- Email: [email protected]
The Brain Prize 2014: complex human functions
Science & Society
The Brain Prize 2014: complex human functions Kristina Grigaityte and Marco Iacoboni Ahmanson-Lovelace Brain Mapping Center, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins were recently awarded the 2014 Grete Lundbeck European Brain Research Prize for their ‘pioneering research on higher brain mechanisms underpinning such complex human functions as literacy, numeracy, motivated behavior and social cognition, and for their effort to understand cognitive and behavioral disorders’. Why was their work highlighted? Is there anything that links together these seemingly disparate lines of research?
Mirror neurons The discovery of mirror neurons by Giacomo Rizzolatti’s laboratory has helped us understand some of the foundational functional mechanisms underlying social cognition, which is the ability to process information that is relevant to our social life. For many years, cognitive neuroscientists wondered how it is that - in most cases - people are able to infer the emotions and feelings of others rather easily, and how people understand others’ actions and intentions effortlessly. The discovery of mirror neurons provided a potential answer to this question. In the 1980s and early 1990s, Rizzolatti and colleagues were investigating the neural mechanisms for grasping control in the ventral premotor cortex of macaque monkeys. In these experiments, they used single-cell recordings and eventually realized that they were consistently observing an unexpected phenomenon. Neurons in area F5 of the ventral premotor cortex fired not only when the monkey was grasping food or objects, but also when the monkey was observing someone else grasping food or objects [1]. No one had previously anticipated, predicted, or hypothesized anything like this observation. The phenomenon was compelling, mirror neurons defied many existing beliefs concerning the properties of individual cortical neurons. This discovery of mirror neurons suggested that perhaps a simple way to recognize the actions of other people is achieved by the brain via the mapping of those actions onto the motor plans of the observer [2]. Subsequent experiments demonstrated that mirror neurons code visually hidden actions [3] (as when one grasps an object that is not visible to the observer) and action sounds [4] (as when one hears someone else breaking a peanut), revealing the multi-modal nature of these cells. Other studies showed that mirror neurons code the same action differently, if there are cues suggesting that the underlying Corresponding author: Iacoboni, M. ([email protected]). 0166-2236/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2014.09.002
intention is different [5] (as for instance when grasping a mug to drink versus grasping the same mug to place it in the dishwasher). The current working hypothesis is that such a mirroring mechanism has been selected to facilitate social interactions and social learning, hence its place as a cornerstone of social cognition. This hypothesis has inspired many studies in humans using noninvasive techniques, such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG) or magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS) [6]. While the interpretation of these studies is obviously less straightforward than single cell recordings, they are the only types of studies that can be routinely performed in human subjects, in health and disease. Indeed, the legacy of the mirror neuron discovery will likely be in the translation of its concepts to clinical populations in the years to come. For instance, in mental health disorders - even when symptoms are controlled by medication - community functioning is poor and related to deficits in social cognition [7]. A better understanding of social cognition mechanisms should lead to more effective interventions in patients suffering from these disorders. In neurological disorders associated with reduced motor functions, action observation may be used as an additional intervention to help patients recover motor functionality [8]. Number sense Stanislas Dehaene has uncovered cognitive and neural mechanisms related to the sense of number that are crucial for our understanding of human cognition. A foundational question in cognitive neuroscience is how the sense of number is related to other broad cognitive domains such as language and the processing of space. In one of the many studies Dehaene has devoted to these questions, his group and collaborators looked at exact versus approximate arithmetic (see below) using both brain imaging and behavioral methods [9]. The intuitions of mathematicians have always been divided, with some pointing to language and others pointing more to space processing when reporting on their own thought processes. This study demonstrated that exact arithmetic – in which subjects had to select the exact solution of calculations – is linked to language whereas approximate arithmetic – in which subjects had only to estimate a solution – is linked to visuo-spatial processing. Indeed, some number sense abilities are present in both human infants and other animals, suggesting that while language is unique to humans, at least some aspects of mathematical thinking originate from different evolutionary paths. Trends in Neurosciences, November 2014, Vol. 37, No. 11
615
