a number of workers, is the degree to which myelination increases conduction velocity; or put another way, whether there is a particular diameter at which myelination begins to confer an advantage. Recently, Ritchie ~"

has examined this issue and has offered some interesting thoughts on the determinants of conduction velocity in peripheral nerve. His analysis suggests the intriguing conclusion that Schwann cell size imposes a lower limit on the diameter at which myelin is useful in terms of increasing conduction velocity. In a now classical paper, Rushton ~7noted that, in peripheral nerve, most axons with a

© 1983, Elsevier Science Publishers B . V , Amsterdam

C a m ~ m e d o a page 158

0378 - 5912/83/$01.00

15~ Mech,mtisms of epilepsy, continued from page 157

rentt4; relatively small current densities, compared to those generated during typical hippocampal synchronous discharge, can produce significant ephaptic field effects 2-". Ephaptic influence on cell excitability and synchrony in the mammalian CNS is not a new idea. It has been discussed and studied by a number of authors a,4a'~, but apparently became unfashionable because it is so difficult to determine in electrophysiological studies of epilepsy. Scbeibel and ScheibeP 5, however, provided a possible morphological substrate for ephaptic interactions in their demonstration of dendritic bundling of neocortical neurons. The recent experiments, in which non-synaptic synchronized bursting was shown to occur in tissues bathed in solutions containing an abnormadly low extracellular calcium concentration, suggest that ephaptic interactions may be involved in epileptiform discharge. However, it is not clear if changes in extracellular ion concentration contribute to cell synchronization, or are a result of synchronous activity5. Do the field effects lead to synchronized bursting, or are they a product of already established epileptiform discharge? (The answer, of course, need not be exclusively one or the other. ) How

Action potemi~ prolmgJian, amtiauatl frmn imge 157

diameter of less than 1 /zm do not have myelin sheaths, while most fibers with a diameter greater than 1/xm are myelinated. Rushton analysed the effects of myelination on conduction velocity, and concluded that 1 /_tin is a 'critical diameter' above which 'myelin increases conduction velocity' and below which 'conduction is faster without myelination' (see Fig. la). This conclusion suggests a critical diameter for myelination in peripheral nerve, reflecting the evolutionary response to a requirement for maximization of conduction velocity at minimal expense in terms of size. Requirements of Rushton's arguments are that the fibers have the same specific membrane properties, and that they are 'dimensionally similar'. For fibers to be dimensionally similar, m~ad length must be constant and internodal length must be proportional to fiber diameter. Since dimensional similarity did appear to hold, Rushton inferred that conduction velocity would be almost proportional to fiber diameter for myelinated fibers. In contrast, conduction velocity of non-myelinated fibers was predicted to be proportional to the square root of fiber diameter. Rushton concluded that 'a very small fiber must conduct faster if it is nonmyelinated than if it is myelinated', and that the critical diameter was 1 /xm. Electron microscopy subsequently showed, how-

a)

spike threshold

C)

¢

spike threshold

d

e

with

~

[ .C,a'+J,and/or t~gh IK'Io

depolarization with EPSP

(no cnemcal synapees)

Fig. 1. Schematic showing how field potentials might influence the discharge probabili~ and characteristics of a hippocampal neuron. Top traces show hypothetical intracellular recordings m a preparation with: (a) synaptic activity blocked (left column); Ca)synaptic activity blockea~ but the cell depolarized by low calcium and/or high potassium concentrations extracellularly (middle column); and (e) depolarizing synaptic drive (right column). Middle traces show the extracellular field potential evoked by stimulation; stimulus (arrows) is adjusted to produce a constant field across all three columns/conditions. Bottom traces show the 'transmembrane" potentials, found by subtracting the field from the b~,acellular records. In the left column, a transmembrane depolarization is evoked, but is not large enough to bring the membrane potential to spike-initiation threshold (dashed line). In the middle and right columns, the same transmembrane depolarization is added to general membrane and PSP depolarization (respectively), triggering action potentials. Note that the inflection between the transmembranc depolarization and the intrinsic action potential can often be observed (dotted linel.

