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Pre-registration of an online study on differences in affective and cognitive empathy towards children's emotions between childless men, first-time fathers, and fathers.

Psychopathy is a neurodevelopmental disorder that has a highly deleterious effect upon both individuals and society at large. Psychopaths grossly neglect and disrespect the interests of others. Their antisocial behavior is thought to originate from a lack of empathy. However, empathy is multidimensional in nature, as evidenced by the considerable heterogeneity in extant theorizing on the subject. Here, we present the "Zipper model of empathy" that reconsiders how both its affective and cognitive components converge in mature empathic behavior. Furthermore, the Zipper model of empathy is expedient for explaining the empathy deficits in psychopathy, insofar as it brings together current theories on the dysfunctional affective components of empathy, violence inhibition, and automatic versus goal-directed attention. According to the literature, the neurobiological underpinnings of these theories are amygdala-centered; however, this article traces this specifically to the basolateral and central amygdala subregions. When viewed together, the cognitive and affective components of empathy are zipped together in a natural fashion in healthy empathic behavior, whereas psychopaths leave the zipper substantially unzipped in pursuit of their purely self-centered goals.

For almost fifteen years, the availability and regulatory acceptance of new approach methodologies (NAMs) to assess the absorption, distribution, metabolism and excretion (ADME/biokinetics) in chemical risk evaluations are a bottleneck. To enhance the field, a team of 24 experts from science, industry, and regulatory bodies, including new generation toxicologists, met at the Lorentz Centre in Leiden, The Netherlands. A range of possibilities for the use of NAMs for biokinetics in risk evaluations were formulated (for example to define species differences and human variation or to perform quantitative in vitro-in vivo extrapolations). To increase the regulatory use and acceptance of NAMs for biokinetics for these ADME considerations within risk evaluations, the development of test guidelines (protocols) and of overarching guidance documents is considered a critical step. To this end, a need for an expert group on biokinetics within the Organisation of Economic Cooperation and Development (OECD) to supervise this process was formulated. The workshop discussions revealed that method development is still required, particularly to adequately capture transporter mediated processes as well as to obtain cell models that reflect the physiology and kinetic characteristics of relevant organs. Developments in the fields of stem cells, organoids and organ-on-a-chip models provide promising tools to meet these research needs in the future.

Childhood trauma fundamentally shapes social cognition and basic processing of social cues, which frequently cascade into adverse behavioral outcomes. Recent studies indicate that epigenetic changes in oxytocin functioning might contribute to these long-term effects, although a deeper understanding of the underlying mechanisms is still lacking. The electroencephalographic N170 response to faces might capture a neural response at the core of these interactive effects of oxytocin gene methylation and childhood adversity, given that this response is considered to reflect fundamental face processing, to be susceptible to oxytocin administration and also to be a biomarker of various psychiatric disorders. We assessed the N170 response to neutral faces in relation to participant's (81, women) recalled childhood trauma, methylation of their oxytocin structural (OXTg) and oxytocin receptor (OXTRg) genes, and endogenous levels of cortisol and testosterone. Additionally, we investigated the interactive effect of OXTg methylation and CTQ across three face sets of varying maturity. Methylation of OXTg relates to a weakened N170 response towards adults, children and infants. Moreover, methylation of both OXTRg and OXTg shaped the directionality of adversity effects, predicting a weakened N170 response in those with high methylation and hyper-vigilance with participants with low methylation. Our results are the first to relate OXT(R)g methylation to the N170 response. They shed light on biological processes linking childhood adversity and epigenetic marks to altered behavior and potentially psychopathologies.

Empathy is an essential component of sensitive caregiving behavior, which in turn is an important predictor of children's healthy social-emotional development. The oxytocin (OXT) system plays a key role in promoting sensitive parenting and empathy. In this study, we investigated how OXT system gene methylation was associated with empathic processes in nulliparous women (M age = 23.60, SD =0.44)—measuring both physiological facial muscle responses and ratings of compassion and positive affect to affective images depicting children. Linear mixed effects analyses demonstrated that lower methylation levels in the OXT and OXTR genes were related to enhanced empathic responses. The effect of OXT system gene methylation on empathic processes was partly qualified by an interaction with individual variations in women's care motivation. Our findings provide experimental evidence for an association between the methylation of OXT system genes and empathy.

Psychopathy is a neurodevelopmental disorder that has a highly deleterious effect upon both individuals and society at large. Psychopaths grossly neglect and disrespect the interests of others. Their antisocial behavior is thought to originate from a lack of empathy. However, empathy is multidimensional in nature, as evidenced by the considerable heterogeneity in extant theorizing on the subject. Here, we present the “Zipper model of empathy” that reconsiders how both its affective and cognitive components converge in mature empathic behavior. Furthermore, the Zipper model of empathy is expedient for explaining the empathy deficits in psychopathy, insofar as it brings together current theories on the dysfunctional affective components of empathy, violence inhibition, and automatic versus goal-directed attention. According to the literature, the neurobiological underpinnings of these theories are amygdala-centered; however, this article traces this specifically to the basolateral and central amygdala subregions. When viewed together, the cognitive and affective components of empathy are zipped together in a natural fashion in healthy empathic behavior, whereas psychopaths leave the zipper substantially unzipped in pursuit of their purely self-centered goals.

Highlights • The sense of touch enables parent-child communication from birth onward. • We theorized that parental touch would reduce children’s social vigilance. • Parental touch reduced children’s attention to social threat. • Parental touch increased trust, specifically among socially anxious children. • These effects occurred before (not after) the transition to adolescence., The sense of touch develops in utero and enables parent-child communication from the earliest moments of life. Research shows that parental touch (e.g., licking and grooming in rats, skin-to-skin care in humans) has organizing effects on the offspring’s stress system. Little is known, however, about the psychological effects of parental touch. Building on findings from ethology and psychology, we propose that parental touch—even as subtle as a touch on the shoulder—tells children that their environment is safe for exploration, thus reducing their social vigilance. We tested this hypothesis in late childhood (ages 8–10) and early adolescence (ages 11–14) in 138 parent-child dyads. Parents were randomly assigned to touch or not touch their child briefly and gently on the shoulder, right below the deltoid. Parental touch lowered children’s implicit attention to social threat. While parental touch lowered trust among socially non-anxious children, it raised trust among those who needed it the most: socially anxious children. The effects were observed only in late childhood, suggesting that parental touch loses its safety-signaling meaning upon the transition to adolescence. Our findings underscore the power of parental touch in childhood, especially for children who suffer from social anxiety.

