RESUMEN
Information exchange between brain regions is key to understanding information processing for social decision-making, but most analyses ignore its dynamic nature. New insights on this dynamic might help us to uncover the neural correlates of social cognition in the healthy population and also to understand the malfunctioning neural computations underlying dysfunctional social behavior in patients with mental disorders. In this work, we used a multi-round bargaining game to detect switches between distinct bargaining strategies in a cohort of 76 healthy participants. These switches were uncovered by dynamic behavioral modeling using the hidden Markov model. Proposing a novel model of dynamic effective connectivity to estimate the information flow between key brain regions, we found a stronger interaction between the right temporoparietal junction (rTPJ) and the right dorsolateral prefrontal cortex (rDLPFC) for the strategic deception compared with the social heuristic strategies. The level of deception was associated with the information flow from the Brodmann area 10 to the rTPJ, and this association was modulated by the rTPJ-to-rDLPFC information flow. These findings suggest that dynamic bargaining strategy is supported by dynamic reconfiguration of the rDLPFC-and-rTPJ interaction during competitive social interactions.
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Mapeo Encefálico , Interacción Social , Humanos , Encéfalo , Conducta Social , Corteza Prefrontal/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
Does early exposure to cognitive and linguistic stimulation impact brain structure? Or do genetic predispositions account for the co-occurrence of certain neuroanatomical phenotypes and a tendency to engage children in cognitively stimulating activities? Low socioeconomic status infants were randomized to either 5 years of cognitively and linguistically stimulating center-based care or a comparison condition. The intervention resulted in large and statistically significant changes in brain structure measured in midlife, particularly for male individuals. These findings are the first to extend the large literature on cognitive enrichment effects on animal brains to humans, and to demonstrate the effects of uniquely human features such as linguistic stimulation.
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Encéfalo , Cognición , Animales , Humanos , Aprendizaje , Estudios Longitudinales , Masculino , Distribución AleatoriaRESUMEN
Criminal convictions require proof that a prohibited act was performed in a statutorily specified mental state. Different legal consequences, including greater punishments, are mandated for those who act in a state of knowledge, compared with a state of recklessness. Existing research, however, suggests people have trouble classifying defendants as knowing, rather than reckless, even when instructed on the relevant legal criteria. We used a machine-learning technique on brain imaging data to predict, with high accuracy, which mental state our participants were in. This predictive ability depended on both the magnitude of the risks and the amount of information about those risks possessed by the participants. Our results provide neural evidence of a detectable difference in the mental state of knowledge in contrast to recklessness and suggest, as a proof of principle, the possibility of inferring from brain data in which legally relevant category a person belongs. Some potential legal implications of this result are discussed.
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Encéfalo/fisiología , Conocimiento , Procesos Mentales , Adulto , Área Bajo la Curva , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Pruebas Psicológicas , Reproducibilidad de los Resultados , Conducta Social , Adulto JovenRESUMEN
Cooperation and competition between human players in repeated microeconomic games offer a window onto social phenomena such as the establishment, breakdown and repair of trust. However, although a suitable starting point for the quantitative analysis of such games exists, namely the Interactive Partially Observable Markov Decision Process (I-POMDP), computational considerations and structural limitations have limited its application, and left unmodelled critical features of behavior in a canonical trust task. Here, we provide the first analysis of two central phenomena: a form of social risk-aversion exhibited by the player who is in control of the interaction in the game; and irritation or anger, potentially exhibited by both players. Irritation arises when partners apparently defect, and it potentially causes a precipitate breakdown in cooperation. Failing to model one's partner's propensity for it leads to substantial economic inefficiency. We illustrate these behaviours using evidence drawn from the play of large cohorts of healthy volunteers and patients. We show that for both cohorts, a particular subtype of player is largely responsible for the breakdown of trust, a finding which sheds new light on borderline personality disorder.
