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Perspectives On Medical Research A Critique of Neurology Experiments at Northwestern University Murry J. Cohen, Deborah N. Black, Roger S. Fouts, Frank W. Dobbs In an attempt to gain information relevant to the neurological basis of human speech, Dr. Charles R. Larson, associate professor of Speech and Language Pathology in the Department of Communication Sciences and Disorders at Northwestern University, has, since 1978, served as principal investigator in invasive experiments that study "neural mechanisms of laryngeal control" in the pig-tailed macaque monkey (Macaca nemestrina). From April 1983 through March 1986, Larson's research was funded by a National Institutes of Health grant (cost unknown).(1) Larson requested a five year grant to continue this line of research, but it was funded for only three years, from April 1986 through March 1989, at a direct cost of $259,334 (indirect costs unknown).(1) This critique will focus on Larson's 1986-1991 grant request. Summary of Larson's 1986-1991 Grant Proposal Stated Aims To study vocalization, Larson proposed investigating how, in monkeys, neuronal activity within the midbrain periaqueductal gray (PAG) and brainstem relates to laryngeal and respiratory muscles (intercostal and abdominal muscles, and the diaphragm).(1) In one group of monkeys, Larson would record PAG activity while monkeys vocalized, to determine whether stimulation of neurons within the nucleus ambiguus (NA, the site of laryngeal motoneurons) results in PAG activity. In a second group, he would stimulate NA neurons and record activity within the respiratory muscles, in a third group, he would trace nerve fibers to and from the PAG via neurochemical markers.(1) Larson justified his project on these grounds: "It is important to study the neural control of vocalization in order to understand the human speech production process itself and to learn how neurologic disorders such as Huntington's Disease, Parkinsonism, and spastic dysphonia affect vocalization. . . The present study will analyze the activity of different PAG neurons with respect to their projections to the nucleus ambiguus and muscles of the respiratory and laryngeal systems." Experimental Method and Procedure For the period 1986-1991, Larson proposed using eight juvenile male pigtailed macaque monkeys each year.(1) Six would be trained to vocalize for recording experiments; the two others would be used in neuroanatomical tracing studies. Those monkeys trained to vocalize would be food-deprived five days of each week and maintained at 90% of their normal weight. All monkeys would be caged alone. During the experimental procedure itself, the monkeys would be placed, one at a time, in a primate restraining chair located in a sound-proof room. Apple juice would reinforce vocalization. A tube to deliver the juice reward, a microphone, and two lights that would serve as cues to vocalize would be located in front of each monkey. During a 2-3 month training period, the monkeys would be taught to enter the restraining chair where, for 1-2 hours each day, they would be conditioned to vocalize. If a monkey emitted a sufficiently loud and long vocalization, he would receive juice (via computer-regulated delivery). Following training, each monkey would undergo three surgical procedures, with a two-week recovery period between each procedure and the next. In the first surgical procedure, a patch of skin two centimeters in diameter would be removed from the back of the monkey's head; a plastic plug would then be fastened to the exposed skull, with screws and dental cement. If a monkey were being used to study the laryngeal muscles, an incision would be made down the center of his throat, sufficient tissue would be cut away to expose his larynx, and electrodes would be inserted into his laryngeal muscles. If, instead, a monkey were being used to study the respiratory muscles, his pectoralis major (a large chest muscle) would be severed from his sternum and, through a needle, electrodes would be inserted into his intercostal muscles (between the ribs) and diaphragm. Electrodes would similarly be placed into abdominal muscles through an abdominal incision. In the second surgical procedure, each monkey would have his upper four neck vertebrae fused to his skull with screws and dental cement, to prevent head movement from interfering with the recording of muscle activity. Larson refers to this procedure as "standard."(1) In the third surgical procedure, each monkey would have his "scalp removed and the underlying skull area scraped bare."(1) Screw holes would then be drilled in his skull, to which the chamber holding recording and stimulating electrodes would be fastened with screws and dental cement. Nuts would be fixed to the skull. During recording sessions, these nuts would be screwed into metal braces of the restraining chair, to hold the monkey's head rigid. One week after the last surgical procedure, the experimental period
would begin, anticipated to last 1-2 months for each monkey. Bound in
the restraining chair, his head completely immobilized, a monkey would
be required to vocalize for juice. Meanwhile, electrodes would record
neuronal and muscular activity. After PAG neurons had been exhaustively
explored for a given monkey, he would be anesthetized, then killed by
electrical current passed through his brain. The body would then be perfused