many cells must fire together to set up a field sufficiently large to influence neighboring neurons? How is the initial synchrony established? These questions have not yet been addressed in studies of how

population activity effects cell polarization within that population. Another potential mechanism of cell synchronization, electrotonic synapses, has

ever, that myelinated fibers much smaller than t ~ m (as small as 0.2 ~ m ) are common in the central nervous system z. Lightmicroscope data on myelin thickness were used in Rushton's analysis, but electron microscopy showed that these data did not apply either to central myelinated fibers or to the smallest peripheral myelinated fibers2'. When the electron mtcroscope data for myelin thickness were used, the conduction velocity--diameter curves for myelinated and non-myelinated fibers were found to cross at a point corresponding to a

diameter of 0.2 btm. This suggested that, above a critical diameter of approximately 0.2 /xm. it should be possible for myelinated fibers to conduct more rapidly than non-myelinated fibers of the same size21. These findings provided a functional explanation for the presence of myelinated fibers as small as 0.2/.,m in the CNS. However, they left unanswered the question of why there are few myelinated fibers smaller than 1 tzm in the PNS. This intriguing question was approached by Ritchie 14. Previous studies s,~5 had

- a

/

Coeallmd e a lml~ 159

4.0 -b

/

/ myelinaled nerves

.~"

/

-'~ 3.0

I

iI

.~

~4

20

e-

"~ 1.0 II

or I 1

[ 2

I 3

Fiber diameter (/tm)

I 4

]

J

I

30

t

1~:

I

40

~o

Temperature (°C)

Fig, 1 (a) The relation between conduction velocity and.tlber diameter, No arbitrariness in scaling. (From Ref. 17.) (b) Conduction velocity (relative to a 20°C value) as a function of temperature, in the rabbit and the frog. (FromRef. 15.) Conttmedoatw~t~

159

TINS - May 1 983 Mechanisms of epilelp~, continued from pQge 158

Actkm potential ~

been tentatively identified in many CNS regions, which develop epileptiform activity ~°. These points of low-resistance communication between neurons are characterized by an anatomical specialization, the gap junction. The frequency, effectiveness and functions of such synapses in population activity have not been determined. Certainly, such connections also exist in regions not known for their epileptogenic properties 8, so that the mere presence of electrotonic synapses does not guarantee seizure-like synchrony. Electrotonic synapses may function either to synchronize or to desynchronize neuronal activity21, depending on coupling ratios, cell characteristics, the pattern of cell connectivity, and the strength and distribution of the triggering events. Very little is known about any of these factors in the mammalian CNS. Traub and Wong' s2° work on hippocampus has indicated that, because of their intrinsic burst propensities, CA3 neurons can be synchronized into an epileptiform population with only minimal local excitatory chemical synaptic connections - connections which have been demonstrated experimentallyL These conventional chemical synaptic mechanisms appear to provide all the necessary substrate for synchronization. The role of non-synaptic influences in cell synchrony is still to be determined. The seizure-like activity seen in the experiments of Taylor and Dudek ~9 and Jefferys and Haas 7 appear somewhat like episodes resulting from anoxia, hypocalcemia or drug withdrawal, rather than activity seen in epileptic brain. In the hippocampal slice, such activity is characteristic of hypoxic tissue but different from the epileptiform events produced with such agents as penicillin or bicuculline~7; it has similarities to tonic (spontaneous rhythmic bursting) and clonic (afterdischarge) phases of ictal activity rather than typical slice interictal discharge. These observations suggest that ephaptic contributions to initiation and synchronization of seizure discharge may be substantial in tissue in which a general pathology has created hyperexcitable instability in each neuronal element. The data indicate that electrotonic coupling and ephaptic interaction do exist and can influence some types of neuronal activity. Present evidence suggests that these mechanisms may modulate the predominartl chemical synaptic mechanisms in the CNS, and could contribute to the excitability and synchrony of cortical and hippocampal neurons.

