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Stimulation-elicited pain
Commentary
Stimulation-elic-ited Pain What Is the Appropriate Memory Model? Michael Gabriel
enz and coauthors marshall a wide array of data in support of an intriguing hypothesis, stating that activation of partioular brain pathways gives rise to the reexperience of pain and emotion (affect) previously engendered by various pathologies (heart disease, panic attacks, etc.). The pain experienced is said to be a product of a memory process, not a direct product of the activation itself, as when a pain is elicited directly by thermal or mechanical stimulation. Likewise, the affective response is said to be associatively coupled to the memory process, not a direct response to the pain. The brain region implicated in the re-experience of pathogenic pain is the region posterior and inferior to the human principal sensory nucleus, the nucleus ventralis caudal is (Vc). Henceforth this area will be referred to as the posteroinferior (PI) region. The principal empirical bases for the hypothesis are findings in studies of effects of presurgical electrical brain stimulation. Electrical stimulation of the PI region in patients with a history of pathological pain evokes pain and associated affective responses. The pain is described by the patients as being the same as the pain experienced during the prior episodes of pathogenic pain (e.g., angina, chest pain associated with panic attack, pain experienced during sexual intercourse). Pain is also elicited by stimulation in patients without a prior history of pathological pain. However, the affective response that accompanies the stimulation occurs only in those patients who have a prior history of pathogenic pain and who identify the stimulation-elicited pain as being the same as their previous pathogenic pain. The authors suggest that the stimulation-elicited pain experience and the associated affective response
L
From the Department of Psychology, Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana, IL. Reprint requests: Michael Gabriel, Department of Psychology, Beckman Institute for Advanced Science and Technology, University of Illinois, 405 North Mathews Avenue, Urbana, IL 61801.
38
depend on neurotransmission from the PI region to secondary somatosensory (SII) and/or insular cortical areas. This brings the hypothesis into register with a theoretical schema of Mishkin, which states that memory depends on "sensory-limbic" flow of information (i.e., the projection of information from various sensory cortical areas to medial temporal lobe structures) [8]. The authors' proposal adds insular and SII cortex to the visual, tactile, and other origins of memory-relevant information flow to the medial temporal lobe. Thus, the hypothesis integrates the clinical data with a wide array of physiologic and anatomical data, and with Mishkin's important theoretical account of brain organization. It helps to make sense of the rather unexpected differentiation of results that occurs when electrical brain stimulation is given to patients with and without a prior history of pain. This commentary suggests some lines of thought that may contribute to the elaboration of the authors' important hypothesis. The area in which there appears to be room for elaboration concerns the nature of the memory processes that mediate the described phenomena. Along these lines, it is necessary that the authors specify precisely which aspects of the patients' behavior and experience are affected by memory. In discussing the results of human thalamic studies, they state that thalamic "stimulation evokes pain with a strong affective dimension in patients who have previously experienced such pain. Similar pains without a strong affective dimension were evoked in patients without previous experience of pain with a strong affective dimension." These statements indicate that the pain response to the thalamic stimulation occurs in all subjects, whether or not they have a history of previous pain experience. It is only the affective response elicited by the thalamic stimulation that is added, as a result of a memory process conditioned by the previous history of pain experience. Yet in the next paragraph, Lenz and co-workers state that the "model predicts that somatic, visceral, or
Pain Forum 6(1): 38-40, 1997
COMMENTARY/Gabriel
emotional inputs projecting to the medial temporal lobe might provoke the previous experience of pain, including the affective dimension." In this statement, the authors appear to assert that both the pain experienced and the affective response are products of a memory process conditioned by the previous history of pain. The remainder of this commentary assumes that the latter interpretation is the one intended by the authors: i.e., that both the pain experienced and the affective response are products of a memory process conditioned by the previous history of pain. That this latter interpretation is the interpretation intended by the authors seems to be implicit throughout the article. Beyond clear specification of the phenomena affected by memory, it is also necessary that the nature of the involved memory process be carefully specified. The assumed interpretation intended by the authors (given above) is reinforced by their characterization of pain elicited by the thalamic stimulation as "memory for pain." However, one can have a memory for pain without actually experiencing pain. Perhaps the phrase "memory-based reexperience of pain" would convey the authors' concept more precisely. Furthermore, the conceptualization of memory represented by the account of Mishkin is hard to apply directly to