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Trastorno de Personalidad Limítrofe/fisiopatología , Conducta Competitiva , Conducta Cooperativa , Teoría del Juego , Relaciones Interpersonales , Algoritmos , Teorema de Bayes , Simulación por Computador , Juegos Experimentales , Culpa , Voluntarios Sanos , Humanos , Aprendizaje , Cadenas de Markov , Modelos Económicos , Modelos Estadísticos , Riesgo , Conducta Social , Temperatura , ConfianzaRESUMEN
In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.
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Conducta de Elección/fisiología , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Recompensa , Neuronas Dopaminérgicas/metabolismo , Juegos Experimentales , Humanos , Imagen por Resonancia Magnética , Enfermedad de Parkinson/metabolismoRESUMEN
Little is known about how prior beliefs impact biophysically described processes in the presence of neuroactive drugs, which presents a profound challenge to the understanding of the mechanisms and treatments of addiction. We engineered smokers' prior beliefs about the presence of nicotine in a cigarette smoked before a functional magnetic resonance imaging session where subjects carried out a sequential choice task. Using a model-based approach, we show that smokers' beliefs about nicotine specifically modulated learning signals (value and reward prediction error) defined by a computational model of mesolimbic dopamine systems. Belief of "no nicotine in cigarette" (compared with "nicotine in cigarette") strongly diminished neural responses in the striatum to value and reward prediction errors and reduced the impact of both on smokers' choices. These effects of belief could not be explained by global changes in visual attention and were specific to value and reward prediction errors. Thus, by modulating the expression of computationally explicit signals important for valuation and choice, beliefs can override the physical presence of a potent neuroactive compound like nicotine. These selective effects of belief demonstrate that belief can modulate model-based parameters important for learning. The implications of these findings may be far ranging because belief-dependent effects on learning signals could impact a host of other behaviors in addiction as well as in other mental health problems.
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Cultura , Nicotina/farmacología , Recompensa , Fumar/efectos adversos , Adulto , Atención/fisiología , Conducta de Elección/efectos de los fármacos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Placebos , Percepción Visual/efectos de los fármacosRESUMEN
Groups of humans routinely misassign value to complex future events, especially in settings involving the exchange of resources. If properly structured, experimental markets can act as excellent probes of human group-level valuation mechanisms during pathological overvaluations--price bubbles. The connection between the behavioral and neural underpinnings of such phenomena has been absent, in part due to a lack of enabling technology. We used a multisubject functional MRI paradigm to measure neural activity in human subjects participating in experimental asset markets in which endogenous price bubbles formed and crashed. Although many ideas exist about how and why such bubbles may form and how to identify them, our experiment provided a window on the connection between neural responses and behavioral acts (buying and selling) that created the bubbles. We show that aggregate neural activity in the nucleus accumbens (NAcc) tracks the price bubble and that NAcc activity aggregated within a market predicts future price changes and crashes. Furthermore, the lowest-earning subjects express a stronger tendency to buy as a function of measured NAcc activity. Conversely, we report a signal in the anterior insular cortex in the highest earners that precedes the impending price peak, is associated with a higher propensity to sell in high earners, and that may represent a neural early warning signal in these subjects. Such markets could be a model system to understand neural and behavior mechanisms in other settings where emergent group-level activity exhibits mistaken belief or valuation.
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Encéfalo/fisiología , Comercio , Emociones/fisiología , Inversiones en Salud , Conducta , HumanosRESUMEN
Social norms and their enforcement are fundamental to human societies. The ability to detect deviations from norms and to adapt to norms in a changing environment is therefore important to individuals' normal social functioning. Previous neuroimaging studies have highlighted the involvement of the insular and ventromedial prefrontal (vmPFC) cortices in representing norms. However, the necessity and dissociability of their involvement remain unclear. Using model-based computational modeling and neuropsychological lesion approaches, we examined the contributions of the insula and vmPFC to norm adaptation in seven human patients with focal insula lesions and six patients with focal vmPFC lesions, in comparison with forty neurologically intact controls and six brain-damaged controls. There were three computational signals of interest as participants played a fairness game (ultimatum game): sensitivity to the fairness of offers, sensitivity to deviations from expected norms, and the speed at which people adapt to norms. Significant group differences were assessed using bootstrapping methods. Patients with insula lesions displayed abnormally low adaptation speed to norms, yet detected norm violations with greater sensitivity than controls. Patients with vmPFC lesions did not have such abnormalities, but displayed reduced sensitivity to fairness and were more likely to accept the most unfair offers. These findings provide compelling computational and lesion evidence supporting the necessary, yet dissociable roles of the insula and vmPFC in norm adaptation in humans: the insula is critical for learning to adapt when reality deviates from norm expectations, and that the vmPFC is important for valuation of fairness during social exchange.
