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3 Four New Technologies: Research Findings This chapter provides technical discussions of each of the four technologies examined by the committee. Each discussion covers four areas: a brief description, the background of relevant research findings, an assessment of the likelihood that progress will be made, and an outline of opportunities for basic and applied research. Our assessments of the likelihood of progress are based on the most recent developments in empirical research, which are reviewed in varying amounts of detail depending on the field. Implications are drawn from the best experimental work reported to date. Research oppor- tunities are discussed in terms of the conceptual foundations estate fished by the current research and the technological breakthroughs that make possible finer definition of brain functions involved in cognitive processes. One unport ant and general conclusion emerges from these discussions, namely the importance of exploiting the com- plementary advantages of the different technologies as, for example, employing both PET and MRl methodologies for solving problems of anatomical localization of physiological processes. Progress will depend, however, on solving the problems considered In detail in Chapter 4. E:VENT-RE:LATED BRAIN POTENTLA[S Event related brain potentials (ERPs) are obtained by placing electrodes on a person's head and recording electroencephalographic (EEG) activity while the subject is engaged in a task. By means of signal averaging it is possible to extract from the EEG (a voltage x 18

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RESEARCH FINDINGS 19 time function) estimates of the portion of the voltage (the ERP) that is time-Iocked to events associated with the task. These ERPs rep- resent the synchronized activity of neuronal ensembles whose fields are so aligned that they sumrnate to produce potentials that are large enough to be recorded over the scalp. The ERP consists of a sequence of named components whose amplitude, latency, and scalp distribution vary systematically with the conditions of stimulation, with the subject, and with the processing required by the eliciting events. Variations in the behavior of the components of the ERP can be used in the study of sensory and cognitive function (Caliaway, Tueting and KosIow, 1978; Hillyard and Kutas, 1983~. Background of Researth Fm~mgs The ERPs provide a rich class of responses that may, within the appropriate research paradigm, allow the study of processes that are not readily accessible to experimental psychologists by other means. The key assumption of cognitive psychophysiology ~ that ERP components are manifestations at the scalp of the activity of specific intracranial processors. The reference is not to specific neuroanatom~cal entities,but rather to specific functional processors. While networks of nuclei may be involved in a dynamic fashion in the activity represented by each ERP component, our current under- standing of the underlying neuroanatomy is, for most components, insufficient to generate meaningful neuroanatom~cal hypotheses. But the available data regarding the consistency with which certain com- ponents measured at the scalp behave permit us to hypothesize that these components do signal the activation of internal subroutines. These remarks do not imply that the electrical activity recorded at the scalp is itself of functional significance. For our purposes, the ERPs may be due solely to the fortuitous summation of electrical fields that surround active neurons. Although some have argued that EEG fields do have functional significance (Freeman, 1975), we remain agnostic on this issue. We are not asserting that the ERPs are epiphenomena. Rather, we are saying that from the perspective of the cognitive scientist, it is sufficient to elucidate the functional role, in information-processing terms, of the subroutines manifested by the ERP components. Once the existence of a component is well established, the es- sential tools of the cognitive psychophysiological paradigm are used

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20 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES to identify the subroutine it manifests and to articulate its param- eters. This search and analysis require that: (~) we elucidate the antecedent conditions under which the component is elicited, from which (2) we derive a mode} of its subroutine that (3) we test by pre- dicting the consequences of "calling the subroutines (i.e., of engaging the processes whose activation is manifested at the scalp). With the information thus gained, psychophysiology provides a repertoire of tools, a collection of components, each of which can be used in the appropriate circumstances to augment the armamentarium of the cognitive scientist (Donchin, 1981~. Likelihood That Progress WiB be Made The ensemble of information-processing activities manifested by the ERPs is already quite rich. Additional components are being discovered and deeper understanding is being reached of components that have been known since the 1960s. In principle, all these compo- nents can be used in cognitive psychophysiology. A good start has been made and, as is made clear in subsequent pages, the area is rich in promise and substantive progress. The following paragraphs list some of the components that have attracted the most substantial investigative efforts. Components are labeled as egative or ositive to indicate the direction of the voltage change from the base line. The number following the character refers to the modal latency, in milliseconds (msec), of the component, measured from the onset of the precipitating event. N100 Direction of Attention Hillyard and his associates have shown that the N100 component is affected by the directions of the subject's attention. Events in the focus of attention tend to elicit a somewhat larger N100. The effect is reliable and can be used to monitor changes in the direction of at- tention or changes in the attentional level. Thus, the N100 can play a role either in ascertaining whether the subject ~ actually following instructions with regard to the allocation of attention or in deter- m~ning whether events in the environment have caused the subject to shift attention. Research on the behavioral correlates of N100, and other negative components, is a very active field of investigation. There ~ considerable interest in resolving the many different negative components that appear in the first 200 msec following the eliciting