with formalin and the brain removed. Fundamental differences between monkey vocalization and human speech, as well as numerous confounding variables, render Larson's work inherently unsound and inapplicable to humans. Differences between Monkey Vocalization and Human Speech In many respects, monkey vocalization and human speech are not homologous. Whereas human vocalizations are generally produced voluntarily and controlled with great ease, monkey vocalizations seem largely dependent on the arousal of strong feeling in the monkey. Experiments on rhesus monkeys (Macaca mulata) have indicated that their vocalizations usually signal intense feelings--such as alarm, hunger, or loneliness--relating to some basic need.(2) In contrast, humans routinely speak without, simultaneously, experiencing strong emotion. Larson himself acknowledges, "It has been suggested that human speech, being propositional in nature, is fundamentally different from most types of animal vocalizations."(3) Researchers' difficulty in conditioning monkey species to vocalize on cue provides support for the view that monkey vocalization ordinarily has an affective basis. Although, in a study coauthored by Larson, researchers claimed that rhesus monkeys had learned to vocalize on cue,(4) Shun-Ichi Yamaguchi and Ronald Myers failed to elicit such conditioned vocalization. They concluded that rhesus monkeys may lack voluntary control of their vocalizations.(5) In the wild, rhesus monkeys produce at least 20 different calls, yet researchers have claimed success in conditioning rhesus monkeys to vocalize very few such sounds. Larson's own work suggests that, in monkeys, the PAG links limbic-system areas and motor nuclei controlling laryngeal and respiratory muscles;(6) since the limbic system mediates emotion, this suggested link provides further evidence that monkey vocalization may be highly emotion-dependent. The PAG's role in vocalization, therefore, may be much more important in monkeys than in humans, in whom PAG function remains poorly defined. Larson admits, "If. . . it is only important for coordination of affective vocalizations, then the PAG may not be that crucial for normal [human] speech."(3)(sic) Larson has also acknowledged that monkey vocalization and human speech
may be "controlled by different neural mechanisms."(3) Anthropologist
Gordon Hewes has noted that "primate cries and calls are handled
by parts of the cortex, bilaterally, some distance away from the lateralized
[human] speech areas,"(sic) which are "localized in an entirely
different portion of the cortex."(7) Further, as Larson himself
has noted, the human cortex extends neural projections to the nucleus
ambiguus, whereas the monkey cortex does not.(3) Metabolic, immunological, and other physiological changes induced by the stress of experimental procedures alter experimental measurements and confound results.(8) In monkeys, psychological stress has been shown to alter plasma cortisol levels, associated with neurotransmitter levels.(9) In Larson's experiments, the stress inflicted on the monkeys is intense. These profoundly social animals are isolated, subjected to multiple highly invasive surgical procedures, deprived of food, and forced to endure severe and prolonged immobilization. Surely, the monkeys experience substantial pain and fear. The mere handling of monkeys can result in measurable physiological changes.(10) Pulse rates of rhesus monkeys change when humans enter the room.(11) Many monkeys find isolation so stressful that they develop self-mutilating behavior.(12) Immobilization stress, too, causes profound biological changes; in monkeys, immobilization "has repeatedly been shown to have major endocrinological and physiological repercussions," including effects on the autoimmune system.(13) In non-human animals, the PAG is known to interact with brain structures that are profoundedly influenced by stress levels, including pain sensitivity and blood pressure.(14) Therefore, it is likely that laboratory stress will confound the research results. Lack of Clinical Relevance Larson claims that his research will help us gain insight into the process whereby human neurological disorders such as Huntington's disease (HD), Parkinson's disease (PD), and spastic dysphonia (SD) affect vocalization. A number of neurologists, neurobiologists, and neuropsychologists who have reviewed Larson's work have disputed this claim, which seems untenable.(15) HD, PD, and SD--chronic, degenerative illnesses—have anatomical, chemical, and physiological characteristics that have never been faithfully reproduced in animals.(16) Larson's research appears to have little relevance to these neurologic diseases. For example, both HD and PD result from loss of neurons, with consequent biochemical deficiency, in brain areas different from those that Larson is studying.(16) Alternatives to Animal Experimentation Major advances in understanding HD, PD, and SD have derived from clinical research and from human gene-mapping (tracing correlations between the existence of abnormal genes and the occurrence of disease).(16,17) Such research has led to improved prevention through genetic counseling. Increasingly, clinical research on neurological diseases involves sophisticated
computer technologies. For example, Positron Emission Tomography (PET)
scans show which portions of the brain come into play during a particular
activity (such as vocalization); these scans now yield three-dimensional
images offering a resolution of about four millimeters in the brainstem.