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Adaptación Psicológica , Daño Encefálico Crónico/fisiopatología , Corteza Prefrontal/fisiología , Normas Sociales , Adulto , Anciano , Daño Encefálico Crónico/psicología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Especificidad de Órganos , Corteza Prefrontal/fisiopatologíaRESUMEN
The habenula is a hub for cognitive and emotional signals that are relayed to the aminergic centers in the midbrain and, thus, plays an important role in goal-oriented behaviors. Although it is well described in rodents and non-human primates, the habenula functional network remains relatively uncharacterized in humans, partly because of the methodological challenges associated with the functional magnetic resonance imaging of small structures in the brain. Using high-resolution cardiac-gated resting state imaging in healthy humans and precisely identifying each participants' habenula, we show that the habenula is functionally coupled with the insula, parahippocampus, thalamus, periaqueductal grey, pons, striatum and substantia nigra/ventral tegmental area complex. Furthermore, by separately examining and comparing the functional maps from the left and right habenula, we provide the first evidence of an asymmetry in the functional connectivity of the habenula in humans. Hum Brain Mapp 37:2602-2615, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
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Técnicas de Imagen Sincronizada Cardíacas , Lateralidad Funcional , Habénula/fisiología , Imagen por Resonancia Magnética , Adulto , Mapeo Encefálico/métodos , Técnicas de Imagen Sincronizada Cardíacas/métodos , Femenino , Habénula/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiología , Tamaño de los Órganos , DescansoRESUMEN
In anorexia nervosa, problems with social relationships contribute to illness, and improvements in social support are associated with recovery. Using the multiround trust game and 3T MRI, we compare neural responses in a social relationship in three groups of women: women with anorexia nervosa, women in long-term weight recovery from anorexia nervosa, and healthy comparison women. Surrogate markers related to social signals in the game were computed each round to assess whether the relationship was improving (benevolence) or deteriorating (malevolence) for each subject. Compared with healthy women, neural responses to benevolence were diminished in the precuneus and right angular gyrus in both currently-ill and weight-recovered subjects with anorexia, but neural responses to malevolence differed in the left fusiform only in currently-ill subjects. Next, using a whole-brain regression, we identified an office assessment, the positive personalizing bias, that was inversely correlated with neural activity in the occipital lobe, the precuneus and posterior cingulate, the bilateral temporoparietal junctions, and dorsal anterior cingulate, during benevolence for all groups of subjects. The positive personalizing bias is a self-report measure that assesses the degree with which a person attributes positive experiences to other people. These data suggest that problems in perceiving kindness may be a consistent trait related to the development of anorexia nervosa, whereas recognizing malevolence may be related to recovery. Future work on social brain function, in both healthy and psychiatric populations, should consider positive personalizing biases as a possible marker of neural differences related to kindness perception.
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Anorexia Nerviosa , Beneficencia , Mapeo Encefálico , Encéfalo/patología , Relaciones Interpersonales , Recuperación de la Función/fisiología , Adolescente , Adulto , Análisis de Varianza , Anorexia Nerviosa/patología , Anorexia Nerviosa/fisiopatología , Anorexia Nerviosa/psicología , Femenino , Juegos Experimentales , Humanos , Imagenología Tridimensional , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Persona de Mediana Edad , Análisis de Regresión , Confianza/psicología , Adulto JovenRESUMEN
Humans assess the credibility of information gained from others on a daily basis; this ongoing assessment is especially crucial for avoiding exploitation by others. We used a repeated, two-person bargaining game and a cognitive hierarchy model to test how subjects judge the information sent asymmetrically from one player to the other. The weight that they give to this information is the result of two distinct factors: their baseline suspicion given the situation and the suspicion generated by the other person's behavior. We hypothesized that human brains maintain an ongoing estimate of the credibility of the other player and sought to uncover neural correlates of this process. In the game, sellers were forced to infer the value of an object based on signals sent from a prospective buyer. We found that amygdala activity correlated with baseline suspicion, whereas activations in bilateral parahippocampus correlated with trial-by-trial uncertainty induced by the buyer's sequence of suggestions. In addition, the less credible buyers that appeared, the more sensitive parahippocampal activation was to trial-by-trial uncertainty. Although both of these neural structures have previously been implicated in trustworthiness judgments, these results suggest that they have distinct and separable roles that correspond to their theorized roles in learning and memory.