Science & Society A related question is whether the mapping of number onto space – a mechanism that plays a crucial role in mathematics – is dependent on education and culture. To investigate this issue Dehaene conducted a study on the people of the Amazonian Mundurucu tribe, which have limited or no formal education [10]. Additionally, the language of this tribe has a reduced mathematical lexicon, they do not have words for numbers above four or five. In this study, their task was to place a specific number of dots on the scale from one to ten or 1–100. The results showed that while American participants place the different amounts of dots in a linear manner, the Mundurucu participants did it in a logarithmic manner. American children also demonstrate a logarithmic number-space mapping, which later becomes linear as children go through formal education in school. Thus, Dehaene’s study suggested that the default mode of mapping numbers onto space in humans is logarithmic, and that education reshapes it. Finally, Dehaene’s human brain mapping work further demonstrated the link between number sense and the broad cognitive domains of spatial processing and language, as well as the role of formal education in reshaping our cognitive organization. To understand the neural basis of the number-space relationship, Dehaene mapped cortical areas associated with the sense of number in the intraparietal sulcus and adjacent inferior parietal lobule [11]. These cortical areas are situated in close proximity, in the former case, to more dorsal areas important for space processing and sensory-motor behavior, and in the latter case, to left inferior parietal areas typically associated with language. Furthermore, when looking at the effect of literacy on cortical representations, he found that literacy can reshape cortical organization not only in childhood but even in adulthood [12]. His work on both number sense and literacy has important implications for remediation strategies in congenital and acquired disorders of mathematical abilities and reading, two essential functions in modern human life. Impulsive behavior: cause or consequence of drug addiction? Individuals that are more prone to risk taking and are impulsive also tend to be more prone to drug abuse and addiction. A longstanding question regarding this association has been whether these individuals tend to abuse drugs because they are impulsive or become impulsive because of cognitive impairments produced by addiction. Trevor Robbins and colleagues demonstrated that more impulsive rats have altered dopamine function, a neurotransmitter important for reward signaling, even before they are exposed to drugs [13]. When given cocaine, these rats tend to get addicted more often than rats with normal dopamine functions. In this study, impulsivity was defined by the presence of high levels of anticipatory responses made to a food-predictive stimulus. Robbins and colleagues then compared dopamine D2/3 receptor availability in the striatum in impulsive and non-impulsive rats and found reduced D2/3 receptor availability in the nucleus accumbens of impulsive rats. They subsequently investigated how impulsivity influenced intravenous 616
Trends in Neurosciences November 2014, Vol. 37, No. 11
cocaine self-administration. Not surprisingly, impulsive rats demonstrated higher rates, relative to non-impulsive rats, of intravenous cocaine self-administration. The impulsive rats, however, became no longer impulsive after prolonged exposure to cocaine. In a previous study, Robbins and colleagues had already studied the causal role of the nucleus accumbens in impulsivity (as when choosing an immediate small reward, rather than a larger but delayed reward) by looking at the effects of brain lesions on behavior [14]. They demonstrated that selective lesions of the nucleus accumbens caused impulsive choices in rats, while damage to two cortical areas connected to it, the anterior cingulate cortex and medial prefrontal cortex, had no effect on impulsivity. Since impulsive behavior is associated with a number of conditions affecting mental health, including drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, it is important to understand not only its neurobiological underpinnings but also to translate the animal work into research on human subjects. Robbins and colleagues used the stop-signal paradigm to do so, since it is a reliable measure of impulse control. In this paradigm, subjects are instructed to respond as fast as possible to a cue (generally visual), unless they receive a stop signal (typically in the form of a beep). In a study on patients with damage to the frontal lobes, Robbins and colleagues found that lesions in the right inferior frontal gyrus are associated with deficits in stopping behavior, a finding in line with neuroimaging evidence implicating this region in impulse control [15]. The stop signal paradigm is now frequently used to investigate stopping behavior in health and disease. Future studies will tell us whether this paradigm is an effective marker for changes induced by interventions in clinical populations. Having solved this cause-effect problem, that is, impulsive behavior is likely to be the cause of addiction rather than the other way around, Robbins and colleagues have opened up a new line of research that should be helpful in designing effective interventions for clinical populations exhibiting impulsive behavior. This new insight into addiction predisposition may help not only already addicted individuals seeking rehabilitation but may also help identify and develop interventions for individuals at high risk of becoming addicted that have yet to be exposed to drugs. The common link Is there a common link between work on mirror neurons and social cognition, number sense and space, and impulsivity? While at first sight the important contributions of Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins seem to tap different cognitive domains, the common denominator of action and its selection, whether in the form of mapping it onto the behavior of others (mirror neurons), or onto space (as with the links between cortical areas for the number sense and sensory-motor behavior), or regarding its control (stopping behavior) clearly emerges. More importantly, all these lines of research have implications for interventions and treatment of cognitive and behavioral disorders that still present many challenges (Figure 1).