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RESEARCH FINDINGS 21 event and in elucidating their functional significance (for reviews see Nastanen and Picton, 1987, and Hillyard and Hansen, 1986~. There is an active examination of the differences and similarities In the nature of selective attention in different sensory modalities. E`urther- more, extensive work that illuminates central issues in the theory of attention is being done (HiDyard and Hansen, 1986~. N200~Detection of Mismatch Considerable evidence exists that the N200 ~ elicited by events that violate a subject's expectations, even if they occur outside the focus of attention. Thus, the N200 seems to be a manifestation of the activation of a mismatch detector. This component seems to be the least susceptible to control by the subject's voluntary actions. The occurrence of any deviation from regularity, indeed any rn~smatch between an event and its immediate predecessor, elicits an N200. Examination of these components continues and is being extended to fairly abstract information-processing activities. Thus, for example, there ~ considerable interest ~ the role that these negative components play in studies of lexical decision (Nastanen, 1982~. P30~A Manifestation of Strategic Proce - sing When subjects are presented with events that are both task rel- evant and rare, a prominent positive component with a latency of at least 300 msec is elicited. The literature concerned with the P300 is quite extensive (see Donchin et al., 1986; Pritchard, 1981; and Rossler, 1983, for reviews). Johnson (198S, in press) has summarized much of the evidence concerning its antecedent conditions and has concluded that the elicitation and amplitude of the P300 depends on a multiplicative relationship between the subjective probability of events (the rarer the event, the larger the P300) and the amount of information and the utility of the information to the subject (the more information, the larger the elicited P300~. Donchin and his colleagues have interpreted these data within the context of a mode} that assumes that the P300 is a manifestation of the revision of mental models (see Donchin and Coles, in press; Donchin, 1981~. Much empirical evidence supports a wide variety of applications of the P300, including the measurement of mental workload (Gopher and Donchin, 1986; Donchin et al., 1986), analyses of memory mech- anis~rm (Neville et al., 1986; Karis, Fabiani, and Donch~n, 1984), and

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22 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES concession making in bargaining situations (Druckman, Karis, and Donchin, 1983; Karm, Druckman, Lmsak, and Donchin, 1984~. The latency of the P300 has also proven to be of use. It can be shown to be relatively independent of response execution processes and can thus serve as a pure measure of mental timing (Kutas, McCarthy, and Donchin, 1977; McCarthy and Donchin, 1983~. N400 Semantic Mismatth Kutas and HiDyard (1980, 1984) have shown that words that are in some way incongruous or unexpected in a semantic sense within a discourse elicit an ERP component that is negative and has a latency of about 400 msec (see Kutas and Van Petten, 1987, for a review). Kutas and her coworkers have subsequently shown that the ampli- tude of the N400 is inversely proportional to the degree to which the context constrains the word eliciting the N400. The measurement of N400 makes it possible to address unresolved issues in psycholinguis- tics. Thus, for example, Van Petten and Kutas (1987) show rather persuasively that they can measure the degree to which sentences im- pose constraints on their constituent words by examining the N400 elicited by these words. This application of N400 in psycholinguistics is increasingly active (touchier et al., 1983, 1985, 1987~. The Readmese Potential and the Contmgent Negative VariationPreparation to Respond Kornhuber and Deecke (1965) have shown that voluntary re- sponses are preceded by a slow negative wave, which they labeled the readiness potential (RP). Walter and hm colleagues (1964) have demonstrated that a slow negative wave develops between a first stimulus, which heralds the later arrival of a second stimulus, to which the subject must respond. They called this wave the contin- gent negative variation (CNV). (Note the different labeling systems.) As on a map of lower Manhattan, the orderly system of letters and numbers used to label the faster components gives way to a system in which each component carries a name given it by its discoverer. The RP and the CNV are among several ERP components that are callecl event-prececling negativities. They are quite clearly related to the activation of preparatory, often unconscious, processes by the sub- ject. Their usefulness in the study of cognitive processes is extensive. For example, Coles and his colleagues (1985) have shown that it is

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RESEARCH FINDINGS 23 possible to deterrn~ne, from the extent to which these potentials are larger over one hemisphere than the other, which response the sum ject was contemplating regardless of the response that has actually been made. Opportunities for Basic and Applied Regears It is not possible in this brief review to do justice to so active a research enterprise. The work reviewed above refers to some of the welI-established research activities. It may be useful, however, to note a number of developing research areas that are likely to play a central role in the coming decade. One of the more significant efforts is the increasing practicality of elucidating the intracranial origin of the components. We referred elsewhere to this work, but it is important to underline the fact that much of the technological and conceptual development required has become readily available only very recently. Several laboratories had access to patients with indwelling electrodes from the earliest days of ERP research. However, only within the last decade has it become possible to deal with the massive data base generated in such studies. Furthermore, there are significant developments in the theoretical un- derstanding of the nature of the models needed to relate intracranial activity to scalp recorded activity (see, for example, Scherg and Von Carmon, 1985; Nunez, 1981~. There also is an increasing number of investigations of analogous processes in nonhuman species (Dead- wyler et al., 1985; Arthur and Starr, 1984~. The work in humans using indwelling electrodes, neuromagnetic recording, and clinical observations on the effects of lesions (Johnson and Fedio, 1986) is likely to combine in the near future with the work in animals to yield much deeper understanding of the neurophysiological basis of the ERPs. The development of display methodology is likely to affect prog- ress in the field, as noted below. It ~ largely the case that inves- tigators are forced to select a very small portion of their data for display and analysis. The number of waveforms analyzed is generally much smaller than can be easily acquired, and the number of mea- surements made on these waveforms Is also rather small. The ability to summarize and combine much larger masses of data provided by mapping approaches is likely to transform the field. However, this will be true only if the summaries and the displays are guided by

