• Keysers C. The straw man in the brain. Science, 2015 Jan 16; 347(6219). doi:10.1126/science.1259030.
  • Valchev N. Zijdewind I. Keysers C. Gazzola V. Avenanti A. Maurits N.M. Weight dependent modulation of motor resonance induced by weight estimation during observation of partially occluded lifting actions. Neuropsychologia. 2014 Nov 25. pii: S0028-3932(14)00450-3. doi: 10.1016/j.neuropsychologia.2014.11.030.
    Seeing others performing an action induces the observers' motor cortex to "resonate" with the observed action. Transcranial magnetic stimulation (TMS) studies suggest that such motor resonance reflects the encoding of various motor features of the observed action, including the apparent motor effort. However, it is unclear whether such encoding requires direct observation or whether force requirements can be inferred when the moving body part is partially occluded. To address this issue, we presented participants with videos of a right hand lifting a box of three different weights and asked them to estimate its weight. During each trial we delivered one transcranial magnetic stimulation (TMS) pulse over the left primary motor cortex of the observer and recorded the motor evoked potentials (MEPs) from three muscles of the right hand (first dorsal interosseous, FDI, abductor digiti minimi, ADM, and brachioradialis, BR). Importantly, because the hand shown in the videos was hidden behind a screen, only the contractions in the actor's BR muscle under the bare skin were observable during the entire videos, while the contractions in the actor's FDI and ADM muscles were hidden during the grasp and actual lift. The amplitudes of the MEPs recorded from the BR (observable) and FDI (hidden) muscle increased with the weight of the box. These findings indicate that the modulation of motor excitability induced by action observation extends to the cortical representation of muscles with contractions that could not be observed. Thus, motor resonance appears to reflect force requirements of observed lifting actions even when the moving body part is occluded from view.
  • Keysers C. Gazzola V. Hebbian learning and predictive mirror neurons for actions, sensations and emotions. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 2014 Apr 28;369(1644):20130175. doi: 10.1098/rstb.2013.0175.
    Spike-timing-dependent plasticity is considered the neurophysiological basis of Hebbian learning and has been shown to be sensitive to both contingency and contiguity between pre- and postsynaptic activity. Here, we will examine how applying this Hebbian learning rule to a system of interconnected neurons in the presence of direct or indirect re-afference (e.g. seeing/hearing one's own actions) predicts the emergence of mirror neurons with predictive properties. In this framework, we analyse how mirror neurons become a dynamic system that performs active inferences about the actions of others and allows joint actions despite sensorimotor delays. We explore how this system performs a projection of the self onto others, with egocentric biases to contribute to mind-reading. Finally, we argue that Hebbian learning predicts mirror-like neurons for sensations and emotions and review evidence for the presence of such vicarious activations outside the motor system.
  • Keysers C. Perrett DI. Gazzola V. Hebbian Learning is about contingency, not contiguity, and explains the emergence of predictive mirror neurons. The Behavioral and Brain Sciences 2014 Apr;37(2):205-6. doi: 10.1017/S0140525X13002343.
    Hebbian Learning should not be reduced to contiguity, as it detects contingency and causality. Hebbian Learning accounts of mirror neurons make predictions that differ from associative learning: Through Hebbian Learning, mirror neurons become dynamic networks that calculate predictions and prediction errors and relate to ideomotor theories. The social force of imitation is important for mirror neuron emergence and suggests canalization.
  • Keysers C. Meffert H. Gazzola V. Reply: Spontaneous versus deliberate vicarious representations: different routes to empathy in psychopathy and autism. Brain. 2014 Apr;137(Pt 4):e273. doi: 10.1093/brain/awt376.
  • Keysers C. Gazzola V. Dissociating the ability and propensity for empathy.Trends in Cognitive Sciences 2014 Apr;18(4):163-6. doi: 10.1016/j.tics.2013.12.011.
    Neuroimaging suggests psychopaths have reduced vicarious activations when simply witnessing pain but less so when asked to empathize. This inspired us to distinguish the ability from the propensity to empathize. We argue that (i) this ability–propensity distinction is crucial to characterizing empathy in psychiatric disorders such as psychopathy and autism, (ii) that costly helping might be best predicted by the propensity for empathy, and (iii) suggest how social neuroscientists can start exploring this distinction.
  • Cui F. Arnstein D. Thomas R. M. Maurits N. M. Keysers C. Gazzola V. Functional Magnetic Resonance Imaging Connectivity Analyses Reveal Efference-Copy to Primary Somatosensory Area, BA2. PLoS One, Jan 2014 9(1): e84367.
    Some theories of motor control suggest efference-copies of motor commands reach somatosensory cortices. Here we used functional magnetic resonance imaging to test these models. We varied the amount of efference-copy signal by making participants squeeze a soft material either actively or passively. We found electromyographical recordings, an efference-copy proxy, to predict activity in primary somatosensory regions, in particular Brodmann Area (BA) 2. Partial correlation analyses confirmed that brain activity in cortical structures associated with motor control (premotor and supplementary motor cortices, the parietal area PF and the cerebellum) predicts brain activity in BA2 without being entirely mediated by activity in early somatosensory (BA3b) cortex. Our study therefore provides valuable empirical evidence for efference-copy models of motor control, and shows that signals in BA2 can indeed reflect an input from motor cortices and suggests that we should interpret activations in BA2 as evidence for somatosensory-motor rather than somatosensory coding alone.
  • Arnstein D. Cui F. Keysers C. Maurits NM. Gazzola V. μ-suppression during action observation and execution correlates with BOLD in dorsal premotor, inferior parietal, and SI cortices. Journal of Neuroscience, Oct 2013 31(40): 14243-14249.
    The discovery of mirror neurons in the monkey, that fire during both the execution and the observation of the same action, sparked great interest in studying the human equivalent. For over a decade, both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) have been used to quantify activity in the human mirror neuron system (MNS)-yet, little is still known about how fMRI and EEG measures of the MNS relate to each other. To test the frequent assumption that regions of the MNS as evidenced by fMRI are the origin of the suppression of the EEG μ-rhythm during both action execution and observation, we recorded EEG and BOLD-fMRI signals simultaneously while participants observed and executed actions. We found that the suppression of the μ-rhythm in EEG covaried with BOLD activity in typical MNS regions, inferior parietal lobe (IPL), dorsal premotor (dPM) and primary somatosensory cortex (BA2), during both action observation and execution. In contrast, in BA44, only nonoverlapping voxels correlated with μ-suppression during observation and execution. These findings provide direct support for the notion that μ-suppression is a valid indicator of MNS activity in BA2, IPL, and dPM, but argues against the idea that mirror neurons in BA44 are the prime source of μ-suppression. These results shed light on the neural basis of μ-suppression and provide a basis for integrating more closely the flourishing but often separate literatures on the MNS using fMRI and EEG.
  • Monfardini E. Gazzola V. Boussaoud D. Brovelli A. Keysers C. Wickers B. Vicarious Neural Processing of Outcomes during Observational Learning. PLoS ONE, 8(9): e73879. doi:10.1371/journal.pone.0073879.
    Learning what behaviour is appropriate in a specific context by observing the actions of others and their outcomes is a key constituent of human cognition, because it saves time and energy and reduces exposure to potentially dangerous situations. Observational learning of associative rules relies on the ability to map the actions of others onto our own, process outcomes, and combine these sources of information. Here, we combined newly developed experimental tasks and functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms that govern such observational learning. Results show that the neural systems involved in individual trial-and-error learning and in action observation and execution both participate in observational learning. In addition, we identified brain areas that specifically activate for others’ incorrect outcomes during learning in the posterior medial frontal cortex (pMFC), the anterior insula and the posterior superior temporal sulcus (pSTS).
  • Engels A. Hijmans B S. Cerliani L. Bangert M. Nanetti L. Keller P E. Keysers C. Inter-individual differences in audio-motor learning of piano melodies and white matter fiber tract architecture. Human Brain Mapping 31 July 2013 [Epub ahead of print].
    Humans vary substantially in their ability to learn new motor skills. Here, we examined inter-individual differences in learning to play the piano, with the goal of identifying relations to structural properties of white matter fiber tracts relevant to audio-motor learning. Non-musicians (n = 18) learned to perform three short melodies on a piano keyboard in a pure audio-motor training condition (vision of their own fingers was occluded). Initial learning times ranged from 17 to 120 min (mean ± SD: 62 ± 29 min). Diffusion-weighted magnetic resonance imaging was used to derive the fractional anisotropy (FA), an index of white matter microstructural arrangement. A correlation analysis revealed that higher FA values were associated with faster learning of piano melodies. These effects were observed in the bilateral corticospinal tracts, bundles of axons relevant for the execution of voluntary movements, and the right superior longitudinal fasciculus, a tract important for audio-motor transformations. These results suggest that the speed with which novel complex audio-motor skills can be acquired may be determined by variability in structural properties of white matter fiber tracts connecting brain areas functionally relevant for audio-motor learning.