Samen leren, werken en innoveren: dat is de kern van een hybride leeromgeving. Wat is nu een hybride leeromgeving, en waar moet je rekening mee houden bij de inrichting en ontwikkeling ervan? In deze kennissynthese bundelen we verschillende inzichten uit onderzoek en bieden we concrete handvatten voor de praktijk.

This is a preregistration for the project Men’s Empathy Towards Children Across the Transition to Parenthood.

Preterm-birth increases the risk of several physical, cognitive, neuromotor, and psychosocial problems in children, and is also related to difficulties in the parent-child relationship. Research suggests that the development of early parent-child interactions in general is affected by deviations from typical infant facial characteristics, which may also be important in the case of small, preterm born infants. Therefore, we examined mothers' (N = 22, of whom 17 had no direct experience with preterm birth) neural responses to pictures of preterm and fullterm infants using functional magnetic resonance imaging (fMRI). We also explored whether neural responses to preterm and full-term infants correlated with mothers' self-reported tendencies to be nurturing and protective with children, and with mothers' ratings of affection or aversion toward pictures of preterm infants. Results revealed that, compared to pictures of full-term infants, those of preterm infants elicited more activity in specific areas of the brain (dmPFC, right insula, left caudate, hippocampi, parahippocampi, and PAG), that have previously been associated with processing of negative emotions and with empathy. In addition, less activity was seen in one area of the brain (vmPFC) known to be associated with reward-motivation or mental state understanding and perspective-taking. Higher self-reported maternal nurturance was associated with increased activity to pictures of preterm infants vs full-term infants in the caudate, which might reflect approach- or reward-related processing. To conclude, neural responses to preterm infants are related to reward-motivation, mentalizing, negative emotions, and empathy. Future studies should examine whether such neural processing of preterm infant stimuli might underlie difficulties in the parent-child relationship of parents with a preterm child.

Infant facial characteristics, i.e., baby schema, are thought to automatically elicit parenting behavior and affective orientation toward infants. Only a few studies, conducted in non-parents, have directly examined the neural underpinnings of this baby schema effect by manipulating distinctiveness of baby schema in infant faces. This study aims to further our understanding of the intuitive nature of parenting, by studying the baby schema effect in mothers of young children (at least one child aged between 2 and 6 years old). Functional magnetic resonance imaging (fMRI) was used to examine mothers’ (N = 23) neural responses to unfamiliar infant faces varying in distinctiveness of baby schema. Also, it was studied how this neural activation to infant faces was associated with maternal nurturance. Results revealed that infant faces elicited widespread activation in bilateral visual cortices, the hippocampus, sensory-motor areas, parietal and frontal cortices, and the insula, which was not modulated by the distinctiveness of baby schema in the infant faces. Furthermore, higher self-reported maternal nurturance was related to increased neural responses to infant faces in the putamen and amygdala, brain regions known to be associated with reward and salience processing. These findings could suggest that in our small sample of mothers some of the core networks involved in reward and salience processing might be less sensitive to variation in distinctiveness of baby schema. Also, unfamiliar infant faces seem to be rewarding only for mothers who report high nurturance. These findings should be considered preliminary, because they need to be replicated in studies with larger samples.

Since the discovery of pain relieving and rewarding properties of opiates such as morphine or heroin, the human mu-opioid system has been a target for medical research on pain processing and addiction. Indeed, pain and pleasure act mutually inhibitory on each other and the mu-opioid system has been suggested as an underlying common neurobiological mechanism. Recently, research interest extended the role of the endogenous mu-opioid system beyond the hedonic value of pain and pleasure towards human social-emotional behavior. Here we propose a mu-opioid feedback model of social behavior. This model is based upon recent findings of opioid modulation of human social learning, bonding and empathy in relation to affiliative and protective tendencies. Fundamental to the model is that the mu-opioid system reinforces socially affiliative or protective behavior in response to positive and negative social experiences with long-term consequences for social behavior and health. The functional implications for stress, anxiety, depression and attachment behaviors are discussed.

Hoge bomen vangen veel wind. Aandeelhouders van slecht presterende bedrijven offeren de hoogste baas, het voetbalteam dat dreigt te degraderen gaat op zoek naar een nieuwe coach. Waar het wel goed gaat wordt de rol van het leiderschap geïdealiseerd en worden zakken gevuld. Ook in het onderwijs is sprake van hooggespannen verwachtingen dan wel diepe teleurstelling als het gaat om de rol van het management. Hoe schatten we de rol van het leiderschap op juiste waarde? Tijd voor meer verdieping.

Certain infant facial characteristics, referred to as baby schema, are thought to automatically trigger parenting behavior and affective orientation toward infants. Electroencephalography (EEG) is well suited to assessing the intuitive nature and temporal dynamics of parenting responses, due to its millisecond temporal resolution. Little is known, however, about the relations between neural processing of infant cues and actual parenting behavior in a naturalistic setting. In the present study we examined the event-related potentials (ERPs) of mothers (N = 33) watching infant faces of varying attractiveness, in relation to activation of the maternal care system and the mothers' observed parenting behavior (sensitivity, nonintrusiveness) with their own child (2-6 years old). The results revealed that, irrespective of the cuteness of the infant face, mothers' neural processing of infant faces involved both early P1 and P2 components (related to orienting/detecting processes) and late positive potentials (LPPs; related to more controlled cognitive evaluation/attentional engagement). Increased early detection and processing of infant faces (reflected by P1 and P2 activity) was related to increased activation of the parental care system. In later stages of face processing, increased attentional engagement with infant faces (as reflected by LPP activity) was associated with more intrusiveness of a mother with her own child during interaction. These findings suggest that individual variations in responses to infant stimuli are associated with individual differences in parental care system activation and parenting quality. Furthermore, the parental care system might be activated relatively automatically, but actual parenting and caregiving behavior requires more conscious control.