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24 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES proper statistical and substantive theories. It ~ to this area of re- search that much attention needs to be paid in the near term (see, for example, Skrandies and Lehman, 1982~. Much work in cognitive psychophysiology is motivated by applied interests. The use of ERPs recorded from the brainstem is routine in neurology and audiology, as are various diagnostic procedures that measure the speed of neuronal conduction in the response of various systems to changes in steady-state stimuli. More controversial at this time are applications of some of the components in the diagnosis of neurological and psychiatric disorders. There is extensive interest in a report (Goodin, Squires, and Starr, 1978) that interpretation of the latency of the P300 may allow a diagnosis of either dementia or depression. Begleiter and his associates (1984) have been applying ERP measures in studies of the familial risk for alcoholism. In addition to the clinical work, there is active interest in the feasibility of using ERPs and other psychophysiological measures in the field known as engineering psychology. Human Factors, the official journal of the Human Factors Society, devoted a special is- sue (Kramer, 1987) to examine psychophysiological measures. The usefulness of the P300 as a measure of mental workload has been examined in some detail by Donchin and his colleagues free Go- pher and Donchin, 1986, for a review). The work ~ continuing and diversifying. Methodological Moues Data acquisition is not a source of serious problems in ERP research, depending as it does on established technologies. However, experimental design, measurement, and data analysis present serious challenges that require attention. We briefly discuss three parts of the methodology: recording techniques, data analysis, and display methodologies. The technology required for recording ERPs ~ largely mature. It is identical to that required for recording the EEG. The EEG is digitized, either on-line or off-line, and the ERP, whose amplitude ranges between 5 and 10 m~crovolts, ~ extracted by signal averaging. This well-established procedure capitalizes on the fact that the part of the signal that is time-Iocked to events has a constant time course following the event while all other activity follows a randomly varying time course. The data base acquired in ERP experiments does present formi-

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RESEARCH FINDINGS 25 cable problems of analysis. Typically, 5 to 10 subjects are run, each in several sessions. In each session, data may be acquired for 5 to 10 separate conditions, where each condition requires the presentation of 30 to 200 repetitions of the same stunulus. For each presentation, the EEG Mom 5 to 32 recording channels is digitized over an epoch lasting as long as 2 to 3 seconds at the digitizing rate of 100 to 500 samples per second. All these data are typically stored on magnetic tape. Full stor- age of single trial data is preferable, especially in studies of cognitive function, because it has proven useful to consider the subject's actual performance on each trial in extracting the ERPs. Thus, for exam- ple, it may be of interest to examine separately trials on which the subject's response was fast and those on which the response was slow. Such selective averaging is one of the most powerful tools available to the cognitive psychophysiologist. Note that saving of the single trials allows the use of off-line filtering of artifacts. This strategy prevents the loss of trials. Currently available procedures render obsolete any study in which a substantial percentage of the data Is rejected. In any event, even when just the average ERPs are retained, the analytical tasks are formidable. An extensive literature beyond the scope of this report is concerned with these issues (see Coles et al., 1986, for a review). Even though considerable sophistication ~ invested in the anal- ysis of data obtained in ERP experunents, the visual inspection of the data remains critically important. It would be rare for a study of ERPs to be published without a visual display of the waveforms. The mere tabulation of measures and the associated statistical tests would be considered inadequate, as they do not allow an evaluation of the quality of recordings. In the past, data were presented largely in the form of plots of voltage changes as a function of tune, one plot for each electrode site; this remains the modality of choice. However, the reduced cost of computing power and the increased sophistication of graphic display devices triggered the emergence of displays that map the variations of the voltage over the head at successive instants in time. These Brain maps represent the changing pattern of activity at varying points In tone in a two-dimensional and easily visualizable display. However, all the mapping techniques discussed in this re- port, including brain mapping, would greatly benefit from an effort to develop statistical methods that can cope with this complex data base.

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26 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES NEUROMAGNETISM: THE MAGNETOENCEPHA[OGRAM The term neuromagnetism refers to the study of the magnetic fields that accompany the flow of ionic currents inside neurons, as opposed to the flow of current within the overall volume of the cranial contents. Neuromagnetic methods are employed in the study of ex- tracranial magnetic fields. By analogy with electroencephalography, which involves the study of electrical potential differences between electrodes attached to the scalp, magnetoencephalography (MEG) is now the standard term used to refer to the study of the brain's vary- ing magnetic field. In addiiton, by analogy with ERPs, extracranial magnetic fields that are t~me-Iocked to physical stimuli (e.g., changes in visual patterns, noise bursts) are referred to as event-related fields (ERFs). As in the study of evoked potentials, it is customary to dis- t~nguish between steady states and transient responses, except that the measures used are time-varying amplitudes of neuromagnetic fields rather than of voltages. Background of Research Fm~mgs The first systematic studies of neuromagnetism appeared in 1975. At first, they took the form of demonstrating that it was possible to detect visually evoked fields. These were rapidly followed by the demonstration that fields also could be evoked by auditory and somatosensory stimuli, and that fields systematically preceded the occurrence of simple motor acts. In 1975, a singularly interesting finding was reported: it was found that the amplitude of the field associated with stimulation of the little finger had a different dis- tribution on the scalp than that associated with stimulation of the thumb (Brenner, Williamson, and Kaufman, 1975~. This led almost immediately to the notion that the mapped field could be compared with that which would be produced by an equivalent current dipole source, and the source could be located within the three-dimensional volume of the brain. The magnetic field is associated with the intracellular currents of a limited population of neurons in the brain. The field produced by these neurons is essentially indistinguishable from that which would be produced by an arbitrarily small segment of current. This small segment is commonly referred to as a current dipole. Various groups began to use this approach, which entailed taking sequential measurements from many places on the head. Since the