  • Meffert H. Gazzola V. den Boer J A. Bartels A A J. Keysers C. Reduced spontaneous but relatively normal deliberate vicarious representations in psychopathy. Brain 2013 136(8) 2550-2562.
    Psychopathy is a personality disorder associated with a profound lack of empathy. Neuroscientists have associated empathy and its interindividual variation with how strongly participants activate brain regions involved in their own actions, emotions and sensations while viewing those of others. Here we compared brain activity of 18 psychopathic offenders with 26 control subjects while viewing video clips of emotional hand interactions and while experiencing similar interactions. Brain regions involved in experiencing these interactions were not spontaneously activated as strongly in the patient group while viewing the video clips. However, this group difference was markedly reduced when we specifically instructed participants to feel with the actors in the videos. Our results suggest that psychopathy is not a simple incapacity for vicarious activations but rather reduced spontaneous vicarious activations co-existing with relatively normal deliberate counterparts.
  • Di Martino A. Yan CG. Li Q. Denio E. Castellanos FX. Alaerts K. Anderson JS. Assaf M. Bookheimer SY. Dapretto M. Deen B. Delmonte S. Dinstein I. Ertl-Wagner B. Fair DA. Gallagher L. Kennedy DP. Keown CL. Keysers C. Lainhart JE. Lord C. Luna B. Menon V. Minshew NJ. Monk CS. Mueller S. Müller RA. Nebel MB. Nigg JT. O'Hearn K. Pelphrey KA. Peltier SJ. Rudie JD. Sunaert S. Thioux M. Tyszka JM. Uddin LQ. Verhoeven JS. Wenderoth N. Wiggins JL. Mostofsky SH. Milham MP. The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Molecular Psychiatry. 18 June, 2013 [epub ahead of print].
    Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) ( Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
  • Mihov Y. Kendrick KM. Becker B. Zschernack J. Reich H. Maier W. Keysers C. Hurlemann R. Mirroring fear in the absence of a functional amygdala. Biological Psychiatry 1 April, 2013 [epub ahead of print].
    From an evolutionary perspective, facial expressions of fear convey highly recognizable emotional signals that serve adaptive functions by promoting survival and reproductive success (1). Current theories of how the brain interprets facial expressions of fear implicate the mirror neuron network (MNN) in echoing the emotional states of others by internal simulation 2 and 3. Originally discovered in the ventral premotor cortex of macaque monkeys 4 and 5, mirror neurons are defined as being responsive to observation and execution of the same actions. Evidence that facial emotion recognition in humans is impaired by damage to MNN-associated cortical regions or the amygdala (6) has stimulated the hypothesis that the amygdala forms an integral component of an emotion MNN 7 and 8. An alternative view holds that the amygdala plays only a supporting role (9), for example, by directing attention to the informative eye region (10), suggesting the emotional MNN could operate independently, without a functional amygdala. To test these hypotheses directly, we studied two 38-year-old female monozygotic twins (patient 1 and patient 2) with equivalent, selective bilateral amygdala calcification damage because of congenital Urbach-Wiethe disease (synonyms hyalinosis cutis et mucosae or lipoid proteinosis; Online Mendelian Inheritance in Man 247100) 11, 12, 13, 14 and 15 and 16 healthy female control subjects (mean age±SD = 35.8±4.6 years). In previous experiments patient 1, but not patient 2, demonstrated preserved recognition of fearful faces and potentiated responses to them in MNN-associated regions suggesting that the MNN might functionally compensate her amygdala damage 14 and 15. We therefore predicted that patient 1, but not patient 2, would exhibit fear-specific supranormal MNN responses in a functional magnetic resonance imaging (fMRI) experiment (experiment 1) probing observation and imitation of dynamic face expressions and hand movements. Furthermore, we expected that if the amygdala forms an essential component of an emotional MNN, then patient 2 would exhibit impaired imitation of fearful faces (experiment 2).
  • Engel A. Bangert M. Horbank B S. Wilkens K. Keller P E.Keysers C. Learning piano melodies in visuo-motor or audio-motor training conditions and the neural correlates of their cross-modal transfer. Neuroimage. 2012 Nov 63(2) 966-78
    To investigate the cross-modal transfer of movement patterns necessary to perform melodies on the piano, 22 non-musicians learned to play short sequences on a piano keyboard by 1) merely listening and replaying (vision of own fingers occluded) or 2) merely observing silent finger movements and replaying (on a silent keyboard). After training, participants recognized with above chance accuracy 1) audio-motor learned sequences upon visual presentation (89±17%), and 2) visuo-motor learned sequences upon auditory presentation (77±22%). The recognition rates for visual presentation significantly exceeded those for auditory presentation (p<.05). fMRI revealed that observing finger movements corresponding to audio-motor trained melodies is associated with stronger activation in the left rolandic operculum than observing untrained sequences. This region was also involved in silent execution of sequences, suggesting that a link to motor representations may play a role in cross-modal transfer from audio-motor training condition to visual recognition. No significant differences in brain activity were found during listening to visuo-motor trained compared to untrained melodies. Cross-modal transfer was stronger from the audio-motor training condition to visual recognition and this is discussed in relation to the fact that non-musicians are familiar with how their finger movements look (motor-to-vision transformation), but not with how they sound on a piano (motor-to-sound transformation).
  • Gazzola V. Spezio M L. Etzel J A. Castelli F. Keysers C. Primary somatosensory cortex discriminates affective significance in social touch. PNAS. 2012 Jun 109(25) E1657-66 
    Another person's caress is one of the most powerful of all emotional social signals. How much the primary somatosensory cortices (SIs) participate in processing the pleasantness of such social touch remains unclear. Although ample empirical evidence supports the role of the insula in affective processing of touch, here we argue that SI might be more involved in affective processing than previously thought by showing that the response in SI to a sensual caress is modified by the perceived sex of the caresser. In a functional MRI study, we manipulated the perceived affective quality of a caress independently of the sensory properties at the skin: heterosexual males believed they were sensually caressed by either a man or woman, although the caress was in fact invariantly delivered by a female blind to condition type. Independent analyses showed that SI encoded, and was modulated by, the visual sex of the caress, and that this effect is unlikely to originate from the insula. This suggests that current models may underestimate the role played by SI in the affective processing of social touch.
  • Lee T M. Sun D. Leung M K. Chu L W. Keysers C. Neural Activities during affective processing in people with Alzheimer's disease. Neurobiology of Aging. 2012 Jul [Epub ahead of print] 
    This study examined brain activities in people with Alzheimer's disease when viewing happy, sad, and fearful facial expressions of others. A functional magnetic resonance imaging and a voxel-based morphometry methodology together with a passive viewing of emotional faces paradigm were employed to compare the affective processing in 12 people with mild Alzheimer's disease and 12 matched controls. The main finding was that the clinical participants showed reduced activations in regions associated with the motor simulation system (the ventral premotor cortex) and in regions associated with emotional simulation—empathy (the anterior insula and adjacent frontal operculum). This regional decline in blood oxygen level-dependent signals appeared to be lateralized in the left hemisphere and was not related to any structural degeneration in the clinical participants. Furthermore, the regions that showed changes in neural activity differed for the 3 emotional facial expressions studied. Findings of our study indicate that neural changes in regions associated with the motor and emotional simulation systems might play an important role in the development of Alzheimer's disease.
  • Keysers C. Copy that. Nature. 2012 Feb 158:158-159
    Clearly, we are different from other primates. I have never seen macaques display anything like a toddler’s eagerness to imitate. The Primate Mind suggests that it may not be the capacity to imitate, but the motivation to do so that sets us apart from other animals. Like all good suggestions, this opens the door to more questions about the mechanisms and evolution of such motivation - and, ultimately, about how our own social minds evolved from the deeply interconnected minds of our primate cousins.
  • Hasson U. Ghazanfar A A. Galantucci B. Garrod S. & Keysers C. Brain-to-brain coupling: a mechanism for creating and sharing a social world. Trends in Cognitive Science. 2012 26(2), 114-121.
    Cognition materializes in an interpersonal space. The emergence of complex behaviors requires the coordination of actions among individuals according to a shared set of rules. Despite the central role of other individuals in shaping one’s mind, most cognitive studies focus on processes that occur within a single individual. We call for a shift from a single-brain to a multi-brain frame of reference. We argue that in many cases the neural processes in one brain are coupled to the neural processes in another brain via the transmission of a signal through the environment. Brain-to-brain coupling constrains and shapes the actions of each individual in a social network, leading to complex joint behaviors that could not have emerged in isolation. 