Intensive discussions are ongoing about the interpretation of pulmonary effects observed in rats exposed to poorly soluble particles. Alveolar clearance differs between rats and humans and becomes impaired in rats at higher exposure concentrations. Some have doubted the human relevance of toxic effects observed in rats under impaired clearance conditions and have suggested that experimental exposures should stay below concentrations inducing impaired clearance. However, for regulatory purposes, insight in potential health effects at relatively high concentrations is needed to fully understand the hazard. Many aspects of impaired particle clearance remain unclear, hampering human health hazard and risk assessment. For an adequate evaluation of the impact of impaired clearance on pulmonary toxicity, a clear definition of alveolar clearance is needed that enables to quantitatively relate the level of impairment to the induction of adverse pulmonary health effects. Also, information is needed on the mechanism of action and the appropriate dose metric for the pulmonary effects observed. In absence of these data, human hazard and risk assessment can only be performed in a pragmatic way. Unless available data clearly point out otherwise, rat pulmonary toxicity including lung inflammation and tumour formation, needs to be considered relevant for human hazard and risk assessment.

The human oxytocin (OXT) system is implicated in the regulation of complex social behaviors, as well as in psychopathologies characterized by social deficits. Emerging evidence suggests that variation in epigenetic regulation of the oxytocin receptor gene (OXTR) provides the oxytocin system with flexibility in response to environmental events, especially those occurring during early childhood. Changes in DNA methylation patterns of OXTR associated with these events may reflect biological alterations of social sensitivity. This is often related to an increased risk of developing mental disorders later in life. Here, we systematically reviewed all human studies (n = 30) discussing OXTR methylation in relation to socio-behavioral phenotypes. As such, we provide a complete and up-to-date overview of the literature that will aid future research in the interdisciplinary field of epigenetics and socio-behavioral sciences.

Positive social cues, like happy facial expressions, activate the brain's reward system and indicate interest in social affiliation. Facial mimicry of emotions, which is the predominantly automatic and unconscious imitation of another person's facial expression, has been shown to promote social affiliation. It has been demonstrated repeatedly that the opioid system is vital to social affiliation in rodents, but there is less evidence in humans. We investigated whether a 50mg administration of naltrexone, an opioid antagonist with highest affinity for the mu-opioid system, modulates emotional mimicry. A passive viewing task with dynamic facial expressions was used in a randomized placebo controlled between-subjects design. Mimicry was measured with electromyography (EMG) on three facial muscles, the corrugator supercilii and the depressor jaw muscle, associated with negatively-valenced emotions, and the zygomaticus major, which is activated during smiling. The results demonstrate an increase of negatively-valenced facial responses (corrugator and depressor) to happy facial expressions after naltrexone compared to placebo, consistent with lowered interest in social interaction or affiliation. Our findings provide evidence for a role of the opioid system in modulating automatic behavioral responses to cues of reward and social interaction, and translate to rodent models of the mu-opioid system and social affiliation.

Zelfsturing vraagt om medewerkers die zelf initiatief nemen. Maar het vraagt ook om een nieuwe vorm van leiderschap. Het bewerkstelligen van een zelfsturende werkcontext is de sleutel tot succes. De leidinggevende in de rol van architect.

Recent evidence suggests that the steroid hormone testosterone can decrease the functional coupling between orbitofrontal cortex (OFC) and amygdala. Theoretically this decoupling has been linked to a testosterone-driven increase of goal-directed behaviour in case of threat, but this has never been studied directly. Therefore, we placed twenty-two women in dynamically changing situations of escapable and inescapable threat after a within-subject placebo controlled testosterone administration. Using functional magnetic resonance imaging (fMRI) we provide evidence that testosterone activates the left lateral OFC (LOFC) in preparation of active goal-directed escape and decouples this OFC area from a subcortical threat system including the central-medial amygdala, hypothalamus and periaqueductal gray. This LOFC decoupling was specific to threatening situations, a point that was further emphasized by an absence of such decoupling in a second experiment focused on resting-state connectivity. These results not only confirm that testosterone administration decouples the LOFC from the subcortical threat system, but also show that this is specifically the case in response to acute threat, and ultimately leads to an increase in LOFC activity when the participant prepares a goal-directed action to escape. Together these results for the first time provide a detailed understanding of functional brain alterations induced by testosterone under threat conditions, and corroborate and extend the view that testosterone prepares the brain for goal-directed action in case of threat.

Summary Rodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans., Graphical Abstract, Highlights • Human bilateral BLA damage and silencing in rats results in maladaptive passive fear • If active escape is feasible, the BLA prevents passive freezing responses via the CeA • BLA action on an inhibitory CeA pathway permits the adaptive shift to active escape • Activation of CeA neurons by oxytocin rescues deficient escape in BLA-silenced rats, Under conditions of imminent threat, by activating an inhibitory central amygdala pathway, the rodent and human basolateral amygdala play a key role in adaptively selecting and executing active escape responses rather than passive freezing behaviors.

Contains fulltext : 194027.pdf (Publisher’s version ) (Open Access) Testosterone and cortisol have both been implicated in human parenting behavior. We investigated the relations between observed quality of caregiving during parent-child interactions and pre- and postnatal testosterone and cortisol levels, in both mothers (N = 88) and fathers (N = 57). Testosterone and cortisol were measured before and after interaction with an infant simulator (prenatal) and with their own child (postnatal) to index basal levels as well as steroid reactivity to the interaction. Our findings are that in fathers, interactions between cortisol and testosterone are related to quality of caregiving both pre- and postnatally. Prenatally there was a stronger negative relation between T and quality of caregiving in fathers with lower cortisol levels, and postnatally there was a stronger negative relation between cortisol and quality of caregiving in fathers high in testosterone levels. Furthermore, prenatal cortisol levels were related to paternal quality of caregiving during interaction with their own child. In mothers, no associations between quality of caregiving and our endocrine measures were observed. We interpret our findings in the context of hyperreactive physiological responses observed in parents at risk for insensitive caregiving, and in light of the dual-hormone hypothesis. The current findings contribute to the growing literature on the endocrine antecedents of human caregiving behavior. 10 p.