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RESEARCH FINDINGS 27 only available instrument at that time incorporated a single super- conducting quantum interference device (SQUID) and sensing coil, the task proved to be very laborious and subject to errors in position- ing the sensing coil over the head. It quickly became apparent that multiple sensors would be necessary to realize the full potential of the technique. The main advantage of magnetic recording Is that, using a m~nnnum number of assumptions, it is possible to determine the three-~unensional location, geometric orientation, and strength of equivalent current dipole sources. This advantage makes it possible to distinguish between changes in field intensity due to a change in amount of neural activity resulting from an experimental manipula- tion and changes in source location and orientation. Multiple sensors are needed for this purpose. The group at the Helsinki Technological University was the first to construct a multichannel system. This included four SQUlDs and four sensing coils. Owing to a specific feature of the Finnish design, one of the four channels was never used in the many useful experiments conducted by that group (Hari et al., 1982, 1984~; their system was functionally a three-channel system. At about the same time, the group at New York University collaborated with the S.H.E. Corp. of San Diego (now Biomagnetic Technologies, Inc.) in designing and developing a five-channl! system that incorporated the newer and more sensitive dc SQUlDs. Actually, nine SQUlDs were used: five were used for sensing the brain's field; three were used for monitoring the field in the x, y, and z axes; and one was used for monitoring the spatial gradient of the field along the z axis of the dewar. In effect, these channels were used to monitor the ambient field. Their gains were empirically adjusted and their outputs subtracted from those of the signal channels to reduce the effect of this ambient noise. This was the first system to employ electronic noise cancellation techniques. It was introduced into the laboratory in 1983 and proved extremely effective, even in the absence of shielding, in making measurements more quickly and accurately than was possible previously. Based on their experience in constructing a five-channel sys- tem, Biomagnetic Technologies, Inc., went on to develop a similar seven-channel system. Such systems are now installed at New York University, the National Institutes of Health, Vanderbilt University, the Scripps Clinic in La JolIa, the Los Alamos National Laboratory, the Free University in West Berlin, the University of Texas School of Medicine in Galveston, and at Henry Ford Hospital in Detroit and

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28 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES in other laboratories in Europe. In some cases two such instruments are present in the same laboratory, thus providing a total of 14 sens- ing channels for concurrent use. CTF, a Vancouver based company, manufactured a single-channel system that ~ in use at Simon Frazer University and at the University of Wisconsin. It should be noted that only three laboratories are devoting a substantial effort to the study of cognitive processes, the rest focusing on clinical problems. [ike];hood That Progress WiB Be Made All this ferment in the development of the technology of neuro- magnetism is undoubtedly related to the very strong cianns made on its behalf. The strongest of these claims is related to the presump- tion that the extracellular volume currents that underlie the EEG and the ERP do not contribute substantially to the magnetic field. Furthermore, the neuromagnetic and electrical methods yield differ- ent and complementary results. Since the distribution of intracranial volume currents is strongly influenced by features of the skull such as the orbits of the eyes, the sutures in the skull, and other anisotropies of conductivity, source localization using s~rnple concentric sphere models should be subject to considerable error. If it is true that these same conditions have little effect on the extracranial magnetic fielcI, then relatively simple models of the head should permit excel- lent source localization. One strong cistern is that it is possible to locate intracranial sources of neuromagnetic fields with a precision that is not possible when using similar electrical measurements. To the extent that investigators find it important that activity of par- ticular portions of the brain be identified with processes underlying cognition, this attribute of neuromagnetism may be of great value. There are empirical bases for this strong claim that we review below. One of the more impressive experiments, demonstrating the abil- ity of neuromagnetic methods to resolve sources, described the tono- topic organization of a portion of the human auditory cortex (Ro- mani, Williamson, and Kaufman, 1982~. Tone stunuli of different frequencies were modulated by a 32 Hz sinusoid. The steady-state evoked field at the frequency of the modulating sinusoid was mea- sured at many places on the side of the head. All the carrier fre- quencies were presented at each position of the single-channel sensor; the sensor was then moved and the responses measured again at an- other position. After the experiment was completed, all the averaged responses associated with each carrier frequency were collected and