  • Keysers C. & McKay, L. S. How to Make Social Neuroscience Social. Psychological Inquiry. 2011 22, 210-216.
    In this article we use the recent work of Zaki & Ochsner (2011) as a starting point to explore how social the field of social neuroscience currently is. Zaki and Ochsner argue that there are 2 goals of mind perception; the first being to accurately perceive what goes on in others and the second being to help us interact better with others and be happier. They argue therefore, that instead of simply asking which brain regions are used during mind perception, we should also ask which of these regions lead to accurate mind perception. On this basis they argue that accuracy is the missing ingredient, and that researchers should pay more attention to how accurate we are at understanding the internal states of others. In the current article, we discuss four points that are inspired by the work of Zaki and Ochsner. Firstly we show how systematically inaccurate mind perception can be highly instructive about how people understand the minds of others. Secondly, we offer examples in which experience sharing is perhaps more useful than Zaki and Ochsner assume. Thirdly, we explore the limitations of measuring accuracy based on reports from the targets and observers in an interaction. Lastly, we look at 3 alternative approaches to social neuroscience, that are conceptually different but related to Zaki & Ochsners accuracy research. Together with the work of Zaki & Ochsner, we provide a framework for making future research in the field of social neuroscience truly social. 
  • Cerliani L. Thomas R M. Jbabdi S. Siero J C W. Nanetti L. Crippa A. Gazzola V. D'Arceuil H. Keysers C. Probabilistic tractography recovers a rostrocaudal trajectory of connectivity variability in the human insular cortex. Human Brain Mapping. 2012 33(9), 2005-2034.
    The insular cortex of macaques has a wide spectrum of anatomical connections whose distribution is related to its heterogeneous cytoarchitecture. Although there is evidence of a similar cytoarchitectural arrangement in humans, the anatomical connectivity of the insula in the human brain has not yet been investigated in vivo. In the present work, we used in vivo probabilistic white-matter tractography and Laplacian eigenmaps (LE) to study the variation of connectivity patterns across insular territories in humans. In each subject and hemisphere, we recovered a rostrocaudal trajectory of connectivity variation ranging from the anterior dorsal and ventral insula to the dorsal caudal part of the long insular gyri. LE suggested that regional transitions among tractography patterns in the insula occur more gradually than in other brain regions. In particular, the change in tractography patterns was more gradual in the insula than in the medial premotor region, where a sharp transition between different tractography patterns was found. The recovered trajectory of connectivity variation in the insula suggests a relation between connectivity and cytoarchitecture in humans resembling that previously found in macaques: tractography seeds from the anterior insula were mainly found in limbic and paralimbic regions and in anterior parts of the inferior frontal gyrus, while seeds from caudal insular territories mostly reached parietal and posterior temporal cortices. Regions in the putative dysgranular insula displayed more heterogeneous connectivity patterns, with regional differences related to the proximity with either putative granular or agranular regions.
  • Atsak P, Orre M, Bakker P, Cerliani L, Roozendaal B, Gazzola V. Moita M. Keysers C. (2011) Experience Modulates Vicarious Freezing in Rats: A Model for Empathy. PLoS ONE 6(7): e21855.
    The study of the neural basis of emotional empathy has received a surge of interest in recent years but mostly employing human neuroimaging. A simpler animal model would pave the way for systematic single cell recordings and invasive manipulations of the brain regions implicated in empathy. Recent evidence has been put forward for the existence of empathy in rodents. In this study, we describe a potential model of empathy in female rats, in which we studied interactions between two rats: a witness observes a demonstrator experiencing a series of footshocks. By comparing the reaction of witnesses with or without previous footshock experience, we examine the role of prior experience as a modulator of empathy. We show that witnesses having previously experienced footshocks, but not naïve ones, display vicarious freezing behavior upon witnessing a cage-mate experiencing footshocks. Strikingly, the demonstrator's behavior was in turn modulated by the behavior of the witness: demonstrators froze more following footshocks if their witness froze more. Previous experiments have shown that rats emit ultrasonic vocalizations (USVs) when receiving footshocks. Thus, the role of USV in triggering vicarious freezing in our paradigm is examined. We found that experienced witness-demonstrator pairs emitted more USVs than naïve witness-demonstrator pairs, but the number of USVs was correlated with freezing in demonstrators, not in witnesses. Furthermore, playing back the USVs, recorded from witness-demonstrator pairs during the empathy test, did not induce vicarious freezing behavior in experienced witnesses. Thus, our findings confirm that vicarious freezing can be triggered in rats, and moreover it can be modulated by prior experience. Additionally, our result suggests that vicarious freezing is not triggered by USVs per se and it influences back onto the behavior of the demonstrator that had elicited the vicarious freezing in witnesses, introducing a paradigm to study empathy as a social loop.
  • Thioux M, Keysers C. "Empathy: shared circuits and their dysfunctions." Dialogues Clin Neurosci. 2010;12(4):546-552.
    Observing another individual acting upon an object triggers cerebral activity well beyond the visual cortex of the observer in areas directly involved in planning and executing actions. This we will call action simulation. Importantly, the brain does not solely simulate the actions of others but also the sensations they feel, and their emotional responses. These simulation mechanisms are most active in individuals who report being very empathic. Simulation may indeed be instrumental for our understanding of the emotional and mental state of people in our sight, and may contribute heavily to the social interactions with our peers by providing a first-person perspective on their inner feelings. Simulation mechanisms are at work at an early stage of social development and might be defective in young individuals with autism spectrum disorders (ASD). However, the results to date regarding ASD are not clearcut, and an equal number of studies report positive and negative findings.
  • Schippers MB, Renken R, Keysers C. The effect of intra- and inter-subject variability of hemodynamic responses on group level Granger Causality analyses. Neuroimage. 2011 57(1), 22-36.
    Granger causality analyses aim to reveal the direction of influence between brain areas by analyzing temporal precedence: if a signal change in area A consistently precedes a signal change in area B, then A Granger-causes B. fMRI-based Granger causality inferences are mediated by the hemodynamic response function which can vary across brain regions. This variability might induce a bias in Granger causality analyses. Here we use simulations to investigate the effect of hemodynamic response variability on Granger causality analyses at the level of a group of twenty participants. We used a set of hemodynamic responses measured by [10] and simulated 200 experiments in which time series with known directions of influence are convolved with these hemodynamic responses and submitted to Granger causality analysis. Results show that the average chance to find a significant Granger causality effect when no actual influence is present in the data stays well below the p-level imposed on the second level statistics. Most importantly, when the analyses reveal a significant directed influence, this direction was accurate in the vast majority of the cases. The sensitivity of the analyses however depended on the neuronal delay between the source and target regions and their relative hemodynamic delay. Influences flowing from regions to one with the same or a slower hemodynamic response function were detected in over 80% of the cases when the neuronal delay was at least 100ms. Influences flowing to a region with a faster hemodynamic delay were detected in over 80% of the cases when delays are above 1s.
  • Schippers MB, Keysers C. Mapping the flow of information within the putative mirror neuron system during gesture observation. Neuroimage. 2011 57(1), 37-44. 
    The putative Mirror Neuron System may either function as a strict feed-forward system or as a dynamic control system. A strict feed-forward system would predict that action observation leads to a predominantly temporal→parietal→premotor flow of information in which a visual representation is transformed into motor-programs which contribute to action understanding. Instead, a dynamic feedback control system would predict that the reverse direction of information flow predominates because of a combination of inhibitory forward and excitatory inverse models. Here we test which of these conflicting predictions best matches the information flow within the putative Mirror Neuron System (pMNS) and between the pMNS and the rest of the brain during the observation of comparatively long naturalistic stretches of communicative gestures. We used Granger causality to test the dominant direction of influence. Our results fit the predictions of the dynamic feedback control system:we found predominantly an information flow within the pMNS from premotor to parietal and middle temporal cortices. This is more pronounced during an active guessing task than while passively reviewing the same gestures. In particular, the ventral premotor cortex sends significantly more information to other pMNS areas than it receives during active guessing than during passive observation.
  • Bastiaansen JA, Thioux M, Nanetti L, van der Gaag C, Ketelaars C, Minderaa R, Keysers C. Age-Related Increase in Inferior Frontal Gyrus Activity and Social Functioning in Autism Spectrum Disorder.  Biol Psychiatry. 2011 69(9), 832-838.
    Hypoactivation of the inferior frontal gyrus during the perception of facial expressions has been interpreted as evidence for a deficit of the mirror neuron system in children with autism. We examined whether this dysfunction persists in adulthood, and how brain activity in the mirror neuron system relates to social functioning outside the laboratory.
