Proprioceptive acuity for landmarks on the hand and digits.

Previous work using visually guided reaches to localize landmarks on a hidden hand has suggested that proprioceptive acuity for hand targets is low and representation of hand dimensions is highly distorted (e.g., hand width estimated to be 60% wider than actual hand width). We re-examined these issues using a pure proprioceptive task in which 20 blindfolded subjects reached in a single movement without terminal corrections to touch the right index-tip to landmarks of the left hand placed in various locations in 3D space. Subjects were also tested with vision allowed to estimate minimal errors. Based on previous reports of high proprioceptive acuity for some hand landmarks, we hypothesized that the proprioceptive representation of the hand was much less distorted than described previously and that errors were not correlated with target hand location. Mean distance errors in proprioceptively guided reaches to the landmarks averaged less than 3 cm and were only 0.5-1.3 cm larger than when vision was allowed. Errors were not correlated with hand location in most subjects. Distortions of hand width averaged less than 20% wider than actual width and were not correlated with hand location in most subjects. We conclude that relatively accurate proprioceptive awareness of locations of hand/digit structures and dimensions is available for use in control of hand movements, which are executed largely subconsciously. Studying acuity of proprioception using conscious perceptual tasks and involving vision may not provide accurate measures of proprioceptive acuity as used by the motor system.

How attention factors into executive function in preschool children.

Executive Function consists of self-regulation processes which underlie our ability to plan, coordinate, and complete goal-directed actions in our daily lives. While attention is widely considered to be central to the emergence and development of executive function during early childhood, it is not clear if it is integral or separable from other executive function processes. Previous studies have not addressed this question satisfactorily because executive function and attention are multidimensional constructs, but they are often studied without differentiating the specific processes that are tested. Moreover, some studies consist of only one task per process, making it difficult to ascertain if the pattern of results is attributable to different processes or more simply to task variance. The main aim of this study was to more fully investigate how attention factored into the underlying structure of executive function in preschool children. Preschool children (n = 137) completed a battery of tasks which included executive function (i.e., response inhibition, working memory) and attentional control (i.e., sustained attention, selective attention) processes; there were two tasks per process. Confirmatory factor analyses (CFA) were conducted to test which of three models fit the data best: (1) a unitary one-factor model with attention loading onto the same factor as other executive function processes, (2) a two-factor model with attention loading onto a separate factor than other executive function processes, or (3) a three-factor model with attention, response inhibition, and working memory as separate factors. Fit indices and model comparisons indicated that the two-factor model fit the data best, suggesting that attentional control and executive function were related, but separable. Although this study is not the first to advocate for a two-factor model during the preschool years, it is the first to suggest that the two factors are attentional control and executive function, not working memory and response inhibition. One important implication of these findings is that a complete assessment of executive function during the preschool years necessitates measuring not only response inhibition and working memory, but attentional control as well.

More than fear: Contributions of biobehavioral synchrony and infants' reactivity to cooperative care.

We present two challenges to the fearful ape hypothesis: (1) biobehavioral synchrony precedes and moderates the effects of fear on cooperative care, and (2) cooperative care emerges in a more bidirectional manner than Grossmann acknowledges. We present evidence demonstrating how dyadic differences in co-regulation and individual differences in infants' reactivity shape caregivers' responses to infant affect.

Coupling between prefrontal brain activity and respiratory sinus arrhythmia in infants and adults.

Self-regulation is an essential aspect of healthy child development. Even though infants depend on their caregivers for co-regulation during the first years, they begin to gain regulatory abilities through social interactions as well as their own developing agency and inhibitory control. These early regulatory abilities continue to increase with the development of both the prefrontal cortex and the vagal system. Importantly, theoretical accounts have suggested that the prefrontal cortex and the vagal system are linked through forward and backward feedback loops via the limbic system. Decreased coupling within this link is suggested to be associated with psychopathology. The primary goal of this study was to examine whether intrapersonal coupling of prefrontal brain activity and respiratory sinus arrhythmia is evident in infancy. Using the simultaneous assessment of functional near-infrared spectroscopy and electrocardiography, we used Cross-Recurrence Quantification Analysis to assess the coupling of prefrontal brain activity and respiratory sinus arrhythmia in 69 4- to 6-month-old infants and their mothers during a passive viewing condition. However, we did not find significant coupling between the PFC and RSA in infants and adult caregivers. Future studies could examine social contexts associated with greater emotional reactivity to deepen our understanding of the pathways involved in self-regulation.