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32 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES responses to novel stimuli. This wave is probably related to the neg- ativity that was described by Hillyard et al. (1973), and its magnetic counterpart appears also to have its source near auditory cortex. Still another contribution of ERF studies is the first report that the equivalent current dipole source of the P300 is in or near the hip- poca~npal formation (Okada, Kaufman, and Williamson, 1982~. This finding is consistent with data obtained using indwelling electrodes in epileptics. But electrical studies in which patients having unilateral temporal lobectom~es show no shift in the distribution of the P300, and studies involving anunal models show results that in some cases are inconsistent with this interpretation and consistent with those of other studies (e.g., Buchwald, 1987~. These inconsistencies remain to be resolved. The literature concerning the relationship between neuromag- netism and cognition is quite slender. As stated earlier, until now the main focus of basic research has been on sensory processes. There are currently several major efforts getting under way that are designed to test the usefulness of neuromagnetism in medical practice, and three laboratories are currently investigating neural processes involved in cognitive processes. Publications should be imTn~nent. While little has been accomplished in directly contributing to cognitive neuroscience, it is clear that the necessary foundations for future progress have been laid. The emergence of multiple sensor neuromagnetometers and of theory and algorithm that allow the processing of data from many such channel is particularly impor- tant. It has led to a growing awareness that source localization and resolution are possible only when an adequate number of sensors is used, whether these be magnetic field sensors or electrodes. At the present time it is possible to study the activity of limited regions of the brain and how this activity IS affected by factors such as cognitive Toad or changes in perception. It seems likely that many studies will employ the paradigms already used with so much success in ERP research in an effort to determine which parts of the brain are actu- ally involved. This modest approach promises to be useful in that it wid enable ERP researchers to determine if a given component they observe is attributable to a single source or to several widely separated sources whose activity overlaps in time. Such efforts will undoubtedly sharpen the skills of workers in neuromagnetism, and they will ultimately result in branching out to develop paradigms that are uniquely suited to their own methodology.

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RESEARCH FINDINGS 33 Opportunities for Basic and Applied ResearEh Several problems associated with the interpretation of ERP re- sults can now be addressed. These include deciding whether the N100 and P200 are attributable to multiple sources and the degree to which the variance in the electrical P300 can be accounted for by changes in the magnetic P300. Such studies will require the joint use of ERP and ERF techniques. The urgent need for concurrent recording of electrical and magnetic data cannot be overstated. Un- less precise and quantitative procedures are employed, it will not be possible to determine the degree to which one of these measurement modalities reveals information that cannot be obtained by means of the other modality. Among the most promising future developments IS the advent of truly large arrays of neuromagnetic sensors. The study of correlated activity among ah of these sensors will make it possible to examine the waxing and waning of activity of multiple sources in the spontaneous MEG ant] also when specific event-related tasks are performed. The complex chains of events occurring at many places within the brain during high-level tasks, e.g., retrieving memories, engaging in speech production, perceiving stereoscopic depth, etc., are very difficult to study with existing instruments. Current topographical EEG studies are essentially two dunensional, and the locations of the sources of the potentials cannot be estimated accurately, even with the use of 30 to 60 electrodes. The promise of this approach can best be realized using large arrays of sensors and analytical tools that will reveal the changes that occur over time in brain activity within a three- dimension e] volume. ~ principle, there is no technical reason why this cannot be achieved, especially if complementary technologies are brought to bear on the problem of how to constrain solutions to the inverse problem, discussed in Chapter 4. As we have already stressed, there are some inherent ambiguities in interpreting neuromagnetic measures. It is not known whether there is a flow of current ~ opposed directions at the same time in many portions of the cortex. If this is a significant occurrence, then it leaves us with an apparently weak response although the underlying activity is in fact very strong. Animal models and methods of current source density analysis applied to their exposed brains should help to clarify this issue. So too would correlated brain imaging studies (see the next section). These, however, should not be mere replications of experiments across different populations of subjects; they should involve the same subjects and the experimenters should have the

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34 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES broad biophysical skills needed to interpret such data. In this same connection, it may be instructive to conduct studies involving clinical populations, including patients with split brams, so that it becomes relatively easy to isolate anatomically symmetrical regions from each other. Thus, the use of both electrical and magnetic measures in split brain patients (and of the many techniques developed to study such patients) can lead to very suggestive results. IMAGING TECHNIQUES I: POSITRON EMISSION TOMOGRAPHY Positron emission tomography (PET) is a nuclear medicine tech- nique that produces an image of the distribution of a previously administered radioactively labeled compound in any desired section of the body (Ra~chie, 1983~. Radioactive labeling is the chemical syn- thesis of a compound in which one of the atoms ~ radioactive. PET images are highly faithful representations of the spatial distribution of these radioactively labeled compounds at selected planes through the tissue. These images reflect the behavior of the particular com- pound that has been labeled. A wide variety of compounds have been labeled permitting measurements of local blood flow, metabolism, and chemistry. Background of Researth Findings Using i8F-labeled fluor>deoxyglucose, PET investigators (Phelps et al., 1979; Reivich et al., 1979) quickly adapted the success- fuT deoxyglucose autoradiographic technique (Sokoloff et al., 1977) for measuring local brain glucose metabolism. PET tended to be- come synonymous with deoxyglucose measurements of local brain glucose metabolism in humans. Many attractive, color-coded images of normal as weld as diseased human brains at work soon appeared in the scientific literature, at scientific meetings, and even in the media. What escaped the notice of many was that PET employs a vari- ety of quantitative tracer techniques. Each of these techniques uses a different mathematical mode! and a different radio-labeled com- pound. These techniques can now be used to make measurements of many different variables, such as local blood flow (Raichie et al., 1983), blood volume (Martin, Powers, and RaichIe, 1987), oxygen consumption (Mintun et al., 1984), pH (Brooks et al., 1984), perme- ability (Herscovitchet al., 1987), receptor binding (PerImutter et al.,

