A Hole in the Head Page 9

  They got their opportunity in 1881 at the International Medical Congress in London. This was the site of a dramatic and widely reported debate between Ferrier and Friedrich Goltz (1834–1902), the leading opponent of localization of function in the cerebral cortex. To defend his arguments, Ferrier displayed a monkey with partial paralysis after a motor cortex lesion (the French neurologist J.-M. Charcot was amazed and, in French, exclaimed “it’s a patient”) and one with a superior temporal gyrus lesion (which was shown to be deaf when it did not flinch when a pistol was discharged near its head). By contrast, Goltz demonstrated that his dogs had their motor and sensory functions relatively intact even after supposedly massive cortical lesions. Ferrier claimed this was because Goltz’s lesions were incomplete. To resolve the issue, the dogs and monkeys were immediately sacrificed and their brains turned over to a panel of experts. The panel found that Goltz’s dogs had much smaller lesions than he had claimed (sparing what we now know to be primary sensory and motor cortex). Ferrier was vindicated (Anonymous, 1881b; Klein et al., 1883).

  The Victoria Street Society had been closely following what scientists were writing and saying and matching it against the published list of those licensed under the act to carry out experiments. They immediately saw that Ferrier did not have a license for the surgery on the monkeys he described at the Congress and had him prosecuted under the act. The defense successfully argued that Ferrier was not liable because his collaborator G. F. Yeo, not Ferrier himself, had actually carried out the surgery and Yeo did have a proper license. The outcome of the trial was viewed as a major defeat by the antivivisectionists. However, the medical and scientific communities were frightened by the fact of the trial and began to organize to protect themselves (Anonymous, 1881b; French, 1975).

  At least up to 1975 there had been only two other prosecutions under the act.

  Ferrier explored the effects of stimulation of much more of the cortical mantle than Fritsch and Hitzig had, and indeed much more than is considered motor cortex today (see figure 4.9). Like Fritsch and Hitzig, Ferrier found that he could evoke movements of different body parts from different regions of cortex. He localized centers related to the movements of the eyelids, face, mouth, tongue, ear, neck, hand, foot, and tail. Furthermore, Ferrier realized how similar the organization of these “centers” were to the map hypothesized by Hughlings Jackson on the basis of his study of human seizures.

  In comparing dogs, cats, and rabbits, Ferrier noticed that the overall organization was the same in different species, but that some parts of the body were more represented in some species. He suggested that these differences depended “on the habits of the animals.” This is the first suggestion of a relationship between the organization of the brain and behavioral specializations in a species.

  In 1874, Ferrier moved to Kings College Hospital in London and expanded his work to monkeys. By doing so he hoped to understand the organization of the motor centers in the human brain. In fact, his localizations in monkeys were soon transferred to the human brain and used to localize and remove tumors and blood clots from the brains of patients, with surprising success and accuracy.59 In the monkey brain he again found that movements of various body parts were localized in different regions of cortex. In monkeys, Ferrier delineated 19 centers related to different movements such as walking, arm retraction, flexion and extension of the wrist, mouth opening and “protrusion of the tongue,” “sneering expressions of the face,” and eye movements.60 Figure 4.9 from his unpublished lab notebook shows examples of these.

  Figure 4.7

  David Ferrier.

  Figure 4.8

  Du Bois–Reymond inductorium used for faradic stimulation. Although there were many different versions of the inductorium, it seems likely that Ferrier used this version, popular in the 1870s, in his stimulation experiments. The primary coil is used to induce a current in the secondary coil. The current was reversed using an electromagnet (b), which opened and closed the circuit using a key (f ). The strength of the stimulus was varied by varying the distance between the primary and secondary coils. From Klein et al., 1873.