High proprioceptive acuity in slow and fast hand movements.

We can accurately reach to touch our index fingertip to various points on the body without vision. Awareness of location/motion of the index fingertip and other body parts through proprioception is required for such movements. Proprioception involves processing sensory information, but it is also debated whether internal model estimates of body state from motor commands improve proprioception. We tested the hypothesis that proprioceptive errors increase with increases in speed of hand movement and whether an internal model contributes to more accurate proprioception, especially in higher speed movements. Ten subjects made voluntary reaching movements with their dominant arm to touch its index-tip to the index-tip of the non-dominant arm that was moved passively or actively at three speeds (slow, comfortable, fast) in various directions. Four conditions required the experimenter to passively move the subject's target arm at slow, comfortable and fast speeds and in different directions. A fifth condition required the subject to actively move both arms to perform the task. Subjects performed these tasks with high accuracy during slow and comfortable speed movements of the target arm. Errors averaged 3.7 mm larger when the target was moved faster and were equivalent to errors for slower movements (p < 0.014). Errors in the active and passive target movement conditions were also equivalent (p < 0.001). These findings show that proprioception is accurate across many different speeds of passive and active target motion and that there was no evidence than an internal model contributes to improved accuracy of proprioception during active movements.

Coupling between prefrontal brain activity and respiratory sinus arrhythmia in infants and adults.

Self-regulation is an essential aspect of healthy child development. Even though infants are dependent on their caregivers for co-regulation during the first years, they begin to gain early regulatory abilities through social interactions as well as their own cognitive development. These early regulatory abilities continue to increase with the maturation of both the prefrontal cortex and the vagal system. Importantly, theoretical accounts have suggested that the prefrontal cortex and the vagal system are linked through forward and backward feedback loops via the limbic system. Decreased coupling within this link is suggested to be associated with psychopathology. The primary goal of this study is to examine whether intrapersonal coupling of prefrontal brain activity and respiratory sinus arrythmia is evident in infancy. Using the simultaneous assessment of functional near-infrared spectroscopy and electrocardiography, we will use Cross-Recurrence Quantification Analysis to assess the coupling of prefrontal brain activity and respiratory sinus arrhythmia in 69 4-6-month-old infants and their mothers during rest. Understanding the developmental emergence of the neurobiological correlates of self- regulation will allow us to help identify neurodevelopmental risk factors.

Associations between acoustic features of maternal speech and infants' emotion regulation following a social stressor.

Caregiver voices may provide cues to mobilize or calm infants. This study examined whether maternal prosody predicted changes in infants' biobehavioral state after the still face, a stressor in which the mother withdraws and reinstates social engagement. Ninety-four dyads participated in the study (infant age 4-8 months). Infants' heart rate and respiratory sinus arrhythmia (measuring cardiac vagal tone) were derived from an electrocardiogram (ECG). Infants' behavioral distress was measured by negative vocalizations, facial expressions, and gaze aversion. Mothers' vocalizations were measured via a composite of spectral analysis and spectro-temporal modulation using a two-dimensional fast Fourier transformation of the audio spectrogram. High values on the maternal prosody composite were associated with decreases in infants' heart rate (ß = -.26, 95% CI: [-0.46, -0.05]) and behavioral distress (ß = -.23, 95% CI: [-0.42, -0.03]), and increases in cardiac vagal tone in infants whose vagal tone was low during the stressor (1 SD below mean ß = .39, 95% CI: [0.06, 0.73]). High infant heart rate predicted increases in the maternal prosody composite (ß = .18, 95% CI: [0.03, 0.33]). These results suggest specific vocal acoustic features of speech that are relevant for regulating infants' biobehavioral state and demonstrate mother-infant bi-directional dynamics.

Proximity and touch are associated with neural but not physiological synchrony in naturalistic mother-infant interactions.