the findings of the elicited pain studies. Mishkin's 1979 model [8] represents an account of discrimination learning in primates , wherein selective behavioral responses are cued by particular rewardpredictive stimuli. In the case of the phenomena described by Lenz and co-workers, the learned response is experience of pain, and associated affect, acquired as a result of prior experience of pain. The circuitry of Mishkin codes particular stimulus cues as reward-predictive, and the learned response is goaldirected approach behavior guided by the predictive cues. It is difficult to find clear points of comparison between the cue-coding process and the learned behavior discussed by Mishkin on the one hand, and the elicited pain phenomena described by Lenz and coworkers on the other. A Pavlovian model of memory is perhaps more applicable to the target phenomena discussed by the authors. In Pavlovian conditioning, a conditional stimulus (CS) acquires capacity to elicit a conditioned response (CR) as a result of associative pairing of the CS with an unconditioned stimulus (US). It is possible to imagine that in individuals with no history of pathogenic pain, the initial experiences of pathogenic pain such as angina, and the accompanying thalamic neuronal activations, could function as Pavlovian CS presentations. Initially, no US follows these CS occurrences. However, after the patient learns that the pain is a product of a life-threatening or otherwise frightening medical condi-
39
tion, occurrences of the pain are followed immediately by a US, the perception and interpretation of the occurrence of a potentially dangerous event (e.g., "I'm having an angina attack"), and a resultant fear/panic unconditional response (UR). Given repeated "pairings" of these putative conditioned and unconditioned stimuli, the results found in the studies cited by the authors would be expected (i.e., the thalamic electrical CS would elicit the affective CR discussed by the authors , a fear/panic CR). Note that by this account the perception and interpretation of the sensory consequences of thalamic activation are not viewed as products of conditioning but rather as manifestations of knowledge gained by the patient as a result of medical consultation. Yet by giving rise to fear and panic, these events could serve as a functional US, and could mediate the observations that led the authors to conclude that the thalamic stimulus elicited the customary affective response in patients having a prior history of pain. But what of the other CR of which the authors speak: the re-experience of previously experienced pain? The Pavlovian view suggested here leaves open the difficult issue of whether the patients' actual experience of the elicited pain is identical to or similar to the previously experienced pathologic (e.g., anginal) pain. It may be that associative processes are at work in this situation that result in identity of the elicited pain with the previously experienced pain. On the other hand, it is possible that the interpretive response to the electrically elicited pain leads the patients to generalize, concluding that two quite distinct pains, electrically elicited and pathological, are identical. An advantage of this position is that it avoids the assertion that the patients in the studies cited by the authors exhibited a conditioned pain experience. This assertion is difficult to accept on a priori grounds, as CRs that take the form of direct experience of pain do not appear to occur. indeed, fear conditioning procedures applied to animal and human subjects, wherein a neutral CS such as a tone or light is paired with an aversive US such as shock, yield conditioned autonomic and somatic CRs, and it is generally believed that aversive CSs elicit the emotional CR of anxiety. However, there is no evidence that the direct experience of pain is acquired as a CR by humans subjected to aversive conditioning procedures [11]. As mentioned earlier, the conceptualization of memory implicit in Mishkin's 1979 article does not conform well to the memory phenomena described by Lenz and co-workers. It is therefore not clear that the complex corticolimbic trajectory of Mishkin's model affords a parsimonious account of the neural substrates of the phenomena under consideration. What is needed is an
40
COMMENTARY/Gabriel
explanation of how an electrical CS elicits an affective fear/panic CR. There is substantial evidence in support of the hypothesis that neurons in the amygdala are critically involved in the elaboration of fear CRs [2,4-6,9,10]. The simplest circuit needed for the thalamic triggering of a fear CR is neurotransmission from-the PI region to the amygdala. Insular cortical or posterior thalamic projections to the amygdala [1 ,3-5] provide possible paths for this effect. Citing a paper by Mehler [7], Lenz and co-workers suggest that direct projections to the amygdala from posterior thalamic areas involved in pain processing, such as the PI region, are lacking in primates. By inference, the authors consider the existence of this pathway doubtful in humans. However, axonal projections to the amygdala have been found to originate in the primate peripeduncular nucleus [1,3]. Amaral and LeDoux have each argued, independently, that the peripeduncular nucleus in primates is homologous to the posterior intralaminar nucleus in rats, a posterior thalamic auditory projection area that contains neurons that project to the amygdala [1 ,5]. Acknowledgments Supported by National Institutes of Health grant NS26736 and National Science Foundation grant BIR 9504842. Thanks are due to Dr. John Freeman for his helpful comments on the commentary.