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Amígdala del Cerebelo/fisiología , Conducta/fisiología , Juegos Experimentales , Giro Parahipocampal/fisiología , Adulto , Algoritmos , Amígdala del Cerebelo/anatomía & histología , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Modelos Neurológicos , Modelos Psicológicos , Giro Parahipocampal/anatomía & histología , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
Social norms in humans constrain individual behaviors to establish shared expectations within a social group. Previous work has probed social norm violations and the feelings that such violations engender; however, a computational rendering of the underlying neural and emotional responses has been lacking. We probed norm violations using a two-party, repeated fairness game (ultimatum game) where proposers offer a split of a monetary resource to a responder who either accepts or rejects the offer. Using a norm-training paradigm where subject groups are preadapted to either high or low offers, we demonstrate that unpredictable shifts in expected offers creates a difference in rejection rates exhibited by the two responder groups for otherwise identical offers. We constructed an ideal observer model that identified neural correlates of norm prediction errors in the ventral striatum and anterior insula, regions that also showed strong responses to variance-prediction errors generated by the same model. Subjective feelings about offers correlated with these norm prediction errors, and the two signals displayed overlapping, but not identical, neural correlates in striatum, insula, and medial orbitofrontal cortex. These results provide evidence for the hypothesis that responses in anterior insula can encode information about social norm violations that correlate with changes in overt behavior (changes in rejection rates). Together, these results demonstrate that the brain regions involved in reward prediction and risk prediction are also recruited in signaling social norm violations.
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Encéfalo/fisiología , Emociones/fisiología , Relaciones Interpersonales , Conducta Social , Adolescente , Adulto , Mapeo Encefálico , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana EdadRESUMEN
Computational models of reward processing suggest that foregone or fictive outcomes serve as important information sources for learning and augment those generated by experienced rewards (e.g. reward prediction errors). An outstanding question is how these learning signals interact with top-down cognitive influences, such as cognitive reappraisal strategies. Using a sequential investment task and functional magnetic resonance imaging, we show that the reappraisal strategy selectively attenuates the influence of fictive, but not reward prediction error signals on investment behavior; such behavioral effect is accompanied by changes in neural activity and connectivity in the anterior insular cortex, a brain region thought to integrate subjective feelings with high-order cognition. Furthermore, individuals differ in the extent to which their behaviors are driven by fictive errors versus reward prediction errors, and the reappraisal strategy interacts with such individual differences; a finding also accompanied by distinct underlying neural mechanisms. These findings suggest that the variable interaction of cognitive strategies with two important classes of computational learning signals (fictive, reward prediction error) represent one contributing substrate for the variable capacity of individuals to control their behavior based on foregone rewards. These findings also expose important possibilities for understanding the lack of control in addiction based on possibly foregone rewarding outcomes.