Recent evidence suggests that the steroid hormone testosterone can decrease the functional coupling between orbitofrontal cortex (OFC) and amygdala. Theoretically this decoupling has been linked to a testosterone-driven increase of goal-directed behaviour in case of threat, but this has never been studied directly. Therefore, we placed twenty-two women in dynamically changing situations of escapable and inescapable threat after a within-subject placebo controlled testosterone administration. Using functional magnetic resonance imaging (fMRI) we provide evidence that testosterone activates the left lateral OFC (LOFC) in preparation of active goal-directed escape and decouples this OFC area from a subcortical threat system including the central-medial amygdala, hypothalamus and periaqueductal gray. This LOFC decoupling was specific to threatening situations, a point that was further emphasized by an absence of such decoupling in a second experiment focused on resting-state connectivity. These results not only confirm that testosterone administration decouples the LOFC from the subcortical threat system, but also show that this is specifically the case in response to acute threat, and ultimately leads to an increase in LOFC activity when the participant prepares a goal-directed action to escape. Together these results for the first time provide a detailed understanding of functional brain alterations induced by testosterone under threat conditions, and corroborate and extend the view that testosterone prepares the brain for goal-directed action in case of threat.

Abundant research has highlighted a disadvantage experienced by children of ethnic minority groups in, for example, educational and health care settings. In order to understand implicit attitudes that contribute to ethnic disparities, underlying neural correlates have been widely studied. However, this has been limited to the context of adults. Using a sample of nulliparous Caucasian females (N = 46), the current study is the first to examine how early attentional and facial perceptual processing stages, assessed with event-related brain potentials (ERPs), differentiate for stimuli of young ingroup (of the same ethnicity) or outgroup (of a different ethnicity) children. Additionally, we assessed how a differentiation in ERPs may relate to subsequent adult responsiveness to children by measuring both cuteness ratings and motivation to view child faces. Similar to previous findings for adult facial stimuli, we found significant differences in attentional (N200) and facial perceptual (N170) processing when adults were faced with children of different ethnicities. Furthermore, increased differentiation in attentional processing (N200) for ingroup and outgroup children was associated with reduced cuteness ratings of outgroup children. Importantly however, participants showed no overall preference for ingroup child faces, as motivation to view child faces was even greater towards outgroup child faces. In addition, increased self-reported motivation for parental care was related to enhanced cuteness appraisals of outgroup child faces. Taken together, these findings reveal how early social categorization processes may lead to biased behavior when interacting with children of ethnic minorities.

Facial expressions are considered central in conveying information about one's emotional state. During social encounters, facial expressions of another individual are often automatically imitated by the observer, a process referred to as 'facial mimicry'. This process is assumed to facilitate prosocial behaviour and is thought to rely on the mirror neuron system, known for its involvement in both observation and execution of motor actions. However, recent studies have revealed mimicry to be a more dynamic process than previously conceptualized, leaving mere perception-action coupling insufficient to explain its behavioural flexibility. In the current review, we describe the consequences of these findings for the theoretical conceptualization of facial mimicry, and present a novel neuroendocrine model for the dynamic modulation of facial mimicry. Our model can guide research on the communicative function of facial expressions and can provide insight into the position of facial mimicry in theoretical models of empathy and social interaction.

This study examined 1) mothers' neural responses to pictures of boys and girls who confirmed or violated social expectations regarding toy preferences, and 2) whether neural sensitivity to targets that violated gendered expectations interacted with mothers' gender stereotypes. In an event-related fMRI experiment, 23 mothers of a 2-6 year-old child viewed and evaluated pictures of boys or girls with their favorite toy. Next, mothers gender stereotypes about children's toys and behavior, and internal motivation to behave without prejudice were assessed. Several neural processes were underlying parents' responses to children's behavior that violates gender-role expectations. Brain regions involved in mentalizing or storage of social knowledge, understanding goal-directed behavior, behavioral control, and conflict monitoring were activated when viewing child targets that violated gender expectations. In these brain areas, increased neural responses to targets that violated traditional gender expectations were associated with more stereotyped expectations about boys' and girls' toys and behavior.

Processes like gender socialization (the ways in which parents convey information to their children about how girls and boys should behave) often happen unconsciously and might therefore be studied best with neuroscientific measures. We examined whether neural processing of gender-stereotype-congruent and incongruent information is more robustly related to mothers' gendered socialization of their child than mothers' implicit and explicit gender stereotypes. To this end, we examined event-related potentials (ERPs) of mothers (N = 35) completing an implicit gender-stereotype task and mothers' gender stereotypes in relation to observed gendered communication with their child (2-6 years old) in a naturalistic picture-book-reading setting. Increased N2 activity (previously related to attentional processes) to gender stimuli in the implicit gender-stereotype task was associated with mothers' positive evaluation of similar gendered behaviors and activities in the picture book they read with their child. Increased P300 activity (previously related to attention to unexpected events) to incongruent trials in the gender-stereotype task was associated with a more positive evaluation of congruent versus incongruent pictures. Compared to mothers' gender stereotypes, neural processing of gendered information was more robustly related to how mothers talk to their children about boys' and girls' stereotype-congruent and incongruent behavior, and masculine and feminine activities.

Positive social cues, like happy facial expressions, activate the brain's reward system and indicate interest in social affiliation. Facial mimicry of emotions, which is the predominantly automatic and unconscious imitation of another person's facial expression, has been shown to promote social affiliation. It has been demonstrated repeatedly that the opioid system is vital to social affiliation in rodents, but there is less evidence in humans. We investigated whether a 50mg administration of naltrexone, an opioid antagonist with highest affinity for the mu-opioid system, modulates emotional mimicry. A passive viewing task with dynamic facial expressions was used in a randomized placebo controlled between-subjects design. Mimicry was measured with electromyography (EMG) on three facial muscles, the corrugator supercilii and the depressor jaw muscle, associated with negatively-valenced emotions, and the zygomaticus major, which is activated during smiling. The results demonstrate an increase of negatively-valenced facial responses (corrugator and depressor) to happy facial expressions after naltrexone compared to placebo, consistent with lowered interest in social interaction or affiliation. Our findings provide evidence for a role of the opioid system in modulating automatic behavioral responses to cues of reward and social interaction, and translate to rodent models of the mu-opioid system and social affiliation.