Caregiver touch plays a vital role in infants' growth and development, but its role as a communicative signal in human parent-infant interactions is surprisingly poorly understood. Here, we assessed whether touch and proximity in caregiver-infant dyads are related to neural and physiological synchrony. We simultaneously measured brain activity and respiratory sinus arrhythmia of 4-6-month-old infants and their mothers (N=69 dyads) in distal and proximal joint watching conditions as well as in an interactive face-to-face condition. Neural synchrony was higher during the proximal than during the distal joint watching conditions, and even higher during the face-to-face interaction. Physiological synchrony was highest during the face-to-face interaction and lower in both joint watching conditions, irrespective of proximity. Maternal affectionate touch during the face-to-face interaction was positively related to neural but not physiological synchrony. This is the first evidence that touch mediates mutual attunement of brain activities, but not cardio-respiratory rhythms in caregiver-infant dyads during naturalistic interactions. Our results also suggest that neural synchrony serves as a biological pathway of how social touch plays into infant development and how this pathway could be utilized to support infant learning and social bonding.

Associations between infant-mother physiological synchrony and 4- and 6-month-old infants' emotion regulation.

In this study we assessed whether physiological synchrony between infants and mothers contributes to infants' emotion regulation following a mild social stressor. Infants between 4 and 6 months of age and their mothers were tested in the face-to-face-still-face paradigm and were assessed for behavioral and physiological self-regulation during and following the stressor. Physiological synchrony was calculated from a continuous measure of respiratory sinus arrhythmia (RSA) enabling us to cross-correlate the infants' and mothers' RSA responses. Without considering physiological synchrony, the evidence suggested that infants' distress followed the prototypical pattern of increasing during the Still Face episode and then decreasing during the reunion episode. Once physiological synchrony was added to the model, we observed that infants' emotion regulation improved if mother-infant synchrony was positive, but not if it was negative. This result was qualified further by whether or not infants suppressed their RSA response during the Still Face episode. In sum, these findings highlight how individual differences in infants' physiological responses contribute significantly to their self-regulation abilities.

An interactionist perspective on the development of coordinated social attention.

Infants' ability to coordinate their attention with other people develops profoundly across the first year of life. Mainly based on experimental research focusing on infants' behavior under highly controlled conditions, developmental milestones were identified and explained in the past by prominent theories in terms of the onset of specific cognitive skills. In contrast to this approach, recent longitudinal research challenges this perspective with findings suggesting that social attention develops continuously with a gradual refinement of skills. Informed by these findings, we argue for an interactionist and dynamical systems view that bases observable advances in infant social attention skills on increasingly fine-tuned mutual adjustments in the caregiver-infant dyad, resulting in gradually improving mutual prediction. We present evidence for this view from recent studies leveraging new technologies which afford the opportunity to dynamically track social interactions in real-time. These new technically-sophisticated studies offer unprecedented insights into the dynamic processes of infant-caregiver social attention. It is now possible to track in much greater detail fluctuations over time with regard to object-directed attention as well as social attention and how these processes relate to one another. Encouraged by these initial results and new insights from this interactionist developmental social neuroscience approach, we conclude with a "call to action" in which we advocate for more ecologically valid paradigms for studying social attention as a dynamic and bi-directional process.

A method for measuring dynamic respiratory sinus arrhythmia (RSA) in infants and mothers.

The measurement of respiratory sinus arrythmia (RSA) in infants, children and adults is critical to the study of physiological regulation, and more recently, interpersonal physiological covariation, but it has been impeded by methods that limit its resolution to 30 s or longer. Recent analytical developments have suggested methods for studying dynamic RSA in adults, and we have extended this work to the study of infants and mothers. In the current paper, we describe a new analytical strategy for estimating RSA time series for infants and adults. Our new method provides a means for studying physiological synchrony in infant-mother dyads that offers some important advantages relative to existing methods that use inter-beat-intervals (e.g. Feldman, Magori-Cohen, Galili, Singer, & Louzoun, 2011). In the middle sections of this paper, we offer a brief tutorial on calculating RSA continuously with a sliding window and review the empirical evidence for determining the optimal window size. In order to confirm the reliability of our results, we briefly discuss testing synchrony by randomly shuffling the dyads to control for spurious correlations, and also by using a bootstrapping technique for calculating confidence intervals in the cross-correlation function. One important implication that emerges from applying this method is that it is possible to measure both positive and negative physiological synchrony and that these categorical measures are differentially predictive of future outcomes.

Intrapatient comparisons of efficacy in a single-arm trial of entrectinib in tumour-agnostic indications.