References 1. Amaral DG, Price JL, Pitkanen A, Carmichael 5T: Anatomical organization of the primate amygdaloid complex. p. 1. In Aggleton JP (ed): The amygdala: neurobiological aspects of emotion, memory and mental dysfunction. Wiley-Liss, New York, 1992 2. Fanselow MS, Kim JJ: Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA
receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala. Behav Neurosci 108: 210-212, 1994 3. Jones EG, Burton H, Saper CB, Swanson LW: Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates. J Comp Neurol 167:385-420, 1976 4. Kapp BS, Wilson A, Pascoe Jp, Supple W, Whalen PJ: A neuroanatomical systems analysis of conditioned bradycardia in the rabbit. p. 53. In Gabriel M, Moore J (eds): Learning and computational neuroscience: foundations of adaptive networks. Bradford Division of the MIT Press, Cambridge, MA, 1990 5. LeDoux JE: Information flow from sensation to emotion: Plasticity in the neural computation of stimulus value. p. 3. In Gabriel M, Moore J (eds): Learning and computational neuroscience: foundations of adaptive networks. Bradford Division of the MIT Press, Cambridge, MA, 1990 6. Maren S, Poremba A, Gabriel M: Multiple-unit activity in the basolateral amygdaloid nucleus during discriminative avoidance learning in rabbits. Brain Res 549:311-316, 1991 7. Mehler WR: Subcortical afferent connections of the amygdala in the monkey. J Neurosci 190:733-762, 1980 8. Mishkin M: Analogous neural models for visual and tactile learning. Neuropsychologia 17:139-151,1979 9. McCabe PM, Gentile CG, Markgraf CG, Teich AH, Schneiderman N: Ibotenic acid lesions in the amygdaloid central nucleus but not in the lateral subthalamic area prevent the acquisition of differential Pavlovian conditioning of bradycardia in rabbits. Brain Res 580:155-163, 1992 10. Miserandino MJD, Sananes CB, Mella KR, Davis M: Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 345:716-718, 1990 11. Obrist PA, Sutterer JR, Howard JL: Preparatory cardiac changes: a psychobiological approach. p. 312. In Black AH, Prokasy WF (eds): Classical conditioning II: current theory and research. Appleton-Century-Crofts, New York, 1972
Stimulation-elic-ited Pain What Is the Appropriate Memory Model? Michael Gabriel
enz and coauthors marshall a wide array of data in support of an intriguing hypothesis, stating that activation of partioular brain pathways gives rise to the reexperience of pain and emotion (affect) previously engendered by various pathologies (heart disease, panic attacks, etc.). The pain experienced is said to be a product of a memory process, not a direct product of the activation itself, as when a pain is elicited directly by thermal or mechanical stimulation. Likewise, the affective response is said to be associatively coupled to the memory process, not a direct response to the pain. The brain region implicated in the re-experience of pathogenic pain is the region posterior and inferior to the human principal sensory nucleus, the nucleus ventralis caudal is (Vc). Henceforth this area will be referred to as the posteroinferior (PI) region. The principal empirical bases for the hypothesis are findings in studies of effects of presurgical electrical brain stimulation. Electrical stimulation of the PI region in patients with a history of pathological pain evokes pain and associated affective responses. The pain is described by the patients as being the same as the pain experienced during the prior episodes of pathogenic pain (e.g., angina, chest pain associated with panic attack, pain experienced during sexual intercourse). Pain is also elicited by stimulation in patients without a prior history of pathological pain. However, the affective response that accompanies the stimulation occurs only in those patients who have a prior history of pathogenic pain and who identify the stimulation-elicited pain as being the same as their previous pathogenic pain. The authors suggest that the stimulation-elicited pain experience and the associated affective response
L
From the Department of Psychology, Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana, IL. Reprint requests: Michael Gabriel, Department of Psychology, Beckman Institute for Advanced Science and Technology, University of Illinois, 405 North Mathews Avenue, Urbana, IL 61801.