Item does not contain fulltext Women on average outperform men in cognitive-empathic abilities, such as the capacity to infer motives from the bodily cues of others, which is vital for effective social interaction. The steroid hormone testosterone is thought to play a role in this sexual dimorphism. Strikingly, a previous study shows that a single administration of testosterone in women impairs performance on the 'Reading the Mind in Eyes' Test (RMET), a task in which emotions have to be inferred from the eye-region of a face. This effect was mediated by the 2D:4D ratio, the ratio between the length of the index and ring finger, a proxy for fetal testosterone. Research in typical individuals, in individuals with autism spectrum conditions (ASC), and in individuals with brain lesions has established that performance on the RMET depends on the left inferior frontal gyrus (IFG). Using functional magnetic resonance imaging (fMRI), we found that a single administration of testosterone in 16 young women significantly altered connectivity of the left IFG with the anterior cingulate cortex (ACC) and the supplementary motor area (SMA) during RMET performance, independent of 2D:4D ratio. This IFG-ACC-SMA network underlies the integration and selection of sensory information, and for action preparation during cognitive empathic behavior. Our findings thus reveal a neural mechanism by which testosterone can impair emotion-recognition ability, and may link to the symptomatology of ASC, in which the same neural network is implicated.

Women on average outperform men in cognitive-empathic abilities, such as the capacity to infer motives from the bodily cues of others, which is vital for effective social interaction. The steroid hormone testosterone is thought to play a role in this sexual dimorphism. Strikingly, a previous study shows that a single administration of testosterone in women impairs performance on the 'Reading the Mind in Eyes' Test (RMET), a task in which emotions have to be inferred from the eye-region of a face. This effect was mediated by the 2D:4D ratio, the ratio between the length of the index and ring finger, a proxy for fetal testosterone. Research in typical individuals, in individuals with autism spectrum conditions (ASC), and in individuals with brain lesions has established that performance on the RMET depends on the left inferior frontal gyrus (IFG). Using functional magnetic resonance imaging (fMRI), we found that a single administration of testosterone in 16 young women significantly altered connectivity of the left IFG with the anterior cingulate cortex (ACC) and the supplementary motor area (SMA) during RMET performance, independent of 2D:4D ratio. This IFG-ACC-SMA network underlies the integration and selection of sensory information, and for action preparation during cognitive empathic behavior. Our findings thus reveal a neural mechanism by which testosterone can impair emotion-recognition ability, and may link to the symptomatology of ASC, in which the same neural network is implicated.

Infant faces have distinctive features that together are described as baby schema, a configuration that facilitates caregiving motivation and behavior, and increases the perception of cuteness. In the current functional magnetic resonance imaging (fMRI) study, we investigated the effect of a within-subjects intranasal oxytocin administration (24 IU) and caregiving motivation on neural responses to infant faces of varying baby schema in 23 healthy nulliparous women. Overall, infant faces elicited activation in several brain regions involved in reward and salience processing, including the ventral tegmental area (VTA), putamen, amygdala, anterior cingulate cortex (ACC), and insula, and this activation was related to self-reported caregiving motivation. Critically, whereas we hypothesized enhanced neural caregiving-related responses after oxytocin administration, we observed reduced activation in the VTA, putamen and amygdala after oxytocin compared to placebo. In nulliparous women, oxytocin has been shown to reduce neural responses in the same regions in response to social stimuli using other paradigms. Oxytocin might affect neural activation toward social stimuli depending on elicited arousal and personal characteristics. The current study is the first to demonstrate this effect in response to infant faces and thereby adds to specify the role of oxytocin in human social information processing.

Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors. Hum Brain Mapp 36:4304-4316, 2015. © 2015 Wiley Periodicals, Inc.

Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors. Hum Brain Mapp 36:4304-4316, 2015. © 2015 Wiley Periodicals, Inc.

Nanomaterials (NMs) display many unique and useful physico-chemical properties. However, reliable approaches are needed for risk assessment of NMs. The present study was performed in the FP7-MARINA project, with the objective to identify and evaluate in vitro test methods for toxicity assessment in order to facilitate the development of an intelligent testing strategy (ITS). Six representative oxide NMs provided by the EC-JRC Nanomaterials Repository were tested in nine laboratories. The in vitro toxicity of NMs was evaluated in 12 cellular models representing 6 different target organs/systems (immune system, respiratory system, gastrointestinal system, reproductive organs, kidney and embryonic tissues). The toxicity assessment was conducted using 10 different assays for cytotoxicity, embryotoxicity, epithelial integrity, cytokine secretion and oxidative stress. Thorough physico-chemical characterization was performed for all tested NMs. Commercially relevant NMs with different physico-chemical properties were selected: two TiO2 NMs with different surface chemistry – hydrophilic (NM-103) and hydrophobic (NM-104), two forms of ZnO – uncoated (NM-110) and coated with triethoxycapryl silane (NM-111) and two SiO2 NMs produced by two different manufacturing techniques – precipitated (NM-200) and pyrogenic (NM-203). Cell specific toxicity effects of all NMs were observed; macrophages were the most sensitive cell type after short-term exposures (24-72h) (ZnO>SiO2>TiO2). Longer term exposure (7 to 21 days) significantly affected the cell barrier integrity in the presence of ZnO, but not TiO2 and SiO2, while the embryonic stem cell test (EST) classified the TiO2 NMs as potentially ‘weak-embryotoxic’ and ZnO and SiO2 NMs as ‘non-embryotoxic’. A hazard ranking could be established for the representative NMs tested (ZnO NM-110 > ZnO NM-111 > SiO2 NM-203 > SiO2 NM-200 > TiO2 NM-104 > TiO2 NM-103). This ranking was different in the case of embryonic tissues, for which TiO2 displayed higher toxicity compared with ZnO and SiO2. Importantly, the in vitro methodology applied could identify cell- and NM-specific responses, with a low variability observed between different test assays. Overall, this testing approach, based on a battery of cellular systems and test assays, complemented by an exhaustive physico-chemical characterization of NMs, could be deployed for the development of an ITS suitable for risk assessment of NMs. This study also provides a rich source of data for modeling of NM effects.