  As had Fritsch and Hitzig, Ferrier found that movements that appeared to be represented at a site would be impaired when he destroyed that site. Furthermore, the larger the lesion, the larger the affected part of the body: lesions of the entire motor area resulted in paralysis of one side of the body; lesions of “centres” that, when stimulated, caused movements of the hand and foot “caused motor paralysis of the same movements and of none other”;61 finally, small lesions of only the “centre for the biceps” caused “the right arm to hang by the right side in a state of flaccid extension . . . [the monkey] had lost the power of flexing the right arm.”62 As described in box 4.2, Ferrier initially had some difficulty in getting his results published in the Philosophical Transactions of the Royal Society because the referees thought he had not given adequate credit to the prior work of Fritsch and Hitzig.

  Figure 4.9

  Pages from Ferrier’s laboratory notebook recording the sites at which he applied stimulation (top) and the results of that stimulation (bottom). In the experiment recorded here Ferrier evoked complex movements of various parts of the body using cortical stimulation. The notebook reads:

  24. extension of foreleg and turning of tail to left adduction of right upper arm with extension of forearm slight right thigh flexed on pelvis and limb adducted and both eyes opened

  25. head to right and upper half of body also thighs approximated

  26. Same as 25.

  27 and 28. eyeballs moved to right and on longer stimulation hand also to right and eyelids opened

  At this point the monkey took some slight refreshment (biscuit) with great gusto bit and chewed

  From the collection of Ferrier’s notebooks from 1873 to 1883 in the archives of the Royal College of Physicians, London (MS 246).

  Differences between the FritschHitzig and the Ferrier Studies

  The basic findings of Fritsch and Hitzig and of Ferrier were very similar. They both found that electrically stimulating the frontal cortex produced discrete contralateral movements. They both found that movements of different body parts could be evoked from different regions of cortex. They both found that when a part of the motor cortex was damaged, the animal appeared to be unable to execute the movement that is evoked by stimulation. However, there were some important differences in their results, their methods, and their interpretations that have influenced the subsequent direction of research on motor cortex.

  The chief difference in their results was the type of movements that each evoked, indeed that each aimed to evoke. Fritsch and Hitzig described the movements they evoke in terms of spasms or twitches (Zuckungen)of a small number of adjacent muscles. By contrast Ferrier described the movements that he observed in terms of the natural movements they resembled, as in the following examples from different species. In the cat, Ferrier notes that stimulation of a particular site causes “the shoulder to be raised, and the limb to be adducted, exactly as when a cat strikes a ball with its paw.” In the dog, stimulation of the supraorbital region caused the following sequence of movements: “The animal opens its mouth, retracts the upper lips, and makes a sort of sniffing or snarling noise.” In the rabbit, during stimulation of the frontal region, “The mouth is drawn to the left, and a munching movement of the left side of the mouth is made, as if the animal is eating.”63 And likewise, in the monkey, stimulating of one site causes “flexion with outward rotation of the thigh, rotation inwards of the leg, with flexion of the toes—the action being such as is seen when the monkey makes a grasping movement, or scratches its chest or abdomen with its foot.”64 At another site, Ferrier reported that stimulation caused the following movement: “Shoulder raised, forearm firmly flexed, hand clenched and supinated. The hand ultimately raised to the mouth, the angle of which is retracted and elevated.” Ferrier, on the basis of replications in 12 other monkeys, identified this site as “the centre for the biceps an
d muscles concerned in bringing the hand to the mouth.”65

  Box 4.2

  Ferrier Quarrels with Referees over Priority

  Ferrier’s first two papers on motor cortex involving dogs, cats, and other infraprimate species (1873, 1874a) were published in his institute’s house organ The West Riding Lunatic Asylum Medical Reports. Then in 1874 he submitted a paper on stimulation of motor cortex in dogs, monkeys, and other animals to The Philosophical Transactions of the Royal Society, then the most prestigious scientific journal in Britain if not the world. The paper began by acknowledging the influence of Hugh-lings Jackson and then mentioned that the findings confirm and extend the work of Fritsch and Hitzig. Initially, the paper was sent to two distinguished referees, Michael Foster (professor of physiology at Cambridge) and George Rolleston (professor of anatomy at Oxford). Both criticized the paper for, among other things, not giving adequate credit to Fritsch and Hitzig’s prior work: it “failed to do justice to them” in Foster’s words.