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Encéfalo/fisiología , Cognición/fisiología , Toma de Decisiones , Inversiones en Salud , Recompensa , Adulto , Anticipación Psicológica/fisiología , Mapeo Encefálico , Femenino , Humanos , Aprendizaje/fisiología , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/fisiología , Pruebas Neuropsicológicas , Psicofísica , Análisis de RegresiónRESUMEN
In many settings, copying, learning from or assigning value to group behavior is rational because such behavior can often act as a proxy for valuable returns. However, such herd behavior can also be pathologically misleading by coaxing individuals into behaviors that are otherwise irrational and it may be one source of the irrational behaviors underlying market bubbles and crashes. Using a two-person tandem investment game, we sought to examine the neural and behavioral responses of herd instincts in situations stripped of the incentive to be influenced by the choices of one's partner. We show that the investments of the two subjects correlate over time if they are made aware of their partner's choices even though these choices have no impact on either player's earnings. We computed an "interpersonal prediction error", the difference between the investment decisions of the two subjects after each choice. BOLD responses in the striatum, implicated in valuation and action selection, were highly correlated with this interpersonal prediction error. The revelation of the partner's investment occurred after all useful information about the market had already been revealed. This effect was confirmed in two separate experiments where the impact of the time of revelation of the partner's choice was tested at 2 seconds and 6 seconds after a subject's choice; however, the effect was absent in a control condition with a computer partner. These findings strongly support the existence of mechanisms that drive correlated behavior even in contexts where there is no explicit advantage to do so.
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Encéfalo/fisiología , Conducta de Elección/fisiología , Modelos Estadísticos , Algoritmos , Encéfalo/anatomía & histología , Humanos , Procesamiento de Imagen Asistido por Computador , Inversiones en Salud , Imagen por Resonancia Magnética , Análisis de Regresión , Recompensa , Análisis y Desempeño de TareasRESUMEN
BACKGROUND: Development and recurrence of 2 eating disorders (EDs), anorexia nervosa and bulimia nervosa, are frequently associated with environmental stressors. Neurobehavioral responses to social learning signals were evaluated in both EDs. METHODS: Women with anorexia nervosa (n = 25), women with bulimia nervosa (n = 30), or healthy comparison women (n = 38) played a neuroeconomic game in which the norm shifted, generating social learning signals (norm prediction errors [NPEs]) during a functional magnetic resonance imaging scan. A Bayesian logistic regression model examined how the probability of offer acceptance depended on cohort, block, and NPEs. Rejection rates, emotion ratings, and neural responses to NPEs were compared across groups. RESULTS: Relative to the comparison group, both ED cohorts showed less adaptation (p = .028, ηp2 = 0.060), and advantageous signals (positive NPEs) led to higher rejection rates (p = .014, ηp2 = 0.077) and less positive emotion ratings (p = .004, ηp2 = 0.111). Advantageous signals increased neural activations in the orbitofrontal cortex for the comparison group but not for women with anorexia nervosa (p = .018, d = 0.655) or bulimia nervosa (p = .043, d = 0.527). More severe ED symptoms were associated with decreased activation of dorsomedial prefrontal cortex for advantageous signals. CONCLUSIONS: Diminished neural processing of advantageous social signals and impaired norm adaptation were observed in both anorexia nervosa and bulimia nervosa, while no differences were found for disadvantageous social signals. Development of neurocognitive interventions to increase responsivity to advantageous social signals could augment current treatments, potentially leading to improved clinical outcomes for EDs.
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Anorexia Nerviosa , Bulimia Nerviosa , Femenino , Humanos , Teorema de Bayes , Imagen por Resonancia Magnética , Satisfacción PersonalRESUMEN
BACKGROUND: Functional connectivity has garnered interest as a potential biomarker of psychiatric disorders including borderline personality disorder (BPD). However, small sample sizes and lack of within-study replications have led to divergent findings with no clear spatial foci. AIMS: Evaluate discriminative performance and generalizability of functional connectivity markers for BPD. METHOD: Whole-brain fMRI resting state functional connectivity in matched subsamples of 116 BPD and 72 control individuals defined by three grouping strategies. We predicted BPD status using classifiers with repeated cross-validation based on multiscale functional connectivity within and between regions of interest (ROIs) covering the whole brain-global ROI-based network, seed-based ROI-connectivity, functional consistency, and voxel-to-voxel connectivity-and evaluated the generalizability of the classification in the left-out portion of non-matched data. RESULTS: Full-brain connectivity allowed classification (â¼70 %) of BPD patients vs. controls in matched inner cross-validation. The classification remained significant when applied to unmatched out-of-sample data (â¼61-70 %). Highest seed-based accuracies were in a similar range to global accuracies (â¼70-75 %), but spatially more specific. The most discriminative seed regions included midline, temporal and somatomotor regions. Univariate connectivity values were not predictive of BPD after multiple comparison corrections, but weak local effects coincided with the most discriminative seed-ROIs. Highest accuracies were achieved with a full clinical interview while self-report results remained at chance level. LIMITATIONS: The accuracies vary considerably between random sub-samples of the population, global signal and covariates limiting the practical applicability. CONCLUSIONS: Spatially distributed functional connectivity patterns are moderately predictive of BPD despite heterogeneity of the patient population.