Social anxiety disorder (SAD) is a highly prevalent and disabling disorder with key behavioral traits of social fearfulness, social avoidance, and submissiveness. Here we argue that hormonal systems play a key role in mediating social anxiety, and so may be important in SAD. Hormonal alterations, often established early in development through the interaction between biological and psychological factors (eg, genetic predisposition x early trauma), predispose to socially fearful, avoidant, and submissive behavior. However, whereas gene variants and histories of trauma persist, hormonal systems can be remodeled over the course of life. Hormones play a key role during the periods of all sensitive developmental windows (ie, prenatal, neonatal, puberty, aging), and are capable of opening up new developmental windows in adulthood. Indeed, the developmental plasticity of our social brain, and thus of social behavior in adulthood, critically depends on steroid hormones such as testosterone and peptide hormones such as oxytocin. These steroid and peptide hormones in interaction with social experiences may have potential for reprogramming the socially anxious brain. Certainly, single administrations of oxytocin and testosterone in humans reduce socially fearful, avoidant, and submissive behavior. Such work may ultimately lead to new approaches to the treatment of SAD.

In rodents, there is abundant evidence for the involvement of the opioid system in the processing of reward cues, but this system has remained understudied in humans. In humans, the happy facial expression is a pivotal reward cue. Happy facial expressions activate the brain's reward system and are disregarded by subjects scoring high on depressive mood who are low in reward drive. We investigated whether a single 0.2. mg administration of the mixed mu-opioid agonist/kappa-antagonist, buprenorphine, would influence short-term memory for happy, angry or fearful expressions relative to neutral faces. Healthy human subjects (n38) participated in a randomized placebo-controlled within-subject design, and performed an emotional face relocation task after administration of buprenorphine and placebo. We show that, compared to placebo, buprenorphine administration results in a significant improvement of memory for happy faces. Our data demonstrate that acute manipulation of the opioid system by buprenorphine increases short-term memory for social reward cues.

Bringing together topic-related European Union-(EU)-funded projects, the so-called “NanoSafety Cluster” aims at identifying key areas for further research on risk assessment procedures for nanomaterials (NM). The outcome of NanoSafety Cluster Working Group 10, this commentary presents a vision for concern-driven integrated approaches for the (eco-)toxicological testing and assessment (IATA) of NM. Such approaches should start out by determining concerns, i.e. specific information needs for a given NM based on realistic exposure scenarios. Recognized concerns can be addressed in a set of tiers using standardized protocols for NM preparation and testing. Tier 1 includes determining physico-chemical properties, non-testing (e.g. structure activity relationships) and evaluating existing data. In tier 2, a limited set of in vitro and in vivo tests are performed that can either indicate that the risk of the specific concern is sufficiently known or indicate the need for further testing, including details for such testing. Ecotoxicological testing begins with representative test organisms followed by complex test systems. After each tier, it is evaluated whether the information gained permits assessing the safety of the NM so that further testing can be waived. By effectively exploiting all available information, IATA allow accelerating the risk assessment process and reducing testing costs and animal use (in line with the 3Rs principle implemented in EU Directive 2010/63/EU). Combining material properties, exposure, biokinetics, and hazard data, information gained with IATA can be used to recognize groups of NM based upon similar modes-of-action. Grouping of substances in return should form integral part of the IATA themselves.

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Acute exposure guideline levels (AEGLs) are derived to protect the human population from adverse health effects in case of single exposure due to an accidental release of chemicals into the atmosphere. AEGLs are set at three different levels of increasing toxicity for exposure durations ranging from 10 min to 8 h. In the AEGL setting for methylene chloride, specific additional topics had to be addressed. This included a change of relevant toxicity endpoint within the 10-min to 8-h exposure time range from central nervous system depression caused by the parent compound to formation of carboxyhemoglobin (COHb) via biotransformation to carbon monoxide. Additionally, the biotransformation of methylene chloride includes both a saturable step as well as genetic polymorphism of the glutathione transferase involved. Physiologically based pharmacokinetic modeling was considered to be the appropriate tool to address all these topics in an adequate way. Two available PBPK models were combined and extended with additional algorithms for the estimation of the maximum COHb levels. The model was validated and verified with data obtained from volunteer studies. It was concluded that all the mentioned topics could be adequately accounted for by the PBPK model. The AEGL values as calculated with the model were substantiated by experimental data with volunteers and are concluded to be practically applicable.

Around 25% of the children in developed countries are affected with immune-based diseases. Juvenile onset diseases such as allergic, inflammatory and autoimmune diseases have shown increasing prevalences in the last decades. The role of chemical exposures in these phenomena is unclear. It is thought that the developmental immune system is more susceptible to toxicants than the mature situation. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements. We reviewed whether developmental immune parameters in rodents would provide relatively sensitive endpoints of toxicity, whose inclusion in regulatory toxicity testing might improve hazard identification and risk assessment of chemicals. For each of the nine reviewed toxicants, the developing immune system was found to be at least as sensitive or more sensitive than the general (developmental) toxicity parameters. Functional immune (antigen-challenged) parameters appear more affected than structural (non-challenged) immune parameters. Especially, antibody responses to immune challenges with keyhole limpet hemocyanine or sheep red blood cells and delayed-type hypersensitivity responses appear to provide sensitive parameters of developmental immune toxicity. Comparison with current tolerable daily intakes (TDI) and their underlying overall no observed adverse effect levels showed that for some of the compounds reviewed, the TDI may need reconsideration based on developmental immune parameters. From these data, it can be concluded that the developing immune system is very sensitive to the disruption of toxicants independent of study design. Consideration of including functional DIT parameters in current hazard identification guidelines and wider application of relevant study protocols is warranted.