  The editor of the Transactions then called in a third referee, T. H. Huxley, perhaps the most politically powerful scientist at the time, “for the purpose of ascertaining . . . whether Dr. Ferrier has or has not done sufficient mention of the labour of his predecessors in the same field of investigation.” Huxley concluded he had not. The views of the referees were sent to Ferrier, and he slightly revised and resubmitted the paper. In that unpublished revision he wrote:

  To Fritsch and Hitzig belong the honour of the discovery of the method of exciting the functional activity of the brain, and of showing that in the anterior part of the brain there are localized regions, the stimulation of which causes certain constant muscular movements of the head and limbs. The exact extent to which they carried out their localization experiments will be found under the head of Experiments in dogs page 53. . . . Since this paper was written Hitzig has published a new series of experiments and a criticism of my paper in the West Riding Reports [“Untersuchungen über das Gehirn,” 1874]. Hitzig differs from me in several important points in regard to method and extent of localization, and his criticisms deserve to be noticed. I have preferred however to leave the present paper as it is, and to reserve a consideration of Hitzig’s researches as well as those of other experimenters in the localization of function in the brain for a future occasion.

  The revised paper was still unacceptable because it still gave inadequate credit to Fritsch and Hitzig, since, for example, its “acknowledgement of Hitzig’s claim to priority was so slight” that its publication would be “unfortunate to English Science.”

  Later that year Ferrier presented the material in this paper at a meeting of the Royal Society and a three-page abstract (unrefereed) was published in its Proceedings (Ferrier, 1874b). The abstract described the work as a confirmation of Hughlings Jackson’s views and did not mention Fritsch and Hitzig. Ferrier then wrote up the monkey stimulation data in detail and it was accepted by the Philosophical Proceedings of the Royal Society (1874c). Although the paper did not even mention Fritsch and Hitzig, the priority issue must have seemed less critical since Fritsch and Hitzig had only worked on dogs and this paper was exclusively on monkeys. Much of the other material in the previously rejected paper was eventually published in his 1876 book. Ferrier did give Fritsch and Hitzig more credit there, and by 1890 he wrote, “The whole aspect of cerebral physiology and pathology was revolutionized by the discovery, first made by Fritsch and Hitzig, that certain definite movements could be excited by the direct application of electrical stimulation to definite regions of the cortex cerebri in dogs” (Ferrier, 1890). (Ferrier’s rejected paper, from which the other quotations in this box were taken, is in the archives of the Royal Society [AP.56.2]. The correspondence with Foster, Rolleston, and Huxley about Ferrier’s rejected paper is in the archives of the Royal Society [RR.7.299-305; MC10.194. 247])

  In light of recent work on motor cortex there appear to be two main reasons for the differences between the results of Fritsch and Hitzig and of Ferrier, namely, the nature of the electrical stimulus and its duration.66

  Fritsch and Hitzig used primarily galvanic stimulation whereas Ferrier used primarily faradic stimulation, and both argued for the superiority of their choice. Ferrier argued that faradic stimulation was critical for evoking complete movements from a motor center and therefore to “properly characterize” that center. Galvanic stimulation, he noted, results in “only a sudden contraction in certain groups of muscles, but fails to call forth the definite purposive combination of muscular contractions, which is the very essence of the reaction and the key to its interpretation.”67

  The second major difference between Fritsch and Hitzig and Ferrier was the duration and strength of stimulation. It was critical in determining whether the evoked movements were twitches or resembled purposive movements. Although Fritsch and Hitzig do not explicitly state the duration of stimulation used in their experiments, it is likely that they used stimulation durations that were very short—possibly less than a second—causing twitches or spasms that they describe as “fast-passing.”68 They were aware of the noxious effect that longer durations of galvanic stimulation could have on the cortex, and consequently advocated the use of short durations and weak currents. Furthermore, Hitzig noted:

  By the use of very weak currents these muscle contractions can be localized to specific narrowly limited muscle groups, with stronger currents, stimulation . . . led to the immediate participation of other muscles or even muscles of the corresponding body half.69

  In contrast, Ferrier stressed the importance of longer durations of stimulation, in keeping with his emphasis on producing a complete movement, and consequently producing the participation of other muscles. In his experiments with different durations of stimulation he found:

  A slight stimulus of short duration causes only a part of a complex action, which is manifested in its completeness when the stimulus is of somewhat greater intensity and duration.70

  In addition to differences in the nature of the movements that Fritsch and Hitzig and Ferrier evoked, Ferrier tested a much greater extent of the cortex. Ferrier located motor centers in several cortical regions, including eye movement areas now known as the frontal eye fields (area 8) and the lateral intraparietal area (LIP). Indeed he thought that posterior parietal cortex was the “visual center” because he elicited eye movements from stimulation there.71 In later work Hitzig did investigate wider regions of cortex and described an “inexcitable zone” that overlaps with regions that Ferrier claimed to be excitable. Hitzig considered this to be due to Ferrier’s general incompetence, such as using too strong a current and failing to replicate his observations sufficiently.72 Ferrier thought Hitzig to have failed to produce movements from these regions because the currents he used were too weak.73

  In summary, Fritsch and Hitzig obtained “twitches” of a few muscles from brief monopolar DC stimulation, whereas Ferrier obtained complex movements from long-duration AC stimulation.

  COMMENT

  Both Fritsch and Hitzig’s and Ferrier’s papers on motor cortex were greeted by much skepticism. Their results went against the generally accepted views that the striatum was the highest motor center, that the cortex was inexcitable, and that functional localization in the cortex was phrenological pseudoscience. The critics usually interpreted the evidence for the localization of motor function in cortex as artifactual, due to a “spread of current” to the striatum. To overcome these criticisms, Victor Horsley (1857–1916), C. S. Sherrington (1857–1952), and others began meticulous “punctate” mapping of cortex using the minimum current to elicit the smallest discernible movement.74 Thus, Ferrier’s search for the full movement became overshadowed by the effort to localize function more and more precisely.

  In the century after the first electrical stimulation experiments on motor cortex, it became possible to evoke smaller and smaller movements, and therefore to localize motor functions in an even more “punctate” fashion. By the 1980s, it was possible to record
small changes in the electromyographic (EMG) activity of muscles in response to single pulses of stimulation.75 Leyton and Sherrington’s map of motor cortex in the chimpanzee, followed by Penfield’s human motor homunculus and Woolsey’s maps of monkeys and other animals, became the standard picture of motor cortex.76 One consequence of this effort to localize the effects of stimulation with increasing precision was that the emphasis of stimulation studies shifted to the representation of muscles, rather than of movements.77 It was not clear, however, how these maps were related to movement. Did motor cortex control relatively low-level aspects of movement such as the muscle tensions required for the flexion and extension of individual joints? Or did it control more complex aspects of movement such as the coordinated muscle activity required for reaching?

  The two contrasting views that first emerged with Fritsch and Hitzig’s stress on brief muscle twitches and Ferrier’s stress on integrated movements became central issues in the study of motor cortex. Some researchers emphasize the cortical control of small groups of muscles and individual joints;78 others emphasize the cortical control of reaching in specific directions.79 Recently, Graziano and colleagues have revisited Ferrier’s idea that motor cortex may control complex, highly integrated behavior.80

  POSTSCRIPT

  Graziano and colleagues electrically stimulated motor cortex with long durations, like Ferrier, and produced complex, coordinated, apparently natural movements, again reminiscent of those reported by Ferrier.81 On the basis of these results they suggested that motor cortex is organized into regions that “emphasize different ethologically relevant categories of actions.” They suggest that the organization of motor cortex may be understood as the result of the superimposition on a somatotopic map of other “maps” such as of ethologically relevant movements and of hand position in space.82