    Twenty-one adult males with autism spectrum disorders and 21 typically developing subjects matched for age, sex, and IQ were scanned in three conditions: observing short movies showing facial expressions, performing a facial movement, and experiencing a disgusting taste. Symptom severity and level of social adjustment were measured with the Autism Diagnostic Observation Schedule and the Social Functioning Scale.
    Inferior frontal gyrus activity during the observation of facial expressions increased with age in subjects with autism, but not in control subjects. The age-related increase in activity was associated with changes in gaze behavior and improvements in social functioning. These age-related neurocognitive improvements were not found in a group of individuals with schizophrenia, who had comparable levels of social functioning.
    The results of this cross-sectional study suggest that mirror neuron system activity augments with age in autism and that this is accompanied by changes in gaze behavior and improved social functioning. It is the first demonstration of an age-related neurocognitive improvement in autism. Increased motor simulation may contribute to the amelioration in social functioning documented in adolescence and adulthood. This finding should encourage the development of new therapeutic interventions directed at emotion simulation.
  • Quadflieg S, Etzel JA, Gazzola V, Keysers C, Schubert TW, Waiter GD, Macrae CN.B" Puddles, Parties, and Professors: Linking Word Categorization to Neural Patterns of Visuospatial Coding. J Cogn Neurosci. 2011 23(10), 2636-2649
    Behavioral evidence suggests that during word processing people spontaneously map object, valence, and power information to locations in vertical space. Specifically, whereas "overhead" (e.g., attic), positive (e.g., party), and powerful nouns (e.g., professor) are associated with "up," "underfoot" (e.g., carpet), negative (e.g., accident), and powerless nouns (e.g., assistant) are associated with "down." What has yet to be elucidated, however, is the precise nature of these effects. To explore this issue, an fMRI experiment was undertaken, during which participants were required to categorize the position in which geometrical shapes appeared on a computer screen (i.e., upper or lower part of the display). In addition, they also judged a series of words with regard to location (i.e., up vs. down), valence (i.e., good vs. bad), and power (i.e., powerful vs. powerless). Using multivoxel pattern analysis, it was found that classifiers that successfully distinguished between the positions of shapes in subregions of the inferior parietal lobe also provided discriminatory information to separate location and valence, but not power word judgments. Correlational analyses further revealed that, for location words, pattern transfer was more successful in the stronger participants' propensity to use visual imagery. These findings indicate that visual coding and conceptual processing can elicit common representations of verticality but that divergent mechanisms may support the reported effects.
  • Bastiaansen JA, Meffert H, Hein S, Huizinga P, Ketelaars C, Pijnenborg M, Bartels A, Minderaa R, Keysers C, de Bildt A. Diagnosing Autism Spectrum Disorders in Adults: the Use of Autism Diagnostic Observation Schedule (ADOS) Module 4. J Autism Dev Disord 2011, 41(9), 1256-1266.
    Autism Diagnostic Observation Schedule (ADOS) module 4 was investigated in an independent sample of high-functioning adult males with an autism spectrum disorder (ASD) compared to three specific diagnostic groups: schizophrenia, psychopathy, and typical development. ADOS module 4 proves to be a reliable instrument with good predictive value. It can adequately discriminate ASD from psychopathy and typical development, but is less specific with respect to schizophrenia due to behavioral overlap between autistic and negative symptoms. However, these groups differ on some core items and explorative analyses indicate that a revision of the algorithm in line with Gotham et al. (J Autism Dev Disord 37: 613-627, 2007) could be beneficial for discriminating ASD from schizophrenia.
  • Kokal I, Keysers C. Granger causality mapping during joint actions reveals evidence for forward models that could overcome sensory-motor delays. PLoS One. 2010 Oct 21;5(10):e13507.
    Studies investigating joint actions have suggested a central role for the putative mirror neuron system (pMNS) because of the close link between perception and action provided by these brain regions [1], [2], [3]. In contrast, our previous functional magnetic resonance imaging (fMRI) experiment demonstrated that the BOLD response of the pMNS does not suggest that it directly integrates observed and executed actions during joint actions [4]. To test whether the pMNS might contribute indirectly to the integration process by sending information to brain areas responsible for this integration (integration network), here we used Granger causality mapping (GCM) [5]. We explored the directional information flow between the anterior sites of the pMNS and previously identified integrative brain regions. We found that the left BA44 sent more information than it received to both the integration network (left thalamus, right middle occipital gyrus and cerebellum) and more posterior nodes of the pMNS (BA2). Thus, during joint actions, two anatomically separate networks therefore seem effectively connected and the information flow is predominantly from anterior to posterior areas of the brain. These findings suggest that the pMNS is involved indirectly in joint actions by transforming observed and executed actions into a common code and is part of a generative model that could predict the future somatosensory and visual consequences of observed and executed actions in order to overcome otherwise inevitable neural delays.
  • Etzel JA, Valchev N, Keysers C. The impact of certain methodological choices on multivariate analysis of fMRI data with support vector machines. Neuroimage. 2011 Jan 15;54(2):1159-67.
    Multivoxel pattern analysis of functional magnetic resonance imaging (fMRI) data is continuing to increase in popularity. Like all fMRI analyses, these analyses require extensive data processing and methodological choices, but the impact of these decisions on the final results is not always known. This study explores the impact of four methodological choices on analysis outcomes and introduces the technique of partitioning on random runs for characterizing temporal dependencies and evaluating partitioning methods. The analyses were performed on two fMRI data sets, which were repeatedly analyzed with support vector machines, varying the method of temporal compression, smoothing, voxel-wise detrending, and partitioning into training and testing sets. Smoothing sometimes slightly increased classification accuracy. Partitioning other than on the runs increased classification accuracy, and the random runs technique allowed us to attribute this improvement to the increased amount of training data, rather than to bias. The impact of the temporal compression and detrending methods varied so strongly with data set that general recommendations could not be drawn. These interactions suggest that, rather than searching for a universally superior set of methodological choices, researchers must carefully consider each choice in the context of each experiment.
  • Keysers C, Kaas J, Gazzola V."Somatosensation in Social Perception." Nature Reviews Neuroscience. 2010 Jun;11(6):417-28.
    The discovery of mirror neurons in motor areas of the brain has led many to assume that our ability to understand other people’s behaviour partially relies on vicarious activations of motor cortices. This review focuses the limelight of social neuroscience on a different set of brain regions: the somatosensory cortices. These have anatomical connections that enable them to have a role in visual and auditory social perception. Studies that measure brain activity while participants witness the sensations, actions and somatic pain of others consistently show vicarious activation in the somatosensory cortices. Neuroscientists are starting to understand how the brain adds a somatosensory dimension to our perception of other people.
  • Schippers MB, Roebroeck A, Renken R, Nanetti L, Keysers C."Mapping the Information flow from one brain to another during gestural communication". Proc Natl Acad Sci U S A. 2010 May 18;107(20):9388-93.
    Both the putative mirror neuron system (pMNS) and the ventral medial prefrontal cortex (vmPFC) are deemed important for social interaction: the pMNS because it “resonates” with the actions of others, the vmPFC because it is involved in mentalizing. The resonance property of the pMNS has never been investigated and classical fMRI experiments have only investigated whether pMNS regions augment their activity when an action is seen or executed. Here we directly explore whether such resonance occurs during continuous streams of actions. We let participants play the game of charades while we measured brain activity of both gesturer and guesser. We then applied a method to localize directed influences between the brains of the participants: between-brain Granger-causality mapping. Results show that a guesser's brain activity in regions involved in mentalizing and mirroring echoes the temporal structure of a gesturer's brain activity. This provides evidence for resonance theories and indicates a fine-grained temporal interplay between regions involved in motor planning and regions involved in thinking about the mental states of others. This method enables experiments to be more ecologically valid by providing the opportunity to leave social interaction unconstrained. This would allow us to tap into the neural substrates of social deficits such as autism spectrum disorder.
  • Keysers C., Gazzola V. "Social Neuroscience: Mirror Neurons recorded in Humans".Current Biology, 2010,20:8.
    New single-cell recordings show that humans do have mirror neurons, and in more brain regions than previously suspected. Some action–execution neurons were seen to be inhibited during observation, possibly preventing imitation and helping self/other discrimination.
  • Keysers C."Mirror Neurons. Where can I find out more?"Current Biology, 2009, 19:21.An interview and a quick guide about mirror neurons.
  • Keysers C, Gazzola V."Expanding the mirror: vicarious activity for actions, emotions and sensations".Current Opinions in Neurobiology, 2009, 19:1-6.