shown that there is an optimal ratio between internodal distance and diameter (in terms of maximizing conduction velocity at any given diameter), and that the optimal value of the ratio is close to the value observed for large peripheral myelinated fibers. For internode lengths close to this optimal value, the curve is relatively flat. However, for substantial decreases in internode distance, conduction velocity falls substantially. Similarly, as internode distance is increased from this optimal value, conduction velocity is initally decreased and conduction finally fails. In his analysis of this problem, Ritchie noted the finding that, along peripheral nerve trunks, the internodes (produced by Schwann cells) generally have a minimal length of no less than 200/xm. Therefore, below a diameter of several /xm, the internode distance/diameter ratio increases (due to the fixed minimal length of the internode) and conduction velocity is consequently reduced. This conclusion is important because it suggests that, below several micrometres, conduction velocity along peripheral axons will be less than the maximal value which could be achieved if internode distance was related linearly to diameter. In Ritchie's revised conduction velocity-diameter curve, the minimal internode distance in peripheral nerve trunks is such that, for diameters smaller than 1 /xm, conduction velocity should be greater in non-myelinated fibers than in myelinated fibers of the same size. Thus, the evolutionary argument, in terms of myelination increasing conduction velocity, appears to provide an explanation for the paucity of peripheral myelinated fibers smaller than 1/zm. On the other hand, the lower range of central internode distance is approximately 10 /xm, and the lower diameter range at which myelination is expected to increase conduction velocity is 0.2 /zm. This work brings up to date the diameter--conduction velocity analysis and points to an important functional difference between central and peripheral myelinated axons. A number of important questions concerning myelination and conduction velocity, however, remain unanswered. It is well established that Schwann cells in preterminal regions of peripheral axons can produce relatively short myelinated internodes; these can be as short at 30 ~m, (Ref. 25). The available evidence suggests that these short internodes provide a mechanism for impedance matching, which facilitates invasion of the action potential from the myelinated parent fiber into the nonmyelinated tenninaP 1'~3. It is not clear, however, why internode distances shorter

Cont i nual ~n i~ge lf,O

,

continued from p q e 1$8

than 200/zm are not observed in a regular fashion along nerve trunks. This leads to the question of the mechanisms which control Schwann cell and internodal length. It would appear, in fact, that mechanisms for specifying internodal length may be different along different parts (axon trunk; preterminal region) of the fiber. Another important question centers around the distinction between modes of conduction in myelinated and nonmyelinated fibers. In an excellent review, Rogart and Ritchie 1'' asked 'which aspects of saltatory conduction are sahatory ?' They pointed out, as did Hodler el al. 1o that the peak of the action potential moves fairly uniformly along the nerve fiber (in contrast, the longitudinal current exhibits discontinuites with respect to time). Moreover, Rogart and Ritchie 1'' noted that the action potential extends over a distance of approximately ten nodes. The implication is that some aspects of conduction in myelinated fibers do not occur in a strictly saltatory manner. These suggestions prompt the converse question 'is conduction in non-myelinated fibers always continuous?' It might be suggested a priori that some degree of differentiation of the axon membrane occurs prior to myelination, since a high density of sodium channels is required at the node for conduction. Cytochemica123 and freezefracture 2°'22.24 studies on developing axons indicate that nodal membrane becomes differentiated before compact myelin is formed. Thus, from a morphological point of view, the axolemma differentiates into regions with nodal and internodal characteristics, prior to the formation of compact myelin. This differentiation suggests the possibility of non-uniform conduction in developing fibers prior to myelination. In studies on remyelinating fibers following application of lysophosphatidyl choline, Bostocket al. 4 and Smithet al. 1, have noted the development of 'phi-nodes' (foci of inward membrane current) at a time when new myelin has not yet been formed. This, too, suggests the possibility of a transitory phase of non-uniform conduction prior to myelin formation. All of this evidence suggests that there may be a gradual process of maturation which occurs between the presumably continuous mode of conduction in premyelinated fibers and the saltatory mode of conduction in myelinated fibers. In fact, developmental studies in the optic nerve 7 show a gradual increase, rather than a clear step increase, in conduction velocity at the time of myelination. The possibility of non-uniform conduction may also be applicable to some mature Continued om page 160