38
depend on neurotransmission from the PI region to secondary somatosensory (SII) and/or insular cortical areas. This brings the hypothesis into register with a theoretical schema of Mishkin, which states that memory depends on "sensory-limbic" flow of information (i.e., the projection of information from various sensory cortical areas to medial temporal lobe structures) [8]. The authors' proposal adds insular and SII cortex to the visual, tactile, and other origins of memory-relevant information flow to the medial temporal lobe. Thus, the hypothesis integrates the clinical data with a wide array of physiologic and anatomical data, and with Mishkin's important theoretical account of brain organization. It helps to make sense of the rather unexpected differentiation of results that occurs when electrical brain stimulation is given to patients with and without a prior history of pain. This commentary suggests some lines of thought that may contribute to the elaboration of the authors' important hypothesis. The area in which there appears to be room for elaboration concerns the nature of the memory processes that mediate the described phenomena. Along these lines, it is necessary that the authors specify precisely which aspects of the patients' behavior and experience are affected by memory. In discussing the results of human thalamic studies, they state that thalamic "stimulation evokes pain with a strong affective dimension in patients who have previously experienced such pain. Similar pains without a strong affective dimension were evoked in patients without previous experience of pain with a strong affective dimension." These statements indicate that the pain response to the thalamic stimulation occurs in all subjects, whether or not they have a history of previous pain experience. It is only the affective response elicited by the thalamic stimulation that is added, as a result of a memory process conditioned by the previous history of pain experience. Yet in the next paragraph, Lenz and co-workers state that the "model predicts that somatic, visceral, or
Pain Forum 6(1): 38-40, 1997
COMMENTARY/Gabriel
emotional inputs projecting to the medial temporal lobe might provoke the previous experience of pain, including the affective dimension." In this statement, the authors appear to assert that both the pain experienced and the affective response are products of a memory process conditioned by the previous history of pain. The remainder of this commentary assumes that the latter interpretation is the one intended by the authors: i.e., that both the pain experienced and the affective response are products of a memory process conditioned by the previous history of pain. That this latter interpretation is the interpretation intended by the authors seems to be implicit throughout the article. Beyond clear specification of the phenomena affected by memory, it is also necessary that the nature of the involved memory process be carefully specified. The assumed interpretation intended by the authors (given above) is reinforced by their characterization of pain elicited by the thalamic stimulation as "memory for pain." However, one can have a memory for pain without actually experiencing pain. Perhaps the phrase "memory-based reexperience of pain" would convey the authors' concept more precisely. Furthermore, the conceptualization of memory represented by the account of Mishkin is hard to apply directly to the findings of the elicited pain studies. Mishkin's 1979 model [8] represents an account of discrimination learning in primates , wherein selective behavioral responses are cued by particular rewardpredictive stimuli. In the case of the phenomena described by Lenz and co-workers, the learned response is experience of pain, and associated affect, acquired as a result of prior experience of pain. The circuitry of Mishkin codes particular stimulus cues as reward-predictive, and the learned response is goaldirected approach behavior guided by the predictive cues. It is difficult to find clear points of comparison between the cue-coding process and the learned behavior discussed by Mishkin on the one hand, and the elicited pain phenomena described by Lenz and coworkers on the other. A Pavlovian model of memory is perhaps more applicable to the target phenomena discussed by the authors. In Pavlovian conditioning, a conditional stimulus (CS) acquires capacity to elicit a conditioned response (CR) as a result of associative pairing of the CS with an unconditioned stimulus (US). It is possible to imagine that in individuals with no history of pathogenic pain, the initial experiences of pathogenic pain such as angina, and the accompanying thalamic neuronal activations, could function as Pavlovian CS presentations. Initially, no US follows these CS occurrences. However, after the patient learns that the pain is a product of a life-threatening or otherwise frightening medical condi-
39