PET scanning and other computerized imaging techniques provide a non-invasive
means of obtaining highly precise information regarding the functional
relationships between the cortex and brainstem in human vocalization.
The Institute of Medicine's Committee on a National Neural Circuitry
Database recommends the use of such computerized techniques,(18) which
have obvious and important advantages over animal experimentation: these
techniques cause no suffering, are both valid and precise, and are directly
relevant to human health. The results of experiments that investigate monkey vocalizations are unlikely to apply to human speech. Whereas monkey vocalization appears highly dependent on the arousal of strong feeling, humans routinely speak without strong emotion. Monkey vocalization and human speech also differ significantly in their underlying neural circuitry. The monkeys used in Larson's experiments are subjected to such extreme stress that any obtained data are further invalidated by such confounding variables as undetermined changes in metabolism, immunology, and other physiological parameters. Along with interspecies differences, such variables preclude the possibility of clarifying the PAG's role in human speech. It is highly improbable that Larson's type of animal experimentation can provide insight into how RD, PD, SD, and other human neurological disorders affect speech. The greatest advances in understanding, treating, and preventing these diseases have derived from clinical research and clinical intervention, including advanced imaging technologies, population studies, human gene-mapping, and genetic counseling. References 1. Neural Mechanisms of Laryngeal Control. Federal grant application PHS 2 ROl NS19290-04, April 1, 1986-March 31, 1991, Charles R. Larson, principal investigator. 2. Myers RE, Comparative neurology of vocalization and speech: Proof of a dichotomy, in Harnad SR, Steklis HD, Lancaster J (eds). Origins and Evolution of Language and Speech. New York Academy of Sciences 1976;280:745-757. 3. Larson CR. The midbrain periaqueductal gray: A brainstem structure involved in vocalization. J Speech Hearing Res 1985;28:241-249. 4. Sutton D, Larson C, Taylor EM, Lindeman RC. Vocalization in rhesus monkeys: Conditionabiity. Brain Res 1973;52:225-231. 5. Yamaguchi S-I, Myers RE. Failure of discriminative vocal conditioning in Rhesus monkey. Brain Res 1972;37:109-114. 6. Larson CR, Kistler MK. The relationship of periaqueductal gray neurons to vocalization and laryngeal EMG in the behaving monkey. Exp Br Res 1986;63:596-606. 7. Hewes G. The current status of the gestural theory of language origin, in Harnad SR, Steklis HD, Lancaster J (eds), Origins and Evolution of Language and Speech. New York Academy of Sciences 1976;280:482-504. 8. Barnard N, Hou S. Inherent stress—the tough life in lab routine. Lab Animal 1988;17:21-27. 9. Hill CW, Greer WE, Felsenfeld O. Psychological stress, early response to foreign protein, and blood cortisol in vervets. Psychosom Med 1967;29:279-283. 10. Fox MW. Laboratory Animal Husbandry Ethology Welfare and Experimenial Variables. Albany, SUNY Pr, 1986. 11. Malinow MR, Hill JD, Ochsner AJ. Heart rate in caged rhesus monkeys (Macaca mulata). Lab An Sci 1974;24:537-540. 12. Crawley JN, Sutton ME, Pickar D, Animal models of self-destructive behavior and suicide. Psychol Clin NA 1985;8:299-310. 13. Katsiia GV, Todua TN, Gorlushkin VM, et al. Effect of immobilization stress on gonadotropic function of the hypophysis in male hamadryas baboons (Papio hamadrysas). Biull Eskp Biol Med 1989; 107:231-234. 14. Bandler R, Carrive P, Zhang SP. Integration of somatic and autonomic reactions within the midbrain pariaquaductal grey: Visceral, somatotopic, and functional organization. Prog Br Res 1991;87:269-305. 15. Charles R, Larson, Northwestern University, Grant #2 ROl N519290-04, Section 2: Independent Evaluations of the Grant. Concerned Citizens for Ethical Research, Evanston, 1991. 16. Kaufman SR, Czarnecki T, Haralabatos I, Richardson M. Animal models of degenerative neurological diseases. Perspec Med Res 1991;3:9-48. 17. Henreen IC, Zweig RM, DeLong MR, Whitehouse PJ, Price DL. Primary dystonias: A review of the pathology and suggestions for new directions of study. Adv Neural 1988;50: 123-132. 18. Pechura CM, Martin JB (eds). Mapping The Brain And its Functions. National Academy Press, Washington, D.C., 1991. |