    The aim of this review is to highlight two developments of the last years about the neural basis of empathy. First, mirror neurons for actions not only exist in the premotor cortex or in monkeys, but also other brain regions and species have similar properties. Second vicarious activity can also be measured for the emotions and sensations of others. Although we still need to empirically explore the function and development of these vicarious activations, we should stop thinking of vicarious brain activity as a peculiar property of the premotor cortex: instead it seems to be a very common phenomenon which leads social stimuli to recruit a wide range of seemingly private neural systems.
  • Perret DI, Xiao D, Barraclough NE, Keysers C, Oram MW."Seeing the future: Natural image sequences produce "anticipatory" neuronal activity and bias perceptual report". Q J Exp Psychol (Colchester). 2009 Nov;62(11):2081-104.
    While most of our work investigates the contributions of simulation to perception, this paper relates human perception to the functioning of cells in the temporal cortex that are engaged in high-level pattern processing. After a review of historical developments concerning the functional organization of cells processing faces and the selectivity for faces in cell responses., this paper focusses on the comparison of perception and cell responses to images of faces presented in sequences of unrelated images. Specifically the cell function and perception in circumstances where meaningful patterns occur momentarily in the context of a naturally or unnaturally changing visual environment. Experience of visual sequences allows anticipation, yet one sensory stimulus also “masks” perception and neural processing of subsequent stimuli. Forward masking has unrecognized benefits for perception because it can transform neuronal activity to make it predictive during natural change.
  • Schippers MB, Gazzola V, Goebel R, Keysers C."Playing Charades in the fMRI: Are Mirror and/or Mentalizing Areas Involved in Gestural Communication?".PlosOne, 2009, 4, Issue 8.
    Spoken language plays an important role in communication between human individuals. Manual gestures however often aid the semantic interpretation of the spoken message, and gestures may have played a central role in the earlier evolution of communication. Here the social game of charades has been used to investigate the neural basis of gestural communication by having participants produce and interpret meaningful gestures while their brain activity was measured using functional magnetic resonance imaging.
  • Kokal I, Gazzola V, Keysers C."Acting together in and beyond the mirror neuron system".Neuroimage. 2009 Oct 1;47(4):2046-56.
    Moving a set dinner table often takes two people, and doing so without spilling the glasses requires the close coordination of the two agents' actions. The mirror neuron system may be the key neural locus of such coordination. Instead, such coordination recruits two separable sets of areas: one that could translate between motor and visual codes and one that could integrate these information to achieve common goals. This finding shows that although the putative mirror neuron system can play a critical role in joint actions by translating both agents' actions into a common code, the flexible remapping of our own actions with those of others required during joint actions seems to be performed outside of the putative mirror neuron system.
  • Nanetti L, Cerliani L, Gazzola V, Renken R, Keysers C."Group analyses of connectivity-based cortical percellation using repeated k-means clustering". Neuroimage. 2009 Oct 1;47(4):1666-77.
    K-means clustering is a popular tool for connectivity-based cortical segmentation using Diffusion Weighted Imaging (DWI) data. Here we show that the output of the algorithm depends on the initial placement of starting points, and that different sets of starting points therefore could lead to different solutions. We found that in both brain regions, repeatedly applying k-means often leads to a variety of rather different cortical based parcellations, that ~256 k-means repetitions are needed to accurately estimate the distribution of possible solutions. We propose a method to employ the variability of clustering solutions to assess the reliability with which certain voxels can be attributed to a particular cluster. In addition, we show that the proportion of voxels that can be attributed significantly to either cluster in the SMA and preSMA is relatively higher than in the insula and discuss how this difference may relate to differences in the anatomy of these regions.
  • Bastiaansen JACJ, Thioux M, Keysers C."Evidence for mirror systems in emotions", Philosophical Transactions of the Royal Society, Biological Sciences, 2009, 364, 2391-2404.
    Why do we feel tears well up when we see a loved one cry? Why do we wince when we see other people hurt themselves? Seeing the emotions of others also recruits regions involved in experiencing similar emotions, although there does not seem to be a reliable mapping of particular emotions onto particular brain regions. Instead, emotion simulation seems to involve a mosaic of affective, motor and somatosensory components. Recent experimental evidence suggests that motor simulation may be a trigger for the simulation of associated feeling states. This mosaic of simulations may be necessary for generating the compelling insights we have into the feelings of others. Through their integration with, and modulation by, higher cognitive functions, they could be at the core of important social functions, including empathy, mind reading and social learning.
  • Joset A. Etzel, Valeria Gazzola, Christian Keysers."An Introduction to Anatomical ROI-based fMRI Classification Analysis", Brain Research, 2009 1282 114-125.
    Modern cognitive neuroscience often thinks at the interface between anatomy and function, hypothesizing that one structure is important for a task while another is not. A flexible and sensitive way to test such hypotheses is to evaluate the pattern of activity in the specific structures using multivariate classification techniques. These methods consider the activation patterns across groups of voxels, and so are consistent with current theories of how information is encoded in the brain: that the pattern of activity in brain areas is more important than the activity of single neurons or voxels. This paper is an introduction to applying classification methods to functional magnetic resonance imaging (fMRI) data, particularly for region of interest (ROI) based hypotheses.
  • Onur O, Walter H, Schlaepfer Th, Rehme A, Schmidt C, Keysers C, Maier W, Hurlemann R. "Noradrenergic ehancement of amygdala responses to fear", Social Cognitive and Affective Neuroscience. 2009. 4(2) 119-126.
    Multiple lines of evidence implicate the basolateral amygdala (BLA) and the noradrenergic (norepinephrine, NE) system in responding to stressful stimuli such as fear signals, suggesting hyperfunction of both in the development of stress-related pathologies including anxiety disorders. However, no causative link between elevated NE neurotransmission and BLA hyperresponsiveness to fear signals has been established to date in humans. To determine whether or not increased noradrenergic tone enhances BLA responses to fear signals, we used functional magnetic resonance imaging (fMRI) and a strategy of pharmacologically potentiating NE neurotransmission in healthy volunteers. 18 subjects were scanned two times on a facial emotion paradigm and given either a single-dose placebo or 4 mg of the selective NE reuptake inhibitor reboxetine 2 h prior to an fMRI session. We found that reboxetine induced an amygdala response bias towards fear signals that did not exist at placebo baseline. This pharmacological effect was probabilistically mapped to the BLA. Extrapolation of our data to conditions of traumatic stress suggests that disinhibited endogenous NE signaling could serve as a crucial etiological contributor to post-traumatic stress disorder (PTSD) by eliciting exaggerated BLA responses to fear signals.
  • Mbemba Jabbi, Christian Keysers."Inferior Frontal Gyrus Activity Triggers Anterior Insula Response to Emotional Facial Expressions", Emotion 2008, 8(6), 775-780.
    The observation of movies of facial expressions of others has been shown to recruit similar areas involved in experiencing one’s own emotions: the inferior frontal gyrus (IFG), the anterior insula and adjacent frontal operculum (IFO). The causal link between activity in these 2 regions, associated with motor and emotional simulation, respectively, has remained unknown. Here using psychophysiological interaction and Granger Causality Modeling, we show that activity in the IFO is causally triggered by activity in the IFG, and that this effective connectivity is specific to the IFG. These findings shed new light on the intricate relationship between motor and affective components of emotional empathy.
  • Del Giudice M, Manera V, Keysers C. "Programmed to learn? The ontogeny of mirror neurons". Developmental Science, 2008, 12(2), 350-363.
    We add a new element to the idea that mirror neurons result from Hebbian learning by suggesting that the infant's perceptual-motor system is optimized to provide the brain with the correct input for Hebbian learning. We review evidence that infants have a marked visual preference for hands, show cyclic movement patterns with a frequency that could be in the optimal range for enhanced Hebbian learning, and show synchronized theta EEG in mirror cortical areas during self- observation of grasping. These conditions allow mirror neurons for manual actions to develop quickly and reliably through experiential canalization. This hypothesis provides a plausible pathway for the emergence of mirror neurons that integrates learning with genetic pre-programming, suggesting research on the link between synaptic processes and behaviour in ontogeny.
  • Kukolja j, Schlapfer TE, Keysers C, Klingmuller D, Maier W, Fink G, Hurlemann R. "Modeling a Negative Response Bias in the Human Amygdala by Noradrenergic-Clucocorticoid Interactions". Journal of Neuroscience, November 26, 2008- 28(48):12868-12876.
    An emerging theme in the neuroscience of emotion is the question how acute stress shapes and distorts social behavior. Acute stress leads to increased levels of norepinephrine (NE) and cortisol (CORT), and seem to influence amygdala responses to social-emotional stimuli. Here we show a causative role of NE-CORT interaction on the way the brain processes the emotions of others: the amygdala, which is not selective for negative emotions under placebo conditions, does respond most to negative emotions while under the influence of NE and CORT.