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RESEARCH FINDINGS 35 1986) and transmitter metabolism (Garnett, Firnau, and Nahm~as, 1983~. It can be anticipated that additional PET techniques will be developed In response to new and important biological questions that justify the time (often 2 to 5 years) and expense required to develop the relevant radio-pharmaceuticals and tracer strategy. Likelihood That Progress WiB Be Made The capacity of PET to contribute to a better understanding of brain function has been demonstrated. Abundant evidence indicates that functional activity, such as somaesthesis, audition, movements of all types, vision, and language, cause striking changes in local brain blood flow and glucose uptake, which can be quite dramatically demonstrated with PET (Raichie, 1987~. Analysis of such images has progressed from simple qualitative, uncontrolled demonstrations of anticipated changes to more sophisticated studies using rigorously controlled experimental paradigms and precise analytical techniques (Petersen et al., 1988~. In the studies by Petersen et al. the objective was to use PET measurements of blood flow to locate the regions of the human cere- bral cortex concerned with the elementary mental operations of visual and auditory word processing. Four behavioral conditions formed a three-level subtractive hierarchy: passively viewing a cross hairs on a television monitor; passively viewing or hearing single words at one per second; repeating the words; and generating a use for the words. Each task state was assumed to add a single process to those of its subordinate control state. Direct evidence to support this assumption is in press (Petersen et al., 1988~. Because of the short measurement tune and the repeatability of the measurement, all tasks were performed by each subject ~ the study. The first- leve] comparison, the presentation of single words without a lexical task, was compared with visual fixation without word presentation. No motor output nor volitional lexical processing was required in this task; rather simple sensory input and involuntary word-form processing were targeted by this subtraction. In the second-level comparison, speaking each presented word was compared with word presentation without speech. Areas involved in output coding and motor control were targeted by this comparison. In the third-level comparison, saying a use for each presented word (e.g., if "cake" was presented, to say "eat"), was compared with speaking presented

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36 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES words. This comparison targeted areas involved in the task of semen tic processing (ver~noun association) as distinguished from speech sensory input, and involuntary word-form processing. Images were analyzed by paired intrasubject subtraction. Task- state minus control-state subtractions created images of the regional blood flow changes associated with the operations of each cognitive level. Intersubject averaging was used to increase the ~i~nal-t~n`,i~e ratio of these subtracted images. ., O _ ~ _ The results of this complex study provide evidence for multiple, parallel routes between localized sensory-specific, phonological, ar- ticulatory, and semantic coding areas. More important, this study may be a prime example of what is required to make elective use of PET in cognitive psychophysiology. The study combined state-of- the-art PET techniques with sophisticated stimulation paradigms; it arose from close collaboration among investigators with exper- tise in PET, human neurobiology, and cognitive neuropsychology. The study seems to provide unique new insights into the functional anatomy of perception, motor control, and language. It should be clear from the above material that PET will play a significant role in understanding the function of the human brain. Opportunities for Basic and Applied Research It may be argued by some that despite the developments de- scribed in this report, it is virtually impossible for PET to reveal the underlying neuronal events participating in such changes (e.g., blood flow and volume or transmitter metabolism), and hence it can con- tribute little to our understanding of how the brain works. However, it seems fair to assume that once PET has safely identified a specific area of normal human or primate cortex involved in a well-defined type of information processing (a task it is uniquely equipped to do), other neurobiological techniques can be brought to bear on the exact nature of the process. Complementary interaction of this type between cognitive psychophysiology and neurobiology can serve to further our understanding of the human brain. IMAGING TECHNIQUES II: MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) is based on the fact that some atomic nuclei act like tiny bar magnets when placed in a magnetic

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RESEARCH FINDINGS 37 field. When they are aligned in a magnetic field they can be excited in controlled ways by irradiation with radio frequency energy. During recovery from such manipulations, these tiny bar magnets or dipoles Ernst radio frequency signals that contain a great deal of information about their chern~cal environment. Depending on the strength of such signals, unages of sections of the body can be obtained with this technique. From such images one can obtain quantitiative infor- mation about tissue biochemistry, acidity, and met embolism as well as anatomy. Background of Research Fm~mge Abundant evidence now supports the use of proton MR! in clini- cal medicine as an excellent way to obtain anatomical information of the human brain in viva. ~ many respects, the images are superior to those produced by X-ray computed tomography (CT). The pri- mary contribution of proton MR! to neurobiology wiD be similar to that of CT, providing accurate information for correlations between specific lesions and the signs and symptoms of ilIne - . Many nuclei other than hydrogen can be studied with MRI. Of the biologically unportant ones, 3iP, 23Na, and i3C have received the most attention. In a recent review of in viva spectroscopy techniques (now often referred to as MRS or magnetic resonance spectroscopy) using these nuclei, Prichard and Schulman (1986) have provided exciting new data from an increasing number of studies showing that it is feasible to measure brain ATP, PCr, Pi, and intracellular pH in viva with phosphorous MRI. Using refined techniques for the hydrogen nuclei, it ~ possible to measure brain lactate concentrations in humans and a variety of amino acids in animals. Techniques still under development with i3C MR! suggest that it may be possible to monitor a number of specific biochemical reactions in viva with MR! spectroscopy. [likelihood Mat Progress WiB Be Made and Opportunities for Research MRI has played a role ahnost identical to that of X-ray computed tomography in providing ever more refined anatomical unages of the living human brain. This permits detailed cI~nical-anatomical correlations. Because of its lack of temporal resolution, however, MRI will not replace PET in the area of functional brain mapping.