Sensitivity for rewarding cues and distress signals from children is fundamental to human caregiving and modulated by the neuropeptide oxytocin. In a functional magnetic resonance imaging study, we investigated whether oxytocin regulates neural responses to reward or distress cues form children. In a placebo-controlled, within-subject design, we measured neural responses to positive, negative, and neutral cues from children in 22 healthy female subjects who received oxytocin (24 IU) versus placebo. Further, based on current literature, we hypothesized that oxytocin effects are modulated by experiences of childhood trauma. The task elicited valence-specific effects—positive images activated the ventromedial prefrontal cortex, left anterior cingulate cortex, and right putamen, and images of children in distress activated the bilateral amygdala, hippocampus, and right medial superior frontal cortex. The effects of oxytocin depended on subjective reports of childhood emotional neglect. Self-reported neglect interacted with oxytocin administration in the amygdala, hippocampus, and prefrontal areas. In individuals with higher scores of emotional neglect, oxytocin increased neural reactivity of limbic structures to positive and neutral images. Our findings need replication in larger samples and can therefore be considered preliminary but are in line with the recent literature on the modulating effect of childhood adversity on the sensitivity to oxytocin administration.

Research on human behavior has frequently shown that it varies as a function of the motivational background of the situation. In other words, an individual might act differently, depending on whether its focus is currently, for example, on establishing a relationship, winning a competition, or coping with a threat. Understanding - and potentially even influencing - drivers of human behavior is vitally important in social context, where it varies extraordinarily in its intention and the effect: ranging from supportive and helpful to detrimental or even fatal. A frequent assumption is that helpful, or pro-social behaviors are motivated by Care. This motivation is suggested to have evolved in the context of offspring nurturance and interactions with close kin and to rely on complex social cognition, as well as related neocortical brain areas and hormones such as oxytocin. By comparison, antisocial actions are often associated with a drive for superiority and dominance, also termed as Power motivation. Power, and the related hormone testosterone, are frequently associated with risk taking and decreased sensitivity for other’s emotions. Hence, they might lay the groundwork for tolerating other’s harm, or even aiming to cause it for personal gain. In this thesis, I systematically probed the role of Power and Care in pro-and antisocial behaviors and sentiments. To this end, I tested how these drivers - on the levels of hormones, environmental cues and epigenetics - impact social cognition and decisions including responses to children and members of in- and outgroups.After all, interactions with offspring and close kin might more closely resemble the context which shaped Care’s postulated role in human evolution. Moreover, given that Power/testosterone and Care/oxytocin might have different adaptive value depending on an individual’s social environment, in my last study I assessed how oxytocin and testosterone shape social responses in interaction with adverse early life experiences.

Research on human behavior has frequently shown that it varies as a function of the motivational background of the situation. In other words, an individual might act differently, depending on whether its focus is currently, for example, on establishing a relationship, winning a competition, or coping with a threat. Understanding - and potentially even influencing - drivers of human behavior is vitally important in social context, where it varies extraordinarily in its intention and the effect: ranging from supportive and helpful to detrimental or even fatal. A frequent assumption is that helpful, or pro-social behaviors are motivated by Care. This motivation is suggested to have evolved in the context of offspring nurturance and interactions with close kin and to rely on complex social cognition, as well as related neocortical brain areas and hormones such as oxytocin. By comparison, antisocial actions are often associated with a drive for superiority and dominance, also termed as Power motivation. Power, and the related hormone testosterone, are frequently associated with risk taking and decreased sensitivity for other’s emotions. Hence, they might lay the groundwork for tolerating other’s harm, or even aiming to cause it for personal gain. In this thesis, I systematically probed the role of Power and Care in pro-and antisocial behaviors and sentiments. To this end, I tested how these drivers - on the levels of hormones, environmental cues and epigenetics - impact social cognition and decisions including responses to children and members of in- and outgroups.After all, interactions with offspring and close kin might more closely resemble the context which shaped Care’s postulated role in human evolution. Moreover, given that Power/testosterone and Care/oxytocin might have different adaptive value depending on an individual’s social environment, in my last study I assessed how oxytocin and testosterone shape social responses in interaction with adverse early life experiences.

This report describes a Logistics Management Systems design project that is performed at KLM Aircraft Services (AS). AS is the part of KLM that is responsible for a large portion of the tasks that must be done to an aircraft that has landed and has to be used again. When an aircraft has landed the resources that are required to service the aircraft should be available. Getting a resource available has a certain lead time and the availability of resources is not infinite. To guarantee the availability of resources a planning must be made. At KLM AS this planning is done in the PRI chain. The basis for the activities in this chain is the timetable. The current PRI chain evolved from practice; on the basis of experiences the chain has originated. Modifications to the chain are made also on the basis of experiences and observations. AS had the feeling that the chain that is currently in place is not functioning optimally. The goal of this assignment was to make a new, ideal PRI chain, preferable derived from a generic chain that has been described in literature, that would result in a better performance of AS. Deriving a generic planning chain from literature was not possible because the chains that have been described in literature are per definition made for a specific situation. Because this was not possible a new PRI chain has to be designed. The new chain that has to be designed should be suitable for the planning problem that AS faces. A danger when making a new chain for the same problem as the current chain, is that the new chain will be very similar to the old chain. To overcome this danger, a constraint approach has been chosen. This means that the constraints that lie on the basis of AS's processes are taken as building blocks for the new chain. A constraint is an artifact that cannot be changed within the scope of this project. The constraints are identified by analyzing current processes, not the choices that AS has already made in the current chain. Based on the constraints, the ideal PRI chain has been described. The new chain describes for AS on what moments in time they have to make a decision. The timing of the decision is based on the constraints that were formulated to be sure that the decision is made in time. The new chain describes for both employee and equipment planning when to make what decision. For some decisions, guidelines are given about subjects that should be taken into account when making the decision. The new PRI chain contains stepwise decisions to be sure that sufficient employees and equipment are available on the day of operation. As the lead time for equipment is longer than for employees, the first step is to determine the required equipment one year ahead. The lead time for buying new equipment is one year, so new equipment is available when it is needed when the buying decision is made one year ahead. The decision whether or not to buy new equipment is based on a forecasted performance model. This model incorporates a forecasted timetable and determines the forecasted performance. Having more equipment available will increase the costs for equipment but will also increase the performance with less non-performance costs as a result. The model can be used to make a financially grounded decision about whether or not to acquire additional equipment. The second step is to make sure that sufficient employees with the right classifications are available. The same model as described above can be used for this purpose. For employees it is very important that a decision is made about the number of KLM employees and the number of flexible employees that is used. The third step of the new PRI chain uses the outcome of the first two steps. At the moment that this step is done, no adjustments on the available equipment and KLM employees can be made anymore. The number of flexible employees that is used can still be changed. In this step, actual information about the timetable is used to determine for every moment on the day of operation the need for equipment and employees. The availability of employees is bounded by CAO constraints. Therefore a planning is made in advance of the day of operation that tells how many employees of what kind are required for different moments of the day. By changing the number of flexible employees that is used shortly before the day of operation, the actual available employees are aligned with the planned number of employees that must be available. The design for the new PRI chain has been compared to the current PRI chain. This analysis revealed that the feeling that AS has about the non-optimal performance of the current PRI chain was true. In the current chain decisions about the required number of employees or the required amount of equipment are made too late or a made without having the required information. Because decisions are made too late or are based on too less information, capacity adjustments are not ready in time or are not in line with actual demand. This will have a negative effect on the performance of AS. This report ends with a set of recommendations to improve the current PRI chain, based on differences with the ideal PRI chain. The recommendations vary on the effort that is required to complete them, the effect they have and the moment in time when they can be fulfilled. The recommendations have been ordered graphically to give AS guidelines about what recommendation to start with. Implementing these recommendations will lead to a PRI chain that will perform better. The costs for executing all steps in the PRI chain will stay about the same.