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Trastorno de Personalidad Limítrofe , Encéfalo , Aprendizaje Automático , Imagen por Resonancia Magnética , Humanos , Trastorno de Personalidad Limítrofe/fisiopatología , Trastorno de Personalidad Limítrofe/diagnóstico , Femenino , Adulto , Masculino , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Adulto Joven , Conectoma/métodos , Estudios de Casos y Controles , Mapeo Encefálico/métodosRESUMEN
Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson's disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value-akin to reward prediction errors-whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia's main output structures reflect distinct social context and value signals.
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Dopamina , Enfermedad de Parkinson , Serotonina , Sustancia Negra , Humanos , Serotonina/metabolismo , Dopamina/metabolismo , Sustancia Negra/metabolismo , Masculino , Femenino , Enfermedad de Parkinson/metabolismo , Persona de Mediana Edad , Anciano , Conducta Social , RecompensaRESUMEN
The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations - termed the "transcriptional program associated with neurotransmission" (TPAWN) - were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.
RESUMEN
Recent evidence in animals has indicated that the mesencephalic dopamine system is heterogeneous anatomically, molecularly, and functionally, and it has been suggested that the dopamine system comprises distinct functional systems. Identifying and characterizing these systems in humans will have widespread ramifications for understanding drug addiction and mental health disorders. Model-based studies in humans have suggested an analogous computational heterogeneity, in which dopaminergic targets in striatum encode both experience-based learning signals and counterfactual learning signals that are based on hypothetical information. We used brainstem-tailored fMRI to identify mesencephalic sources of experiential and counterfactual learning signals. Participants completed a decision-making task based on investing in markets. This sequential investment task generated experience-based learning signals, in the form of temporal difference (TD) reward prediction errors, and counterfactual learning signals, in the form of "fictive errors." Fictive errors are reinforcement learning signals based on hypothetical information about "what could have been." An additional learning signal was constructed to be relatable to a motivational salience signal. Blood oxygenation level dependent responses in regions of substantia nigra (SN) and ventral tegmental area (VTA), where dopamine neurons are located, coded for TD and fictive errors, and additionally were related to the motivational salience signal. These results are highly consistent with animal electrophysiology and provide direct evidence that human SN and VTA heterogeneously handle important reward-harvesting computations.
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Simulación por Computador , Toma de Decisiones/fisiología , Dopamina/metabolismo , Aprendizaje/fisiología , Mesencéfalo/fisiología , Modelos Neurológicos , Adulto , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Mesencéfalo/irrigación sanguínea , Persona de Mediana Edad , Oxígeno/sangre , Adulto JovenRESUMEN
Reciprocating exchange with other humans requires individuals to infer the intentions of their partners. Despite the importance of this ability in healthy cognition and its impact in disease, the dimensions employed and computations involved in such inferences are not clear. We used a computational theory-of-mind model to classify styles of interaction in 195 pairs of subjects playing a multi-round economic exchange game. This classification produces an estimate of a subject's depth-of-thought in the game (low, medium, high), a parameter that governs the richness of the models they build of their partner. Subjects in each category showed distinct neural correlates of learning signals associated with different depths-of-thought. The model also detected differences in depth-of-thought between two groups of healthy subjects: one playing patients with psychiatric disease and the other playing healthy controls. The neural response categories identified by this computational characterization of theory-of-mind may yield objective biomarkers useful in the identification and characterization of pathologies that perturb the capacity to model and interact with other humans.