Science & Society
Trends in Neurosciences November 2014, Vol. 37, No. 11
TRENDS in Neurosciences
Figure 1. The award ceremony for the Brain Prize 2014. From the left: Trevor Robbins, Stanislas Dehaene, Giacomo Rizzolatti, Crown Princess Mary, and chairman of the board of the Grete Lundbeck Foundation Povl Krogsgaard-Larsen.
References 1 Gallese, V. et al. (1996) Action recognition in the premotor cortex. Brain 119, 593–609 2 Rizzolatti, G. et al. (1996) Premotor cortex and the recognition of motor actions. Brain Res. Cogn. Brain Res. 3, 131–141 3 Umilta`, M.A. et al. (2001) I know what you are doing: a neurophysiological study. Neuron 31, 155–165 4 Kohler, E. et al. (2002) Hearing sounds, understanding actions: action representation in mirror neurons. Science 297, 846–848 5 Fogassi, L. et al. (2005) Parietal lobe: from action organization to intention understanding. Science 308, 662–667 6 Iacoboni, M. and Dapretto, M. (2006) The mirror neuron system and the consequences of its dysfunction. Nat. Rev. Neurosci. 7, 942–951 7 Green, M.F. and Horan, W.P. (2010) Social cognition in scihzophrenia. Curr. Dir. Psychol. Sci. 19, 243–248 8 Small, S.L. et al. (2012) The mirror neuron system and treatment of stroke. Dev. Psychobiol. 54, 293–310
9 Dehaene, S. et al. (1999) Sources of mathematical thinking: behavioral and brain-imaging evidence. Science 284, 970–974 10 Dehaene, S. et al. (2008) Log or linear? Distinct intuitions of the number scale in Western and Amazonian indigene cultures. Science 320, 1217–1220 11 Simon, O. et al. (2002) Topographical layout of hand, eye, calculation, and language-related areas in the human parietal lobe. Neuron 33, 475–487 12 Dehaene, S. et al. (2010) How learning to read changes the cortical networks for vision and language. Science 330, 1359–1364 13 Dalley, J.W. et al. (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315, 1267–1270 14 Cardinal, R.N. et al. (2001) Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 292, 2499–2501 15 Aron, A.R. et al. (2003) Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat. Neurosci. 6, 115–116
617
The Brain Prize 2014: complex human functions Kristina Grigaityte and Marco Iacoboni Ahmanson-Lovelace Brain Mapping Center, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins were recently awarded the 2014 Grete Lundbeck European Brain Research Prize for their ‘pioneering research on higher brain mechanisms underpinning such complex human functions as literacy, numeracy, motivated behavior and social cognition, and for their effort to understand cognitive and behavioral disorders’. Why was their work highlighted? Is there anything that links together these seemingly disparate lines of research?
Mirror neurons The discovery of mirror neurons by Giacomo Rizzolatti’s laboratory has helped us understand some of the foundational functional mechanisms underlying social cognition, which is the ability to process information that is relevant to our social life. For many years, cognitive neuroscientists wondered how it is that - in most cases - people are able to infer the emotions and feelings of others rather easily, and how people understand others’ actions and intentions effortlessly. The discovery of mirror neurons provided a potential answer to this question. In the 1980s and early 1990s, Rizzolatti and colleagues were investigating the neural mechanisms for grasping control in the ventral premotor cortex of macaque monkeys. In these experiments, they used single-cell recordings and eventually realized that they were consistently observing an unexpected phenomenon. Neurons in area F5 of the ventral premotor cortex fired not only when the monkey was grasping food or objects, but also when the monkey was observing someone else grasping food or objects [1]. No one had previously anticipated, predicted, or hypothesized anything like this observation. The phenomenon was compelling, mirror neurons defied many existing beliefs concerning the properties of individual cortical neurons. This discovery of mirror neurons suggested that perhaps a simple way to recognize the actions of other people is achieved by the brain via the mapping of those actions onto the motor plans of the observer [2]. Subsequent experiments demonstrated that mirror neurons code visually hidden actions [3] (as when one grasps an object that is not visible to the observer) and action sounds [4] (as when one hears someone else breaking a peanut), revealing the multi-modal nature of these cells. Other studies showed that mirror neurons code the same action differently, if there are cues suggesting that the underlying Corresponding author: Iacoboni, M. ([email protected]). 0166-2236/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2014.09.002