BACKGROUND: Entrectinib is a tropomyosin receptor kinase inhibitor approved for the treatment of neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours based on single-arm trials. Traditional randomised clinical trials in rare cancers are not feasible; we conducted an intrapatient analysis to evaluate the clinical benefit of entrectinib versus prior standard-of-care systemic therapies. METHODS: Patients with locally advanced/metastatic NTRK fusion-positive tumours enrolled in the global phase II, single-arm STARTRK-2 trial were grouped according to prior systemic therapy and response. The key analysis used growth modulation index [GMI; ratio of progression-free survival (PFS) on entrectinib to time to discontinuation (TTD) on the most recent prior therapy]; ratio ≥1.3 indicated clinically meaningful efficacy. Additional analyses investigated TTD and objective response rate (ORR) for entrectinib and prior therapies. RESULTS: Seventy-one patients were included; 51 received prior systemic therapy. In 38 patients who progressed on prior therapy, ORR was 60.5% (23/38) with entrectinib and 15.8% (6/38) with the most recent prior therapy. Median PFS [11.2 months; 95% confidence interval (CI) 6.7-not estimable] for entrectinib exceeded median TTD (2.9 months; 95% CI 2.0-4.9) for most recent prior therapy. From the intrapatient analysis of GMI, 65.8% had a ratio ≥1.3 and median GMI was 2.53. Consistent results were observed at more stringent GMI thresholds; 60.5% of patients had GMI ≥1.5 or ≥1.8 and 57.9% had GMI ≥2.0. CONCLUSIONS: ORR was high and PFS was longer on entrectinib versus TTD on prior therapy. Furthermore, 65.8% of patients experienced clinically meaningful benefit based on GMI. This intrapatient analysis demonstrates comparative effectiveness of entrectinib in a rare, heterogeneous adult population.

The temporal dynamics of infants' joint attention: Effects of others' gaze cues and manual actions.

Infants' development of joint attention shows significant advances between 9 and 12 months of age, but we still need to learn much more about how infants coordinate their attention with others during this process. The objective of this study was to use eye tracking to systematically investigate how 8- and 12-month-old infants as well as adults dynamically select their focus of attention while observing a social partner demonstrate infant-directed actions. Participants were presented with 16 videos of actors performing simple infant-directed actions from a first-person perspective. Looking times to faces as well as hands-and-objects were calculated for participants at each age, and developmental differences were observed, although all three groups looked more at hands-and-objects than at faces. In order to assess whether visual attention was coordinated with the actors' behaviors, we compared participants looking at faces and objects in response to gaze direction as well as infant-directed actions vs. object-directed actions. By presenting video stimuli that involved continuously changing actions, we were able to document that the likelihood of joint attention changes in both real and developmental time. Overall, adults and 12-month-old infants' visual attention was modulated by gaze cues as well as actions, whereas this was only partially true for 8-month-old infants. Our results reveal that joint attention is not a monolithic process nor does it develop all at once.

Statistical Models for Predicting Threat Detection From Human Behavior.

Users must regularly distinguish between secure and insecure cyber platforms in order to preserve their privacy and safety. Mouse tracking is an accessible, high-resolution measure that can be leveraged to understand the dynamics of perception, categorization, and decision-making in threat detection. Researchers have begun to utilize measures like mouse tracking in cyber security research, including in the study of risky online behavior. However, it remains an empirical question to what extent real-time information about user behavior is predictive of user outcomes and demonstrates added value compared to traditional self-report questionnaires. Participants navigated through six simulated websites, which resembled either secure "non-spoof" or insecure "spoof" versions of popular websites. Websites also varied in terms of authentication level (i.e., extended validation, standard validation, or partial encryption). Spoof websites had modified Uniform Resource Locator (URL) and authentication level. Participants chose to "login" to or "back" out of each website based on perceived website security. Mouse tracking information was recorded throughout the task, along with task performance. After completing the website identification task, participants completed a questionnaire assessing their security knowledge and degree of familiarity with the websites simulated during the experiment. Despite being primed to the possibility of website phishing attacks, participants generally showed a bias for logging in to websites versus backing out of potentially dangerous sites. Along these lines, participant ability to identify spoof websites was around the level of chance. Hierarchical Bayesian logistic models were used to compare the accuracy of two-factor (i.e., website security and encryption level), survey-based (i.e., security knowledge and website familiarity), and real-time measures (i.e., mouse tracking) in predicting risky online behavior during phishing attacks. Participant accuracy in identifying spoof and non-spoof websites was best captured using a model that included real-time indicators of decision-making behavior, as compared to two-factor and survey-based models. Findings validate three widely applicable measures of user behavior derived from mouse tracking recordings, which can be utilized in cyber security and user intervention research. Survey data alone are not as strong at predicting risky Internet behavior as models that incorporate real-time measures of user behavior, such as mouse tracking.