160

I/,,V.S - M a y ! 9 8 3

Mechanismsorepilepsy, continuedfrompqe 159

Reading list 1 Ayala, G. F., Dichter, M., Gunmit, R. J., Matsumoto, H. and Spencer, W. A. (1973) Brain Res. 52, 1-17 2 Gardner-Modwin, A. R. (1976) Exp. Brain Res. Suppl. 1,218-222 3 Green, J. D. (1964)PhysioL Rev. 44, 561--608 4 Grundfest, H. (1959) Handbook of Physiology Section 1: Neurophysiology Volume 1 (Field, J., ed.), pp. 147-197, American Physiological Society, Washington, DC 5 Heinemann, U., Lux, H. D. and Gutnick, M. J. (1977) Exp. Brain Res. 27,237-243 6 Jefferys, J. G. R. (19811J. Physiol. (London) 319, 143--152 7 Jefferys, J. G. R. and Haas, H. L. (1982)Nature (London) 300, 448-450 8 Llinas, R. (19751Golgi CentenniaISymposium:

Act~l pOK'mbllprolpqati~n, cml~m~l frumpqe I$9

non-myelinated fibers. The nonmyelinated axon segments of rat ganglion cells, within the intraretinal nerve fiber layer, exhibit discrete patches of membrane with nodal properties (E-face particle aggregates in freeze-fractured material; dense undercoating subjacent to the axolemma, and overlying astrocytic fingers in the case of transmission microscopy) 3.9. An example is shown in Fig. 2. The observation of these loci of 'node-like' membrane along non-myelinated fibers indicates that the non-myelinated axolemma may be spatially differentiated, and suggests the possibility of non-uniform conduction along some specialized non-myelinated fibers. This latter mode of conduction remains to be demonstrated by electrophysiological experiments. Finally, the role of conduction velocity in determining physiological properties of neuronal systems remains to be further explored. There is no question that, in some systems, conduction times must be carefully matched to functional requirements (for example, see Ref. 1 ). In other systems, however, functional requirements are such that conduction velocity need not be constant. Conduction velocity in both peripheral 6,12 and central TM axons varies with temperature (see Fig. lb). The fact that mammalian circadian rhythms are accompanied by variations in body core temperature of 1-2°C imposes a need for relative insensitivity to conduction latency in some systems. Similarly, it is now well established that visual function can return to near-normal levels after bouts of demyetination, despite substantial delays in the latency of the visual evoked response s . It would be of interest to determine whether there are psychophysical changes, for example in the discrimination of interaural

9 10 11

12 13

14 15

Perspectives in Neurobiology (Santini, M., ed. ), pp. 379-386, Raven Press, New York MacVicar, B. A. and Dudek, F. E. (1980)Brain Res. 184, 220-223 MacVicar, B. A. and Dudek, F. E. (19821 J. Neurophysiol. 47,579-592 Minsky, M. (1969) Basic Mechanisms of the Epilepsies (Jasper, H. H., Ward, A. A., Jr and Pope. A., eds), pp. 755-767, Little, Brown and Company, Boston Prince, D. A. (19781Annu. Rev. Neurosci. 1, 395-415 Purpura, D. P. (1969) Basic Mechanisms of the Epilepsies (Jasper, H. H., Ward, A. A., Jr and Pope, A., eds), pp. 441-.451, Little, Brown and Company, Boston Purpura, D. P. and Malliani, A. (1966) Brain Res. 1,403--406 Scheibel, M. E. and Scheibel, A. B. (19751Golgi Centennial Symposium (Sanfini, M., ed.), pp.

stimulation differences, as core body temperature changes. We have clearly come a long way in terms of understanding conduction velocity and its determinants in terms of biophysical as well as geometrical properties. Ritchie's paper makes an important point which relates Schwann celt structure to the constraints which determine conduction velocity in peripheral myelinated fibers. Nevertheless, detailed mechanisms of axonal conduction, and of the specification of conduction properties along various axonal pathways, remain incompletely understood. The problem is obviously an

347-354, Raven Press, Nev, ~t,rk 16 Schwartzkroin, P. A. and Prince, D A (197,~I Brain Res. 147.117-130 17 Schwartzkroin, P. A. and th'mce, D A. (I9801 Brain Res. 183, 61-76 18 Schwartzkroin, P. A. and Wyler, A. R (19801 Ann. Neurol. 7, 95-107 19 Taylor, C P. and Dudek, F. E. (19821 Science 218, 8t0-812 20 Traub, R. D. and Wong, R. K. S. (19811Neuroscience" 6, 223-230 21 Traub, R. D. and Wong, R. K S. (1983)Neurology 33,257-266 PHILIP A. SCHWARTZKROIN