  • Valeria Gazzola and Christian Keysers, "The Observation and Execution of Actions Share Motor and Somatosensory Voxels in all tested Subjects: Single Subject Analyses of Unsmoothed fMRI Data". Cerebral Cortex, 2008. 19(6), 1239-1255.
    This study provides a more detailed description of the location and reliability of shared voxels (sVx), underlining the importance of somatosensory cortices in motor simulation, and proposes a model that extends the original idea of the mirror neuron system to include forward and inverse internal models and somatosensory simulation, distinguishing the MNS from a more general concept of shared Voxels.
  • Christian Keysers & Luciano Fadiga (Editors, 2008), Special Issue: The Mirror Neuron System. Social Neuroscience, 3/4
    This special issue of the journal Social Neuroscience explores some of the most exciting questions surrounding the mirror system: What does the mirror system code? Where is it located? How does it develop? How is the mirror system embedded into the mosaic of circuits that compose our brain? How does the mirror system contribute to communication, language and social interaction? Can the principle of mirror neurons be extended to emotions, sensations and thoughts?
  • Etzel JA, Gazzola V, Keysers C, "Testing Simulation Theory with Cross-Modal Multivariate Classification of fMRI Data". PlosOne, 2008, 3(11), e3690.
    Critical to the idea of simulation is the fact that the pattern of activity in premotor and parietal areas is similar between action execution and action perception. Here we show that if we train a pattern classifier to distinguish the sound of hand and mouth actions based on either premotor (BA44/6) or posterior parietal activity, it can tell hand and mouth actions apart while participants execute these two classes of actions. This is therefore the first demonstration that we do not only activate the same brain areas during action execution and perception, but that the pattern of activity is indeed similar enough to support simulation theories.
  • Jabbi M, Bastiaansen J, Keysers C. "A Common Anterior Insula Representation of Disgust Observation, Experience and Imagination Shows Divergent Functional Connectivity Pathways". PlosOne, 2008, 3(8), e2939.
    Humans can achieve vivid emotional feeling states in the absence of actual emotional encounters in a myriad of ways. Here we show that the Insula and adjacent frontal operculum, which we have shown previously to respond to the sight and experience of disgust, also becomes active while reading a disgusting story, showing how imagination and text can be plugged into our mirror system for emotions.
  • Christian Keysers & Luciano Fadiga, "The mirror system: New frontiers". Social Neuroscience, 2008, 3, 193-198.
    As an introduction to a special issue of Social Neuroscience, we review briefly what we know about the mirror system and point out what we believe to be some of the new frontiers of the study of neuroscience: What does the mirror system code? How is the mirror system embedded into the mosaic of circuits that compose our brain? How does the mirror system contribute to communication, language and social interaction? Can the principle of mirror neurons be extended to emotions, sensations and thoughts? Papers using a wide range of methods, including single cell recordings, fMRI, TMS, EEG and psychophysics, collected in the remainder of that special issue, start to give us some impressive answers.
  • Thioux M, Gazzola V, Keysers C, "Action Understanding: How, What and Why", Current Biology. 2008. 18(10), R431-R434.
    This study shows that our action perception system is highly integrated. Visual areas and regions of the mirror neuron system computing “how”and “what”are likely to be as important as mentalizing areas, for understanding “why”. Also a split between “how”and “what” between visual areas and mirror neuron system is artificial. All mirror neurons need visual input and different mirror neurons represent both “how”and “what”.
  • van der Gaag C, Minderaa R, Keysers C, "Facial expressions: What the mirror neuron system can and cannot tell us", Social Neuroscience. 2007. 2,179-222.
    Here we show that observing facial expressions recruits a circuit composed of temporal, parietal and inferior frontal regions that are also active while subjects execute similar facial expressions. The inferior frontal and temporal nodes of this putative mirror system were selectively more active during the viewing of emotional facial expressions than other control stimuli including moving patterns and neutral facial expressions. Such activations were found in 3 separate experiments, including passive viewing, an emotion discrimination and imitation task, suggesting that the putative mirror system for facial expressions is spontaneously active. We failed to find brain areas that reliably discriminate between different facial expressions during both observation and execution.
  • Gazzola V, van der Worp H, Mulder T, Wicker B, Rizzolatti G, Keysers C "Aplasics born without hands mirror the goal of hand actions with their feet", Current Biology. 2007. 17(14), 1235-1240.
    While it is generally assumed that the sight of actions activates corresponding motor representations in the observer, what 'corresponding' really means remained unclear. Here we show that subjects born without hands and arms activate a combination of effector independent motor representations and motor representations of their foot actions while observing the hand actions of other individuals. These activations are as strong as those of control subjects, suggesting that the mirror system transforms the goal of hand actions into motor representation with similar goals despite differences in effectors. This finding may help understand why non-human primates with mirror systems do not imitate the way in which an action is performed despite their ability to learn to achieve a goal through observation. By showing that mirroring is thus a subjective interpretation of the actions of others in terms of our own, personal motor programs even if these deviate significantly from those observed, we both show the remarkable flexibility of the mirror system and the fact that rather than being an accurate mirror of other people's behaviour, the mirror system performs an interpretation, that may also introduce the potential for misinterpretation. Supplemental Material
  • Keysers C and Gazzola V "Integrating simulation and theory of mind: from self to social cognition". Trends in Cognitive Sciences. 2007. 11(5), 194-196.
    In this article we propose how simulation and ToM could work together based on the idea that regions in the medial prefrontal cortex that introspect our own states could reflect about the states of others by introspecting the simulated states of others induced by mirror like systems
  • van der Gaag C, Minderaa R, Keysers C, "The BOLD signal in the amygdala does not differentiate between dynamic facial expressions", Social Cognitive and Affective Neuroscience. 2007. 2(2) 93-103.
    In this article we show that the amygdala responds similarly to movies of happy, fearful, disgusted and neutral facial expressions, suggesting that fear selectivity in the amygdala might be an artifact of using static images in previous studies
  • Gazzola V, Rizzolatti G, Wicker B, Keysers C, "The Anthropomorphic Brain: the mirror neuron system responds to human and robotic actions", NeuroImage. 2007. 35(4). 1674-1684.
    In this article we show that the mirror system responds also to the actions of robots. This suggests that the mirror system matches the goal of an action and not its kinematic details
  • Jabbi M., Swart M., Keysers C, "Empathy for positive and negative emotions in the gustatory cortex", Neuroimage 2007 34(4), 1744-1753, 744-53.
    In this article we show that activations in the anterior insula during the observation of the emotions of others correlate with empathy, and that the insula responds both to the sight of positive and negative emotions
  • Gazzola V, Aziz-Zadeh L, Keysers C, "Empathy and the somatotopic auditory mirror system in humans", Current Biology. 2006. 16:1824-9.
    In this article we show that action programs in the premotor cortex become activated both by the vision and the sound of the actions of others in a somatotopical matter. Most importantly, we show a link between empathy and the mirror system: more empathic individuals activate their mirror system more while listening to the actions of others.
  • Keysers C, Gazzola V, "Towards a unifying neural theory of social cognition", Progress in Brain Research. 2006. 16(18), 1824-1829.
    In this article we provide a framework in which we combine our data on the observation/listening of actions, sensations and emotions with patient lesion data to propose a parsimonious hypothesis on the neural basis of social cognition. We examine the responses of that system to non-human agents and discuss the relationship between ToM and simulation.
  • Gallese V, Keysers C, Rizzolatti G, "A unifying view of the basis of social cognition", Trends in Cognitive Sciences. 2004. 8, 396-403.
    In this article we provide a unifying neural hypothesis on how individuals understand the actions and emotions of others. Our main claim is that the fundamental mechanism at the basis of the experiential understanding of others' actions is the activation of the mirror neuron system. A similar mechanism, but involving the activation of viscero-motor centers, underlies the experiential understanding of the emotions of others.
  • Keysers C, Wicker B, Gazzola V, Anton JL, Fogassi L, Gallese V. "A touching sight: SII/PV activation during the observation and experience of touch", Neuron. 2004. 42, 335-346.
    Watching the movie scene in which a tarantula crawls on James Bond's chest can make us literally shiver-as if the spider crawled on our own chest. What neural mechanisms are responsible for this "tactile empathy"? The observation of the actions of others activates the premotor cortex normally involved in the execution of the same actions. If a similar mechanism applies to the sight of touch, movies depicting touch should automatically activate the somatosensory cortex of the observer. Here we found using fMRI that the secondary but not the primary somatosensory cortex is activated both when the participants were touched and when they observed someone or something else getting touched by objects. The neural mechanisms enabling our own sensation of touch may therefore be a window also to our understanding of touch.