This Logistics Design Project was carried out at KLM Aircraft Services (AS), from February 2008 - April 2009. The project focuses on ideal description of KLM operational controls for daily executions at the hub and within the AS processes. The daily execution at the hub is managed by the Hub Control Center (HCC). There are several services provided to all aircrafts during their ground time, including AS, Passenger Service (PS), Baggage Service (BS), and maintenance. In details, AS processes comprise the following services: towing, fueling, distribution, cleaning, security, water, toilet, towing, push-back and de-icing. In the last years, KLM operation has achieved its operational targets in terms of arrival and delay punctuality. However, AS management still views lots of operational inefficiency within their processes. Hence, there have been several steps developed by AS management. First, they have been developing the IT with real-time feedback system since 2006. Second, there has been a plan to centralize the operational controls. This issue will be the highlight of this project. The results of this project are expected to support the centralization planning from the conceptual point of view. AS processes entail high complexity. There are different characteristics and process interdependencies. During the daily operations, the key of an efficient process lies in the dispatch decision. Each process has its own regie (job dispatcher) who is responsible for making the best dispatch decision. There are different factors which influence this dispatch decision, including: (1) quality of coordination, (2) information reliability on the aircraft position, (3) quality of IT system, (4) quality of resources and (5) quality of capacity management. Further, the decision should be made within the standard norms, priorities and operational agreements, given the available resources at particular point of time. During our investigations, we found out that the success for making the dispatch decision also depends on the other hub processes. We saw the whole processes as a concept of Ground Time Management (GTM). Ideally, GTM function will monitor the status of all processes during the ground time and take necessary decisions when disruptions happen. The more information gathered, the better the decision will be, as long as the rules are properly defined. Currently, the needs of having the GTM are implicitly realized by several parties as they started to share data and information for their own processes. Further, the GTM can help the hub operations to manage the system dynamics, especially in giving feedback to KLM Operation Control (OC). Concerning the proposal, there are two designs which are proposed for introducing the GTM function at the hub. First, Design 1 brings the GTM function as an information broker without authority to manage the ground time. Second, Design 2 proposes GTM function with authority. Both designs have their own benefits and risks. We analyzed that Design 1 is simpler than Design 2 as it only requires information collection and sharing. In Design 1, each process still works to optimize its local resources. The decision making process remains the same as current situation. Coordination between the regies is required to solve the operational conflicts. It is important that all rules and operational agreements are developed to give clear decision making procedures. Failures to this provision might lead to opportunistic behaviors which can jeopardize the operations. Design 2 is more complex, as it needs to determine the allocation of available ground time. Implementation of Design 2 takes hub optimization as its objective. An advanced integrated IT system is required to speed-up the decision making process. Further, if human intervention is needed, the person should be highly skilled and understand the complexity of the hub operations. Seeing the analysis, we propose that implementation of Design 1+ (Design 1 with formal agreements and standards) can be taken as the first step to introduce the GTM concept. In the future, there might be evolution to Design 2 based on the reactions and developments of the other parties. The decision to implement the design depends on the readiness of the hub management. We believe that each design brings its own benefits. However, determining the most appropriate design is not such an easy task. There should be clear benefits-costs analysis. In this way, KLM management should be able to judge the following statement: "Does it pay-off to move from Design 1+ to Design 2?" Operational Excellence: "How can a Ground Time Manager improve hub performance (reduce delay while keeping all standards) which might lead to higher customer satisfaction?" Efficiency: "How can a Ground Time Manager improve hub performance (increase resources optimization) which might lead to less resource investment?" There are some practical steps that should be made to have successful introduction of either Design 1 or Design 2, which are: (1) design fitness to current operational structure, (2) design all rules and work procedures, (3) develop IT system and (4) develop performance measurements. At the last part of the report, we design a GTM framework for executing, monitoring and improving the hub system. All feedbacks should be recorded and the proper KPIs should be defined. The performance measurements are divided in three different areas, which are system performance, process performance and resource planning performance. Seeing all measurements as a whole will bring a fair judgment. In the future, this will help the management to focus on the problematic areas. From this project, we believe that GTM is a promising step to improve the performance of the hub operation. However, more quantitative analysis is required to estimate the expected pay-off. At the end, we hope that this project will enlighten KLM management to bring the GTM concept into practice.