Associate Professor, Departments of Neurological Surgery, and Physiology and Biophysics, University of Washington, Seattle, WA 98195, U.S.A.

important one. as attested to by the fact that the nervous system seems to have expended considerable effort in meeting structural requirements which will match functional requirements. Reading list I Bennetl. M. V. L. ( 1968) in I he Central Nervous System and Fish Behavior Ilngle, D.. ed. ), pp. 147-169. Universily of Chicago Press, Chicago 2 Bishop. G. M and Smith. J M. 119641 Exp

Neurol. 9.483-501 3 Black. J. A Fosler. R. E. and Waxman S. G tl9821 ('ell Hssue Res. 224. 239-246 4 Bostock. M.. Hall. S. M. and Smith. K. J. (19801 J. Ph.vsiol. (London. 308.21-23P

~tg. 2, Electron micrograph showing non-myelinated axons of rat retinal nerve fiber layerin transverse section. ? wo axons (1, 2) exhibita distinctaxolemmal undercoating (between arrows), similar to that observed at nodes of Ranvicr. Glialprofiles(g) are associated with the axolemmal regions which exhibitthisundercoating. Examination of serialsectionsindicatesthatthese undercoated regions represent spatial!vdiscrete patches of axolemmal specialization.Bar indicates0.25 p.m. (Modified from Ref. 9. )

161

T I N S - M a y 1983 5 Brill, M. H., Waxman, S. G., Moore, J. W. and Joyner, R. W. (1977)J. Neurol. Neurosurg. Psychiatry ad), 796-774 6 De.Jesus, P. V., Jr, Hausmanova-Petrusewicz, I. and Barchi, R. L. (1973) Neurology 23, 1182-1189 7 Foster, R. E., Connors, B. W. and Waxman, S. G. (1982) Dev. Brain Res. 3,361-376 8 Halliday, A. M., McDonald, W. I. and Mushin, J. (1973)Br. Med. J. 4, 661~64 9 Hildebrand, C. and Waxman, S. G. (1983) Brain Res. 258, 23-32 10 Hodler, J., Stampfli, R. and Tasaki, 1. (1952)Am. J. PhysioL 170. 745-756 11 Ito, M. and Takahashi, 1. (1960) in Electrical Activity of Single (?ells (Katsuki, Y., ed. ), pp. 159-179, Ikago Shoin Lid, Tokyo 12 Paintal, A. S. (1965)J. Physiol. (London) 180,

20--49 13 Revenko, S.-V., Timin, Y. N. and Khodorov, B. I. (1973)Biophysics 18, 1140-1145 14 Ritchie, J. M. (1982)Proc. R. Soc. London, Ser. B 217, 29-35 15 Ritchie, J. M. and Stagg, D. (1982)J. Physiol. (London) 328, 32-33P 16 Rogart, R. B. and Ritchie, J. M. (1977) in Myelin (Morell, P., ed.), pp. 117-159, Plenum Press, New York 17 Rushton, W. A. H. (1951)J. Physiol. (London) 115, 101-122 18 Smith, D. J., Bostock, H. and Hall, S. M. (1982) J. Neurol. Sci. 54, 13-31 19 Swadlow, H. A., Waxman, S. G. and Weyand, T. G. (1981)Exp. Neurol. 71,383-389 20 Tao-Cheng, J. H. and Rosenbluth, R. (1980) Proc. 38th Annu. EMSA Meet. 1980, 626~527