Viral infections and breast cancer - A current perspective.

Sporadic human breast cancer is the most common cancer to afflict women. Since the discovery, decades ago, of the oncogenic mouse mammary tumour virus, there has been significant interest in the potential aetiologic role of infectious agents in sporadic human breast cancer. To address this, many studies have examined the presence of viruses (e.g. papillomaviruses, herpes viruses and retroviruses), endogenous retroviruses and more recently, microbes, as a means of implicating them in the aetiology of human breast cancer. Such studies have generated conflicting experimental and clinical reports of the role of infection in breast cancer. This review evaluates the current evidence for a productive oncogenic viral infection in human breast cancer, with a focus on the integration of sensitive and specific next generation sequencing technologies with pathogen discovery. Collectively, the majority of the recent literature using the more powerful next generation sequencing technologies fail to support an oncogenic viral infection being involved in disease causality in breast cancer. In balance, the weight of the current experimental evidence supports the conclusion that viral infection is unlikely to play a significant role in the aetiology of breast cancer.

Infants' motor simulation of observed actions is modulated by the visibility of the actor's body.

Previous research suggests that 9-month-old infants will develop a response bias in the A-not-B search paradigm after only observing an experimenter search for a hidden object on A-trials. In the current experiment, we tested whether infants would persist in making errors when only the hands-and-arms of the experimenter were visible. Three different conditions were included: (1) the experimenter was silent while hiding and finding the object, (2) the experimenter communicated with the infant via infant-directed speech, or (3) the body of the experimenter was visible during the training phase before his head and body were occluded during the test phase. Unlike previous studies, the results revealed that a significant proportion of infants searched correctly when the body of the experimenter was not visible, and only the combination of infant-directed speech and familiarization with a fully-specified body resulted in a majority of infants committing search errors. These results are interpreted as suggesting that the likelihood of infants committing search errors is dependent on their motor simulation of the experimenter's reaching. The strength of this simulation is graded by the similarity between the observed action and the motor representation.

Infants' observation of others' actions: Brief movement-specific visual experience primes motor representations.

Recent research suggests that infants' observation of others' reaching actions activates corresponding motor representations which develop with their motor experience. Contralateral reaching develops a few months later than ipsilateral reaching, and 9-month-old infants are less likely to map the observation of these reaches to their motor representations. The goal of the current study was to test whether a brief familiarization with contralateral reaching is sufficient to prime this less developed motor representation to increase the likelihood of its activation. In Experiment 1, infants were familiarized with contralateral reaching before they were tested in an observational version of the A-not-B paradigm. A significant number of infants searched incorrectly, suggesting that the observation of contralateral reaching primed their motor representations. In Experiment 2, infants were familiarized with ipsilateral reaching, which shared the goals but not the movements associated with the contralateral reaches observed during testing, and they did not show a search bias. Taken together, these results suggest that a brief familiarization with a movement-specific behaviour facilitates the direct matching of observed and executed actions.

When do infants begin to follow a point?

Infants' understanding of a pointing gesture represents a major milestone in their communicative development. The current consensus is that infants are not capable of following a pointing gesture until 9-12 months of age. In this article, we present evidence from 4- and 6-month-old infants challenging this conclusion. Infants were tested with a spatial cueing paradigm in Experiment 1 (500-ms stimulus-target onset asynchrony [SOA]) and Experiment 2 (100-ms SOA). The results revealed that the younger infants shifted their attention in the cued direction when presented with a pointing gesture and with a foil (i.e., same size and shape as pointing gesture) at both SOAs. Older infants shifted their attention only in response to the pointing gesture at 100-ms SOA. Experiment 3 tested infants' preferences for the social stimulus (i.e., pointing gesture) relative to the foil and a non-social stimulus (i.e., an arrow). The results revealed that infants are biased to selectively attend to the pointing gesture. Taken together, these results suggest that 4- and 6-month-old infants are capable of preferentially selecting and following a pointing gesture. It is theorized that this early capacity assists infants in their developing understanding of triadic forms of communication.