intention is different [5] (as for instance when grasping a mug to drink versus grasping the same mug to place it in the dishwasher). The current working hypothesis is that such a mirroring mechanism has been selected to facilitate social interactions and social learning, hence its place as a cornerstone of social cognition. This hypothesis has inspired many studies in humans using noninvasive techniques, such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG) or magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS) [6]. While the interpretation of these studies is obviously less straightforward than single cell recordings, they are the only types of studies that can be routinely performed in human subjects, in health and disease. Indeed, the legacy of the mirror neuron discovery will likely be in the translation of its concepts to clinical populations in the years to come. For instance, in mental health disorders - even when symptoms are controlled by medication - community functioning is poor and related to deficits in social cognition [7]. A better understanding of social cognition mechanisms should lead to more effective interventions in patients suffering from these disorders. In neurological disorders associated with reduced motor functions, action observation may be used as an additional intervention to help patients recover motor functionality [8]. Number sense Stanislas Dehaene has uncovered cognitive and neural mechanisms related to the sense of number that are crucial for our understanding of human cognition. A foundational question in cognitive neuroscience is how the sense of number is related to other broad cognitive domains such as language and the processing of space. In one of the many studies Dehaene has devoted to these questions, his group and collaborators looked at exact versus approximate arithmetic (see below) using both brain imaging and behavioral methods [9]. The intuitions of mathematicians have always been divided, with some pointing to language and others pointing more to space processing when reporting on their own thought processes. This study demonstrated that exact arithmetic – in which subjects had to select the exact solution of calculations – is linked to language whereas approximate arithmetic – in which subjects had only to estimate a solution – is linked to visuo-spatial processing. Indeed, some number sense abilities are present in both human infants and other animals, suggesting that while language is unique to humans, at least some aspects of mathematical thinking originate from different evolutionary paths. Trends in Neurosciences, November 2014, Vol. 37, No. 11
615
Science & Society A related question is whether the mapping of number onto space – a mechanism that plays a crucial role in mathematics – is dependent on education and culture. To investigate this issue Dehaene conducted a study on the people of the Amazonian Mundurucu tribe, which have limited or no formal education [10]. Additionally, the language of this tribe has a reduced mathematical lexicon, they do not have words for numbers above four or five. In this study, their task was to place a specific number of dots on the scale from one to ten or 1–100. The results showed that while American participants place the different amounts of dots in a linear manner, the Mundurucu participants did it in a logarithmic manner. American children also demonstrate a logarithmic number-space mapping, which later becomes linear as children go through formal education in school. Thus, Dehaene’s study suggested that the default mode of mapping numbers onto space in humans is logarithmic, and that education reshapes it. Finally, Dehaene’s human brain mapping work further demonstrated the link between number sense and the broad cognitive domains of spatial processing and language, as well as the role of formal education in reshaping our cognitive organization. To understand the neural basis of the number-space relationship, Dehaene mapped cortical areas associated with the sense of number in the intraparietal sulcus and adjacent inferior parietal lobule [11]. These cortical areas are situated in close proximity, in the former case, to more dorsal areas important for space processing and sensory-motor behavior, and in the latter case, to left inferior parietal areas typically associated with language. Furthermore, when looking at the effect of literacy on cortical representations, he found that literacy can reshape cortical organization not only in childhood but even in adulthood [12]. His work on both number sense and literacy has important implications for remediation strategies in congenital and acquired disorders of mathematical abilities and reading, two essential functions in modern human life. Impulsive behavior: cause or consequence of drug addiction? Individuals that are more prone to risk taking and are impulsive also tend to be more prone to drug abuse and addiction. A longstanding question regarding this association has been whether these individuals tend to abuse drugs because they are impulsive or become impulsive because of cognitive impairments produced by addiction. Trevor Robbins and colleagues demonstrated that more impulsive rats have altered dopamine function, a neurotransmitter important for reward signaling, even before they are exposed to drugs [13]. When given cocaine, these rats tend to get addicted more often than rats with normal dopamine functions. In this study, impulsivity was defined by the presence of high levels of anticipatory responses made to a food-predictive stimulus. Robbins and colleagues then compared dopamine D2/3 receptor availability in the striatum in impulsive and non-impulsive rats and found reduced D2/3 receptor availability in the nucleus accumbens of impulsive rats. They subsequently investigated how impulsivity influenced intravenous 616
Trends in Neurosciences November 2014, Vol. 37, No. 11