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38 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES Because of the exquisite anatomical detail provided by MRI pro- ton images, this technique will probably become the technique of choice for detailed clinical-anatorrucal correlations. In addition, one can anticipate that MRI proton images wall also be used to anatomi- cally constrain PET images with their somewhat poorer anatomical resolution. Thus, brain edges and ventricles can be identified and radioactive counting data blurred into these regions on PET moved back into the brain. Such interaction will require PET and MRI scans in each subject with proper alignment of the planes of section. This wiD be both expensive and time-consuming; however, at least in selected cases (e.g., cases of aging and dementia with brain atrophy), such an interaction wiD be essential. More speculative will be the use of MRI to further constrain PET data by defining gray-white matter differences. COGNITIVE CONSEQUENCES OF BRAIN DAMAGE OR ALTERATIONS This approach allows for insights into the functioning of the nor- mal human brain. Dissociations, disabilities, and other phenomena instruct the student of cognition at two levels. First, studies on brain-damaged patients are suggestive of the functional architecture of cognition. Second, with the advent of new brain unaging tech- niques, these same studies can also be suggestive of the brain areas involved with particular functions. This is true not only for cases of hemispheric disconnection but also for the correct characterization of patients with focal brain damage (Jouandet et al., 1987, 1988~. Background of Research Findmge There are two main views on how brain-damaged patients can be used to study cognitive processes. The first assumes that psycholog- ical processes are localized in discrete brain areas and that damage to these areas will provoke discrete psychological disturbances. In terms of the doctrine of modularity in cognitive science, the approach hopes to identify brain areas that subserve particular functions as specified in perceptual and cognitive models. With the proliferation of models that become more complex in terms of the processes and subprocesses that are active in perceptual and cognitive processes, the hope has been that new and better brain imaging techniques will assist in a finer-grained identification of the brain areas involved in

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RESEARCH FINDINGS 39 cognitive and perceptual activities. This position has traditionally not entertained the view that focal brain damage may reveal deficits that are part of a larger process. It has maintained that discrete deficits following prescribed lesions are managed by the brain site in question. This limitation has given rise to an alternative view of how to gain knowledge about cognition from "broken brains." The second view holds that, since psychological or cognitive processes are widely distributed throughout neural networks, both focal and diffuse brain damage can reveal clues only to the functional structure of cognitive processes; direct clues to brain correlates of cognitive processes are not revealed. The idea here is that cognitive processes are generated by interactions of neural systems that are widely distributed In the brain, and that damage to one area affects other areas. This makes it difficult to ascertain which brain area actually controls a particular function. Yet what is learned, by deduction, is how the cognitive system is structured given how it works in physical disrepair. The brain lesion approach has yielded some of the most semi- nal and basic observations to date about brain function. In animal research, many of the major functional areas of the brain have been described (Mishk=, 1982~. In humans, the clinical cases have offered major insights into the mechanisms of memory (MiIner, 1970; Squire, 1987), perception (We~skrantz et al., 1974; Holtzman, 1984), atten- tion tHillyard and Picton, 1987), language (Zurif and Caramazza, 1976), and cerebral lateral specialization (Gazzaniga and Sperry, 1967), to mention a few areas. It was the work on humans, for exam- ple, that first implicated the hippocampus in memory mechanisms and gave the first physical evidence that the distinctions between short- and long-term memory were useful for both the brain and psychological sciences. Recent work by Poener has underlined how attentional processes, viewed through cases of brain damage, can be thought of as working independently of other mental structures and yet contributing to most of them. Work on aphasia has made im- portant distinctions about the structure of language, suggesting that different brain areas contribute to syntax as opposed to semantics. The split-brain work that emphasizes the separate capacities of each half brain has now shown how dominant the left brain is for most computational skills, including thinking (Gazzaniga, 1985), imagery (Kosslyn et al., 1985), and belief generation (Gazzaniga, 1985~. Fi- nally, work on perceptual processes has continued to identify discrete