Thinking about thinking The Cognitive Neuroscience Institute held its first conference in September 1982, in Kusadasi, Turkey. The institute was recently established in New York to promote research in cognitive neuroscience, and in December 1982 it presented the Hermann yon Helmholtz Award to Vernon Mountcastle (see TINS, January 1983, Vol. 6, p. 9). The meeting was attended by individuals whose specialities range from molecular biology to philosophy. Their common aim was to investigate the role o f cognitive neuroscience in establishing a theory o f mental processing which combines the knowledge derived from cognitive psychology and from neuroscience. How this synthesis is to be achieved, and indeed the extent to which it is possible, was the subject o f wide-ranging and ofien vigorous debate. But, as many disciplines begin to converge on common problems, the prospects for cognitive neuroscience appear encouraging. Thus, as neuroscientists start to unravel the molecular mechanisms o f learning and memory, it is interesting to consider what constraints such mechanisms might place on the operational rules for learning and memory in man. Conversely, while enormous progress has been made in correlating single-neuron activity and behaviour in invertebrates, it has been argued that similar progress in understanding the mammalian brain will come from the application o f models, derived from cognitive psychology, to neurophysiology. Artificial intelligence provides an opportunity to model many cognitive processes, but how close do the models come to reflecting underlying mental states? Indeed, the problem or non-problem o f self-awareness dominated many conversations, tantalizing some participants by its intractability and accepted by others as a naturally emergent attribute o f the mechanics o f the mind. The analysis of complex mental processes in terms of their constituent mechanisms is the core of cognitive psychology. One powerful contribution of the neurosciences to this dissection is in the study of cognitive processes in brain-damaged patients recently the subject of a Royal Society discussion meeting 2. Comparisons can be made between the fragmentation of processing observed following brain damage and the component mechanisms revealed in normal subjects by cognitive psychology. Particularly dramatic consequences of brain lesions are seen in patients with callosal sections, but to what extent do the observed differences between the hemispheres depend on the lateralization of the language faculty? Experimental approaches to this problem were presented by the Director of the Cognitive Neuroscience Institute,

Michael Gazzaniga (Cornell, USA)5. These approaches included the investigation of split-brain subjects who have developed right-hemisphere language, and the examination of patients with partial callosal section, in which only certain conical areas are disconnected. Gazzaniga suggested that the language mechanism frequently operates as an independent subsystem, imposing post hoc rationalizations on behaviours generated by mental processes divorced from the language faculty. Similarly the selective disruption of visual naming (i.e. naming of objects presented visually), which can occur after a partial callosal section that leaves tactile naming (i.e. naming of objects presented by touch) of objects presented to the right hemisphere unimpaired, demonstrates that the information transmitted across the callosum repre-

21 Waxman, S. G. and Bennett, M. V. L. (1972) Nature (London), New Biol. 238, 217-219 22 Waxman, S. G., Black, J. A. and Foster, R. E. (1982)Neurology 32,418-421 23 Waxman, S. G. and Foster, R. E. (1980)Proc. R.

Soc. London, Set. B 209, 441~46 24 Wiley-Livingston, C. A. and Ellisman, M. H. (1980) Dev. Biol. 79, 334--355 25 Zenker, W. (1964) Z. Zellforsch. ~ikrosk. Anat. 62,531-545 STEPHEN G. WAXMAN

Professor and Associate Chairman, Department of Neurology, Stanford University School of Medicine; and Chief,, Neurological Unit, Veterans' Administration Medical Center, Palo Alto, CA 94304, USA.

sents indirect attributes of the object. The language system in the left hemisphere is not presented with information which enables instant recognition; it appears to deduce the nature of the object from more complex associations. Neuropsychological studies of braindamaged patients have made important contributions to our understanding of cognition, but they do have the inherent drawback of investigating the deficits consequent on the lesion. Much discussion focused on the application of neuroscience techniques to •intact brains. Recent developments in brain scanning (for example, see Ref. 3) which permit more accurate localization of lesions in brain-damaged patients (NMR imaging), the measurement of local cerebral blood flow, or the measurement of local brain metabolism in intact subjects excited much interest. These techniques afford the opportunity to investigate regional changes in brain activity during a variety of cogni•tive tasks (for example selective attention). They add a temporal dimension to studies of localization of function, and complement information obtained from studies of cognitive deficits localized brain lesions. The imaging techniques provide information about the involvement of various cortical areas. Can additional insights be derived from neurophysiological procedures which display higher spatial and temporal resolutions? Steven Hillyard (San Diego, USA) introduced us to event-related potentials, generated by computer averaging of the electroencephalogram 4, which show both quantitative and qualitative changes as the cognitive (especially semantic) or attentional aspects of a task are altered. By examining tasks which produce similar changes in the potentials, information can be obtained about the neurophysiological segregation of various cognitive subroutines. Single-unit recording is con-

~%1983,ElsevierSciencePublishersB.V. Amsterdam 0378 5912/S3/$01.00