cocaine self-administration. Not surprisingly, impulsive rats demonstrated higher rates, relative to non-impulsive rats, of intravenous cocaine self-administration. The impulsive rats, however, became no longer impulsive after prolonged exposure to cocaine. In a previous study, Robbins and colleagues had already studied the causal role of the nucleus accumbens in impulsivity (as when choosing an immediate small reward, rather than a larger but delayed reward) by looking at the effects of brain lesions on behavior [14]. They demonstrated that selective lesions of the nucleus accumbens caused impulsive choices in rats, while damage to two cortical areas connected to it, the anterior cingulate cortex and medial prefrontal cortex, had no effect on impulsivity. Since impulsive behavior is associated with a number of conditions affecting mental health, including drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, it is important to understand not only its neurobiological underpinnings but also to translate the animal work into research on human subjects. Robbins and colleagues used the stop-signal paradigm to do so, since it is a reliable measure of impulse control. In this paradigm, subjects are instructed to respond as fast as possible to a cue (generally visual), unless they receive a stop signal (typically in the form of a beep). In a study on patients with damage to the frontal lobes, Robbins and colleagues found that lesions in the right inferior frontal gyrus are associated with deficits in stopping behavior, a finding in line with neuroimaging evidence implicating this region in impulse control [15]. The stop signal paradigm is now frequently used to investigate stopping behavior in health and disease. Future studies will tell us whether this paradigm is an effective marker for changes induced by interventions in clinical populations. Having solved this cause-effect problem, that is, impulsive behavior is likely to be the cause of addiction rather than the other way around, Robbins and colleagues have opened up a new line of research that should be helpful in designing effective interventions for clinical populations exhibiting impulsive behavior. This new insight into addiction predisposition may help not only already addicted individuals seeking rehabilitation but may also help identify and develop interventions for individuals at high risk of becoming addicted that have yet to be exposed to drugs. The common link Is there a common link between work on mirror neurons and social cognition, number sense and space, and impulsivity? While at first sight the important contributions of Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins seem to tap different cognitive domains, the common denominator of action and its selection, whether in the form of mapping it onto the behavior of others (mirror neurons), or onto space (as with the links between cortical areas for the number sense and sensory-motor behavior), or regarding its control (stopping behavior) clearly emerges. More importantly, all these lines of research have implications for interventions and treatment of cognitive and behavioral disorders that still present many challenges (Figure 1).
Science & Society
Trends in Neurosciences November 2014, Vol. 37, No. 11
TRENDS in Neurosciences
Figure 1. The award ceremony for the Brain Prize 2014. From the left: Trevor Robbins, Stanislas Dehaene, Giacomo Rizzolatti, Crown Princess Mary, and chairman of the board of the Grete Lundbeck Foundation Povl Krogsgaard-Larsen.
References 1 Gallese, V. et al. (1996) Action recognition in the premotor cortex. Brain 119, 593–609 2 Rizzolatti, G. et al. (1996) Premotor cortex and the recognition of motor actions. Brain Res. Cogn. Brain Res. 3, 131–141 3 Umilta`, M.A. et al. (2001) I know what you are doing: a neurophysiological study. Neuron 31, 155–165 4 Kohler, E. et al. (2002) Hearing sounds, understanding actions: action representation in mirror neurons. Science 297, 846–848 5 Fogassi, L. et al. (2005) Parietal lobe: from action organization to intention understanding. Science 308, 662–667 6 Iacoboni, M. and Dapretto, M. (2006) The mirror neuron system and the consequences of its dysfunction. Nat. Rev. Neurosci. 7, 942–951 7 Green, M.F. and Horan, W.P. (2010) Social cognition in scihzophrenia. Curr. Dir. Psychol. Sci. 19, 243–248 8 Small, S.L. et al. (2012) The mirror neuron system and treatment of stroke. Dev. Psychobiol. 54, 293–310
9 Dehaene, S. et al. (1999) Sources of mathematical thinking: behavioral and brain-imaging evidence. Science 284, 970–974 10 Dehaene, S. et al. (2008) Log or linear? Distinct intuitions of the number scale in Western and Amazonian indigene cultures. Science 320, 1217–1220 11 Simon, O. et al. (2002) Topographical layout of hand, eye, calculation, and language-related areas in the human parietal lobe. Neuron 33, 475–487 12 Dehaene, S. et al. (2010) How learning to read changes the cortical networks for vision and language. Science 330, 1359–1364 13 Dalley, J.W. et al. (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315, 1267–1270 14 Cardinal, R.N. et al. (2001) Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 292, 2499–2501 15 Aron, A.R. et al. (2003) Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat. Neurosci. 6, 115–116
617