  • Keysers C, Perrett DI, "Demystifying social cognition: a Hebbian perspective", Trends in Cognitive Sciences. 2004. 8, 501-507.For humans and monkeys, understanding the actions of others is central to survival. Here we review the physiological properties of three cortical areas involved in this capacity: the STS, PF and F5. Based on the anatomical connections of these areas, and the Hebbian learning rule, we propose a simple but powerful account of how the monkey brain can learn to understand the actions of others by associating them with self-produced actions, at the same time discriminating its own actions from those of others. As this system appears also to exist in man, this network model can provide a framework for understanding human social perception.
  • Keysers C, Kohler E, Umilta MA, Nanetti L, Fogassi L, Gallese V."Audiovisual mirror neurons and action recognition", Experimental Brain Research. 2003. 153, 628-636.
    Many object-related actions can be recognized both by their sound and by their vision. Here we describe a population of neurons in the ventral premotor cortex of the monkey that discharge both when the animal performs a specific action and when it hears or sees the same action performed by another individual. These 'audiovisual mirror neurons' therefore represent actions independently of whether these actions are performed, heard or seen. The magnitude of auditory and visual responses did not differ significantly in half the neurons. A neurometric analysis revealed that based on the response of these neurons, two actions could be discriminated with 97% accuracy.
  • Wicker B, Keysers C, Plailly J, Royet JP, Gallese V, Rizzolatti G. "Both of us disgusted in My Insula: The common neural basis of seeing and feeling disgust", Neuron. 2004. 40, 655-664.
    What neural mechanism underlies the capacity to understand the emotions of others? Does this mechanism involve brain areas normally involved in experiencing the same emotion? We performed an fMRI study in which participants inhaled odorants producing a strong feeling of disgust. The same participants observed video clips showing the emotional facial expression of disgust. Observing such faces and feeling disgust activated the same sites in the anterior insula and to a lesser extent in the anterior cingulate cortex. Thus, as observing hand actions activates the observer's motor representation of that action, observing an emotion activates the neural representation of that emotion. This finding provides a unifying mechanism for understanding the behaviors of others.
  • Kohler E, Keysers C, Umilta MA, Fogassi L, Gallese V, Rizzolatti G, "Hearing sounds, understanding actions: Action representation in mirror neurons", Science. 2002. 297, 846-848.
    Many object-related actions can be recognized by their sound. We found neurons in monkey premotor cortex that discharge when the animal performs a specific action and when it hears the related sound. Most of the neurons also discharge when the monkey observes the same action. These audiovisual mirror neurons code actions independently of whether these actions are performed, heard, or seen. This discovery in the monkey homolog of Broca's area might shed light on the origin of language: audiovisual mirror neurons code abstract contents - the meaning of actions - and have the auditory access typical of human language to these contents.
  • Gallese V, Keysers C, "Mirror neurons: A sensorimotor representation system", Behavioral and Brain Sciences. 2001. 24, 983.
    Positing the importance of sensorimotor contingencies for perception is by no means denying the presence and importance of representations. Using the evidence of mirror neurons we will show the intrinsic relationship between action control and representation within the logic of forward models.
  • Umilta MA, Kohler E, Gallese V, Fogassi L, Fadiga L, Keysers C, Rizzolatti G, "I know what you are doing: A neurophysiological study", Neuron. 2001. 31, 155-165.
    In the ventral premotor cortex of the macaque monkey, there are neurons that discharge both during the execution of hand actions and during the observation of the same actions made by others (mirror neurons). In the present study, we show that a subset of mirror neurons becomes active during action presentation and also when the final part of the action, crucial in triggering the response in full vision, is hidden and can therefore only be inferred. This implies that the motor representation of an action performed by others can be internally generated in the observer's premotor cortex, even when a visual description of the action is lacking. The present findings support the hypothesis that mirror neuron activation could be at the basis of action recognition.

Key publications on The rapid visual processing of biological stimuli:

  • Edwards R, Xiao DK, Keysers C, Foldiak P, Perrett D. "Color sensitivity of cells responsive to complex stimuli in the temporal cortex", Journal of Neurophysiology, 2003. 90, 1245-1256.
    The inferotemporal (IT) cortex of the monkey lies at the head of the ventral visual pathway and is known to mediate object recognition and discrimination. It is often assumed that color plays a minor role in the recognition of objects and faces because discrimination remains highly accurate with black-and-white images. Furthermore it has been suggested that for rapid presentation and reaction tasks, object classification may be based on a first wave of feedforward visual information, which is coarse and achromatic. The fine detail and color information follows later, allowing similar stimuli to be discriminated. To allow these theories to be tested, this study investigates whether the presence of color affects the response of IT neurons to complex stimuli, such as faces, and whether color information is delayed with respect to information about stimulus form in these cells. Color, achromatic, and false-color versions of effective stimuli were presented using a rapid serial visual presentation paradigm, and responses recorded from single cells in IT of the adult monkey. Achromatic images were found to evoke significantly reduced responses compared with color images in the majority of neurons (70%) tested. Differential activity for achromatic and colored stimuli was evident from response onset with no evidence to support the hypothesis that information about object color is delayed with respect to object form. A negative correlation ( P < 0.01) was found between cell latency and color sensitivity, with the most color-sensitive cells tending to respond earliest. The results of this study suggest a strong role for color in familiar object recognition and provide no evidence to support the idea of a first wave of form processing in the ventral stream based on purely achromatic information.
  • Foldiak P, Xiao DK, Keysers C, Edwards R, Perrett DI, "Rapid serial visual presentation for the determination of neural selectivity in area STSa", Roots of Visual Awareness. 2003. 144, 107-116.
    We show that rapid serial visual presentation (RSVP) in combination with a progressive reduction of the stimulus set is an efficient method for describing the selectivity properties of high-level cortical neurons in single-cell electrophysiological recording experiments. Rapid presentation allows the experimental testing of a significantly larger number of stimuli, which can reduce the subjectivity of the results due to stimulus selection and the lack of sufficient control stimuli. We prove the reliability of the rapid presentation and stimulus reduction methods by repeated experiments and the comparison of different testing conditions. Our results from neurons in area STSa of the macaque temporal cortex provide a well-controlled confirmation for the existence of a population of cells that respond selectively to stimuli containing faces. View tuning properties measured using this method also confirmed earlier results. In addition, we found a population of cells that respond reliably to complex non-face stimuli, though their tuning properties are not obvious.
  • Keysers C, Perrett DI. "Visual masking and RSVP reveal neural competition", Trends in Cognitive Sciences. 2002. 6, 120-125.
    A test visual stimulus is harder to recognize when another stimulus is presented in close temporal vicinity; presenting stimuli in close spatial vicinity of a test stimulus reduces its visibility; presenting a stimulus to one eye can render invisible another stimulus presented to the other eye; and perceiving one interpretation of an ambiguous image prevents the simultaneous perception of other visual interpretations. A single, neurophysiological theory, which may be called 'neural competition' might explain all these phenomena: when two alternative neural visual representations co-exist in the brain,they compete against each other.
  • Baker CI, Keysers C, Jellema T, Wicker B, Perrett DI, "Neuronal representation of disappearing and hidden objects in temporal cortex of the macaque", Experimental Brain Research. 2001. 140, 375-381.
    Neurons in the anterior regions of the banks of the superior temporal sulcus (STSa) of the macaque monkey respond to the sight of biologically significant stimuli such as faces, bodies and their motion. In this study the responses of STSa neurons were recorded during the gradual occlusion of the experimenter and other mobile objects behind screens at distances of 0.5-4 in from the monkeys. The experimenter or other object remained out of sight for 3-15 s before emerging back in to view. We describe a population of neurons (n=33) showing increased activity during the occlusion of objects that was maintained for up to 11 s following complete occlusion (when only the occluder itself was visible). This increase in activity was selective for the position of the occlusion within the testing room. Many neurons showed little or no change in activity prior to occlusion when the object or experimenter was completely in view. By coding for the presence and location of recently occluded objects, these responses may contribute to the perceptual capacity for object permanence.
  • Keysers C, Xiao DK, Foldiak P, Perrett DI, "The speed of sight", Journal of Cognitive Neuroscience. 2001. 13, 90-101.
    Macaque monkeys were presented with continuous rapid serial visual presentation (RSVP) sequences of unrelated naturalistic images at rates of 14-222 msec/image, while neurons that responded selectively to complex patterns (e.g., faces) were recorded in temporal cortex. Stimulus selectivity was preserved for 65% of these neurons even at surprisingly fast presentation rates (14 msec/image or 72 images/sec). Five human subjects were asked to detect or remember images under equivalent conditions, Their performance in both tasks was above chance at all rates (14-111 msec/image). The performance of single neurons was comparable to that of humans anti responded in a similar way to changes in presentation rate, The implications for the role of temporal cortex cells in perception are discussed.