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40 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES brain areas associated with particular properties of the visual system such as color and motion detection. Likelihood That Progress Win Be Made In the continuing effort to bring greater and greater specificity to structure-function correlates, studying the partially disconnected human brain has been iDum~nating. Now, using MRI in cases of inadvertent sparing, during brain surgery, of the major fiber pathway in the brain (the corpus caDosum), it has been possible to make an exact identification of what the small and discrete fiber systems transmit that is of psychological interest (Gazzaniga et al., 1985~. Using this approach, the high degree of specificity of this fiber system for perceptual and cognitive functions Is now being demonstrated. The use of MRI for categorizing cortical brain lesions is just beginning (as noted in the previous section). The localization of function in the human brain has been one of the great classical themes in neurology since at least the time of Paul Broca (1861~. Since then, many authors have attempted to correlate various sensory, motor, language, and other higher associ- ational functions to various cortical structures. These results have helped to delineate the functional territories of the human cerebral cortex (Jackson, 1864; Gudden, 1870; Fritsch and Hitzig, IS70; Wer- nicke, 1864; Dusser de Barrenne, 1916; Gushing, 1932; Gazzaniga and Sperry, 1967~. Today, many workers in this field seem uncomfortable vnth the functional maps of the human cortex as they now stand: these maps appear insufficiently differentiated, whereas more accurate maps would reveal highly specialized functional processes correlated to highly circumscribed zones in the cortical mantle. Over the last century, there have been three major obstacles to the development of more highly differentiated functional maps of the human cortex. First, the field of experimental cognitive psychology has had to grow in sophistication; it has and no longer poses an obstacle. But cognitive dysfunction still had to be correlated with some localized cortical damage. This was difficult to do in the days before CT and MRI; then it was necessary either to do a craniotomy or to wait for the final pathology report in order to localize a cortical lesion independently of signs and symptoms. The development of CT and MRI, which precisely and immediately identify the anatomical locations and extents of intracerebral lesions, has removed this major

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RESEARCH FINDINGS 41 obstacle. MRT, for example, has already allowed for the identification of discrete callosal fiber systems with their functional role specified (Gazzaniga et al., 1985; Gazzaniga, l98Ba, 198Bb). There remains, however, the problem of obtaining accurate maps of the human cortex, especially when one considers the incredible variation that exists in the patterning of the gyri and suIci, a pattern apparently as diverse as are fingerprints in the population. It remains unclear to what extent a lesion in a given gyrus in one individual Is functionally comparable to a similarly placed le- sion In the same gyrus in another individual. The degree to which the functional fields are similarly distributed across individuals, the randomness with which secondary and tertiary suIcal folds position themselves during the growth of the cortex in late prenatal develop- ment, and the randomness with which various subzones of the func- tional fields are either entrapped within the suIcal walls or exposed on the gyral crests still remain to be determined. These questions might be approachable given techniques allowing us to look beyond the suici to examine the full expanse of the cortical mantle. Opportunities for Basic and Applied Research The next generation of cortical maps should allow identification of landmarks both on the surface of the gyri and within the depths of the suici, permitting measurement of the dimensions of cortical areas and lesions and clarifying the relations of damaged zones to surrounding cortical regions. Two kinds of cortical flat map tech- niques, straight line (SL) maps and contour (Ct) maps have emerged in the literature in the last several years. Until recently, these tech- niques have been applied only to studies of restricted cortical regions in nonhuman primates and cats. Each technique has as its goal the unfolding of the rounded, three-dimensional cerebral cortex into a map having the geometry of a table top, and each has its respective advantages and disadvantages. The major goal of some new studies has been to demonstrate that stra~ght-line two-~mensional (SL2D) flat maps can be constructed to represent extensive areas of the human cortex (Jouandet et al., 1987, in press). These studies chose not merely to open a restricted area of cortex, but undertook the most challenging test possible: the full unfolding of the entire human cerebral cortex. While MR] renders the human cortex immediately accessible, it remains very difficult

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42 BRAIN AND COGNITION: SOME NEW TECHNOLOGIES to appreciate the Mansion and relation of a cortical lesion vi~a- vis other cortical landmarks, when portions of the lesion and the landmarks are distributed over several individual brain slice images. SL2D maps take the next step in organizing the data. They open and unfold the cortex, simplify neocortical geometry, preserve the richness of its complexity, and fully represent the cortical territories in a manner providing the only adequate structural foundation on which functional information may, in the future, be interfaced In the construction of highly difl5erentiated correlative maps. The promise of this new technique is that once users familiarize themselves with it, they will be able to see beyond the suici and behold a landscape rich in previously obscured information and possibilities. Bringing greater specificity to brain areas involved in cognition is the task of many enterprises, including the imaging techniques reviewed in the previous section. It is at this junction that the sep- arate technologies begin to converge on common problems. Within the context of traditional neuropsychology, MRI combined with flat mapping of the cortical mantle wild begin to provide the kind of greater specificity called for by modern cognitive theories. The discussion in this section is not intended to convey the im- pression that all that is needed to understand human brain function are more detailed road maps of the human brain, particularly of the neocortex. The mapping techniques are discussed only as an- other technological accomplishment with implications for research on human brain processes and functions. It may well be the case that even the most up-to-date mapping wiD not provide a complete understanding of the dynamic patterns of activity in cortical neural processing. These ongoing patterns are the neurochemical bases for the observed plasticity of human behavior as manifested in devel- opment and change thoughout the life-span. Of particular interest is the transmission of nerve impulses and those processes associated with the ability of neurons to produce and release neurotransr~iit- ters (Iverson, 1979~. Further research may address such questions as "Which neurotransm~tters moderate or enhance which cognitive functions?" (See I,erner, 1984, for a theoretical discussion of these issues.)