tion, occurrences of the pain are followed immediately by a US, the perception and interpretation of the occurrence of a potentially dangerous event (e.g., "I'm having an angina attack"), and a resultant fear/panic unconditional response (UR). Given repeated "pairings" of these putative conditioned and unconditioned stimuli, the results found in the studies cited by the authors would be expected (i.e., the thalamic electrical CS would elicit the affective CR discussed by the authors , a fear/panic CR). Note that by this account the perception and interpretation of the sensory consequences of thalamic activation are not viewed as products of conditioning but rather as manifestations of knowledge gained by the patient as a result of medical consultation. Yet by giving rise to fear and panic, these events could serve as a functional US, and could mediate the observations that led the authors to conclude that the thalamic stimulus elicited the customary affective response in patients having a prior history of pain. But what of the other CR of which the authors speak: the re-experience of previously experienced pain? The Pavlovian view suggested here leaves open the difficult issue of whether the patients' actual experience of the elicited pain is identical to or similar to the previously experienced pathologic (e.g., anginal) pain. It may be that associative processes are at work in this situation that result in identity of the elicited pain with the previously experienced pain. On the other hand, it is possible that the interpretive response to the electrically elicited pain leads the patients to generalize, concluding that two quite distinct pains, electrically elicited and pathological, are identical. An advantage of this position is that it avoids the assertion that the patients in the studies cited by the authors exhibited a conditioned pain experience. This assertion is difficult to accept on a priori grounds, as CRs that take the form of direct experience of pain do not appear to occur. indeed, fear conditioning procedures applied to animal and human subjects, wherein a neutral CS such as a tone or light is paired with an aversive US such as shock, yield conditioned autonomic and somatic CRs, and it is generally believed that aversive CSs elicit the emotional CR of anxiety. However, there is no evidence that the direct experience of pain is acquired as a CR by humans subjected to aversive conditioning procedures [11]. As mentioned earlier, the conceptualization of memory implicit in Mishkin's 1979 article does not conform well to the memory phenomena described by Lenz and co-workers. It is therefore not clear that the complex corticolimbic trajectory of Mishkin's model affords a parsimonious account of the neural substrates of the phenomena under consideration. What is needed is an
40
COMMENTARY/Gabriel
explanation of how an electrical CS elicits an affective fear/panic CR. There is substantial evidence in support of the hypothesis that neurons in the amygdala are critically involved in the elaboration of fear CRs [2,4-6,9,10]. The simplest circuit needed for the thalamic triggering of a fear CR is neurotransmission from-the PI region to the amygdala. Insular cortical or posterior thalamic projections to the amygdala [1 ,3-5] provide possible paths for this effect. Citing a paper by Mehler [7], Lenz and co-workers suggest that direct projections to the amygdala from posterior thalamic areas involved in pain processing, such as the PI region, are lacking in primates. By inference, the authors consider the existence of this pathway doubtful in humans. However, axonal projections to the amygdala have been found to originate in the primate peripeduncular nucleus [1,3]. Amaral and LeDoux have each argued, independently, that the peripeduncular nucleus in primates is homologous to the posterior intralaminar nucleus in rats, a posterior thalamic auditory projection area that contains neurons that project to the amygdala [1 ,5]. Acknowledgments Supported by National Institutes of Health grant NS26736 and National Science Foundation grant BIR 9504842. Thanks are due to Dr. John Freeman for his helpful comments on the commentary.
References 1. Amaral DG, Price JL, Pitkanen A, Carmichael 5T: Anatomical organization of the primate amygdaloid complex. p. 1. In Aggleton JP (ed): The amygdala: neurobiological aspects of emotion, memory and mental dysfunction. Wiley-Liss, New York, 1992 2. Fanselow MS, Kim JJ: Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA
receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala. Behav Neurosci 108: 210-212, 1994 3. Jones EG, Burton H, Saper CB, Swanson LW: Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates. J Comp Neurol 167:385-420, 1976 4. Kapp BS, Wilson A, Pascoe Jp, Supple W, Whalen PJ: A neuroanatomical systems analysis of conditioned bradycardia in the rabbit. p. 53. In Gabriel M, Moore J (eds): Learning and computational neuroscience: foundations of adaptive networks. Bradford Division of the MIT Press, Cambridge, MA, 1990 5. LeDoux JE: Information flow from sensation to emotion: Plasticity in the neural computation of stimulus value. p. 3. In Gabriel M, Moore J (eds): Learning and computational neuroscience: foundations of adaptive networks. Bradford Division of the MIT Press, Cambridge, MA, 1990 6. Maren S, Poremba A, Gabriel M: Multiple-unit activity in the basolateral amygdaloid nucleus during discriminative avoidance learning in rabbits. Brain Res 549:311-316, 1991 7. Mehler WR: Subcortical afferent connections of the amygdala in the monkey. J Neurosci 190:733-762, 1980 8. Mishkin M: Analogous neural models for visual and tactile learning. Neuropsychologia 17:139-151,1979 9. McCabe PM, Gentile CG, Markgraf CG, Teich AH, Schneiderman N: Ibotenic acid lesions in the amygdaloid central nucleus but not in the lateral subthalamic area prevent the acquisition of differential Pavlovian conditioning of bradycardia in rabbits. Brain Res 580:155-163, 1992 10. Miserandino MJD, Sananes CB, Mella KR, Davis M: Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 345:716-718, 1990 11. Obrist PA, Sutterer JR, Howard JL: Preparatory cardiac changes: a psychobiological approach. p. 312. In Black AH, Prokasy WF (eds): Classical conditioning II: current theory and research. Appleton-Century-Crofts, New York, 1972