Dissertations of the Social Brain Lab

  • Atsak, Piray (2012) Stress and cognition : mechanisms regulating memory and empathy.
    Stress kan cognitie op vele manieren beïnvloeden. Het is algemeen bekend dat niet al onze herinneringen even sterk zijn. Emotionele en traumatische levenservaringen worden beter opgeslagen in ons geheugen dan alledaagse gebeurtenissen. Daartegenover is het bekend dat stress juist het oproepen van eerder aangeleerde informatie uit ons geheugen kan verminderen. Voorbeelden van dit verschijnsel zijn de moeilijkheden die we kunnen hebben met het herinneren van simpele informatie tijdens een stressvol examen of sollicitatiegesprek. Eerder onderzoek heeft aangetoond dat stresshormonen (glucocorticoïden en adrenaline) die vrijkomen uit de bijnieren tijdens stressvolle gebeurtenissen een belangrijke rol spelen bij beide processen. Van oudsher is bekend dat glucocorticoïdhormonen werken via een langzaam mechanisme door middel van het beïnvloeden van genexpressie. Recent onderzoek heeft echter bewezen dat er ook hele snelle, niet-genomische glucocorticoïd effecten zijn. Maar het mechanisme dat hier achter zit is nauwelijks bekend. De resultaten van dit proefschift tonen aan dat het endocannabinoïde systeem, een snelwerkend lipide systeem in de hersenen, vooral bekend vanwege de psychoactieve effecten van cannabis, onmisbaar is bij deze snelle geheugeneffecten van glucocorticoïden. Deze bevindingen kunnen niet alleen leiden tot nieuwe inzichten bij het bestrijden van emotionele of traumatische geheugenprocessen in mensen met een post-traumatische stressstoornis maar kunnen mogelijk ook verklaren waarom het gebruik van cannabis zo hoog is in mensen met traumatische levenservaringen.
  • Meffert, Harma (2012) Empathy under arrest? : functional and structural neural correlates of empathy in psychopathy.
    Om interacties met anderen goed te laten verlopen, is het belangrijk dat we begrijpen wat zij doen en ervaren. Uit onderzoek is gebleken dat een van de mogelijke mechanismen hierachter ligt in het ‘heractiveren’van hersengebieden - die we gebruiken om acties uit te voeren en emoties en aanrakingen te ervaren - wanneer we anderen waarnemen die deze handelingen uitvoeren of emoties en aanrakingen ervaren. Deze ‘heractivatie’ van hersengebieden zou ons een soort privé ervaring van het gevoel van een ander kunnen geven. Neem als voorbeeld van de pijn die we zelf voelen, wanneer we iemand anders zien die zich in de vinger snijdt. In dit proefschrift onderzochten we het neurale mechanisme dat hieraan ten grondslag ligt bij een groep mensen gediagnosticeerd met psychopathie. Een belangrijk kenmerk van deze mentale stoornis is het verminderd vermogen om mee te voelen met de emoties van anderen en deze te herkennen. Wij hebben in dit onderzoek bekeken of dit samenhangt met een vermindere activatie van de hersengebieden voor emoties, acties en sensaties, wanneer mensen met psychopathie kijken naar andere mensen die iets meemaken. De resultaten van dit proefschrift suggereren dat psychopathie niet zozeer een onvermogen is om deze gebieden te activeren, maar wel dat zij dit spontaan minder sterk doen. Aangezien het de eerste keer is dat soortgelijk onderzoek is uitgevoerd bij deze doelgroep, zullen de resultaten nog moeten worden geverifieerd in vervolgonderzoek. Deze informatie zou dan mogelijk kunnen leiden tot alternatieve therapeutische strategieën.
  • Jojanneke Bastiaansen (2011) Neural correlates of emotion processing in autism, schizophrenia, and mental health.
    Humans can feel tears well up when they see a loved one cry, and often wince when they see other people hurt themselves. In this thesis, we investigate whether this entwining of emotion perception and emotion experience is also evident at the level of the brain. Does our brain mirror the images of other people’s emotions? And what happens in people with autism and schizophrenia, who often experience difficulties in understanding other people’s emotions? In what respect do these disorders mirror each other and in what respect do they differ? To this end, we use behavioral observation, measures of social cognition and social function, and functional magnetic resonance imaging (fMRI) mainly focused on the perception of facial displays of emotion. The unique combination of autism and schizophrenia in the reported studies will generate more knowledge on these disorders and on possible neural mechanisms underlying social dysfunction. These insights could provide important pointers for the development of more effective therapies.
  • Idil Kokal (2011) When we move together: the neural correlates of joint action.
    Moving a set dinner table often takes two people, and doing so without spilling the glasses requires the close coordination of the two agents' actions. With the current thesis we aimed at investigating how our brain processes true social interactions in which a participant directly interacts with another agent. We investigated a range of joint actions in a series of functional magnetic resonance imaging (fMRI) experiments in which our participants (1) engaged in joint actions with an experimenter standing next to them during a cooperation game, (2) played the same cooperation game with a computer and (3) drummed a simple rhythm with a drum partner. In addition, we employed Granger causality mapping (GCM) to test the contribution of the Mirror Neuron System (MNS) to joint actions. Besides, we took the line of research investigating joint action one crucial step further by exploring the continuum from action to social behavior. Recently, interest in the behavioral effects of music making as a collective activity has surged. Many studies have demonstrated a link between joint action in musical context and a change in future social behavior. In the last chapter of this thesis we investigated this link with fMRI by measuring the neural processes associated with synchronized drumming in a reward area, caudate, and testing the effects of drumming together on prosocial behavior.
  • Marleen Scheepers (2011) Brains in Action.
    Over the decades, two important networks in the brain have been identified about how people interact: the mirror system and the mentalizing network. This thesis investigates how these networks work together during social interaction. We performed an experiment in which brain activity of two persons was measured while they engaged in a social communication game (Charades). Results showed that the mirror system is highly involved during the game, while the main mentalizing area does not show any involvement. We then extended a connectivity analysis, Granger causality, which is usually applied within one brain, to a between-brain analysis. With this method, we used brain activity of the gesturer to map regions in the brain of the guesser, whose brain activity has a Granger-causal relation to that of the gesturer. The mirror system of the gesturer shows a Granger-causal relation to the mirror system of the guesser, but also to the main mentalizing area of the guesser. This means that, even while this mentalizing area does not show involvement when analyzed using a classic method, it does show a temporal relationship with the brain activity of the gesturer. We furthermore performed simulations to investigate a possible confound of Granger causality: inter- and intrasubject variability in hemodynamic responses. Results show high sensitivity and accuracy for Granger causality between-brains, while sensitivity of within-brain Granger causality remains low. However, if a Grangercausality is found, this indicates the correct underlying direction in 80% of the cases. Finally, we used within-brain Granger causality to investigate how areas in the mirror system influence each other during gesturing and guessing.
  • Valeria Gazzola (2007) Action in the Brain: Shared neural circuits for action observation and execution.
    Hearing rhythmic steps and music coming from above we might feel that the neighbors are having a dance party. Frequently, such guesses will be right. What are the neural bases of such spontaneous understanding? Gallese and colleagues found mirror neurons in the premotor cortex of macaques that discharge both when the monkey performs an action and when it sees another individual acting similarly. Those neurons appear to translate what the monkey observes into the way in which it would perform a similar act. Despite the lack of single cell recording in the human premotor cortex, a similar system seems to exist in humans: using functional magnetic resonance imaging, we found that when seeing or hearing someone else s actions participants activate the same regions involved in executing similar acts (premotor, parietal and temporal). The action s goal is a key aspect translated by the system: while observing someone else grasping a glass with the hand, individuals born without arms recruit regions involved in their own way of grasping the glass - their foot  while observers that do have hands also activate areas specifically controlling the hand. We show that the sight of an industrial robot also activates the same circuit suggesting why robots in Star Wars are so engaging. Sharing goals provides a tool for interpreting the behavior of organisms even if their bodies differ from ours. Although every participant shared observed acts, more empathic individuals activated this system more strongly. A similar system seems to exist also for sensation and emotion
  • Christiaan van der Gaag (2007) "Face Value: The neural mechanisms of the social meaning of faces studied with fMRI"
    Abstract Not Available
  • Mbemba Jabbi (2007) "Integrating the Homeostatic Imbalances Genetics and Physiology of Stress and the Emotions"
    Abstract Not Available