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1.  A Flexible Analysis Tool for the Quantitative Acoustic Assessment of Infant Cry 
In this article, the authors describe and validate the performance of a modern acoustic analyzer specifically designed for infant cry analysis.
Utilizing known algorithms, the authors developed a method to extract acoustic parameters describing infant cries from standard digital audio files. They used a frame rate of 25 ms with a frame advance of 12.5 ms. Cepstral-based acoustic analysis proceeded in 2 phases, computing frame-level data and then organizing and summarizing this information within cry utterances. Using signal detection methods, the authors evaluated the accuracy of the automated system to determine voicing and to detect fundamental frequency (F0) as compared to voiced segments and pitch periods manually coded from spectrogram displays.
The system detected F0 with 88% to 95% accuracy, depending on tolerances set at 10 to 20 Hz. Receiver operating characteristic analyses demonstrated very high accuracy at detecting voicing characteristics in the cry samples.
This article describes an automated infant cry analyzer with high accuracy to detect important acoustic features of cry. A unique and important aspect of this work is the rigorous testing of the system’s accuracy as compared to ground-truth manual coding. The resulting system has implications for basic and applied research on infant cry development.
PMCID: PMC4956095  PMID: 23785178
cry; acoustics; analysis; infants; developmental disorders
2.  Methylation of the Glucocorticoid Receptor (NR3C1) in Placenta Is Associated with Infant Cry Acoustics 
Epigenetic mechanisms regulating expression of the glucocorticoid receptor gene (NR3C1) promoter may influence behavioral and biological aspects of stress response in human infants. Acoustic features of infant crying are an indicator of neurobehavioral and neurological status not yet investigated in relation to epigenetic mechanisms. We examined NR3C1 methylation in placental tissue from a series of 120 healthy newborn infants in relation to a detailed set of acoustic features extracted from newborn infant cries. We identified significant associations of NR3C1 methylation with energy variation in infants' cries as well as with the presence of very high fundamental frequency in cry utterances. The presence of high fundamental frequency in cry (above 1 kHz) has been linked to poor vocal tract control, poor regulation of stress response, and may be an indicator or poor neurobehavioral integrity. Thus, these results add to evidence linking epigenetic alteration of the NR3C1 gene in the placenta to neurodevelopmental features in infants.
PMCID: PMC4889592  PMID: 27313516
infancy; human; placenta; epigenetic; neurodevelopment; cry; acoustics
3.  Parasympathetic Response Profiles Related to Social Functioning in Young Children with Autistic Disorder 
Autism Research and Treatment  2013;2013:868396.
Psychophysiology studies of heart rate and heart rate variability can be employed to study regulatory processes in children with autism. The objective of this study was to test for differences in respiratory sinus arrhythmia (RSA; a measure of heart rate variability) and to examine the relationship between physiologic responses and measures of social behavior. Participants included 2- to 6-year-old children with Autistic Disorder and children without autism. Heart rate and RSA were derived from ECG recordings made during a baseline period and then a stranger approach paradigm. Social and adaptive behavior was assessed by parent report. Groups did not differ in mean heart rate or RSA at baseline or in response to social challenge. However, children with autism were more likely to show a physiologic response to intrusive portions of the stranger approach than to less intrusive portions of this procedure. Nonautistic children were equally likely to respond to intrusive and less intrusive social events. Within the autistic group, physiologic response to the intrusive stranger approach corresponded to higher ratings of social adaptive behaviors. These results suggest that physiologic responses to social challenge may help understand differences in social behavioral outcomes in children with autism.
PMCID: PMC3794559  PMID: 24175094
4.  Structural Brain Imaging in Children and Adolescents Following Prenatal Cocaine Exposure 
Developmental neuroscience  2014;36(0):316-328.
Brain morphometry of 21 children, who were followed from birth and underwent structural brain magnetic resonance imaging (MRI) at 8–10 years, were studied. This cohort included 11 children with prenatal cocaine exposure (CE) and 10 non-cocaine exposed children (NCE). We compared the CE versus NCE groups using FreeSurfer to automatically segment and quantify the volume of individual brain structures. In addition, we created a pediatric atlas specifically for this population and demonstrate the enhanced accuracy of this approach. We found an overall trend towards smaller brain volumes among CE children. The volume differences were significant for cortical gray matter, thalamus and putamen. Here, reductions in thalamic and putaminal volumes showed a robust inverse-correlation with exposure levels, thus highlighting effects on dopamine rich brain regions that form key components of brain circuitry known to play important roles in behavior and attention. Interestingly, head circumferences (HCs) at birth as well as at the time of imaging showed a tendency for smaller size among CE children. HCs at the time of imaging correlated well with the cortical volumes, for all subjects. In contrast, HCs at birth were predictive of the cortical volume only for the CE group.
A subgroup of these subjects (6 CE and 4 NCE) was also scanned at 13–15 years old. In subjects who were scanned twice, we found that the trend for smaller structures continues into 13–15 years of age. We found that the differences in structural volumes between CE and NCE groups are largely diminished when the HCs are matched by study design or controlled for. Participants in this study were drawn from a unique longitudinal cohort, and while the small sample size precludes strong conclusions, the results point to reductions in HCs and in specific brain structures that persist through teenage years in children who were exposed to cocaine in utero.
PMCID: PMC4125447  PMID: 24994509
structural brain imaging; prenatal cocaine exposure; Developing brain; Magnetic resonance imaging; Prenatal cocaine
5.  Regional Brain Morphometry and Impulsivity in Adolescents Following Prenatal Exposure to Cocaine and Tobacco 
JAMA pediatrics  2013;167(4):348-354.
Animal studies have suggested that prenatal cocaine exposure (PCE) deleteriously influences the developing nervous system, in part attributable to its site of action in blocking the function of monoamine reuptake transporters, increasing synaptic levels of serotonin and dopamine.
To examine the brain morphologic features and associated impulsive behaviors in adolescents following prenatal exposure to cocaine and/or tobacco.
Magnetic resonance imaging data and behavioral measures were collected from adolescents followed up longitudinally in the Maternal Lifestyle Study.
A hospital-based research center.
A total of 40 adolescent participants aged 13 to 15 years were recruited, 20 without PCE and 20 with PCE; a subset of each group additionally had tobacco exposure. Participants were selected and matched based on head circumference at birth, gestational age, maternal alcohol use, age, sex, race/ethnicity, IQ, family poverty, and socioeconomic status.
Main Outcome Measures
Subcortical volumetric measures of the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens; cortical thickness measures of the dorsolateral prefrontal cortex and ventral medial prefrontal cortex; and impulsivity assessed by Conners' Continuous Performance Test and the Sensation Seeking Scale for Children.
After controlling for covariates, cortical thickness of the right dorsolateral prefrontal cortex was significantly thinner in adolescents following PCE (P=.03), whereas the pallidum volume was smaller in adolescents following prenatal tobacco exposure (P=.03). Impulsivity was correlated with thalamic volume following either PCE (P=.05) or prenatal tobacco exposure (P=.04).
Conclusions and Relevance
Prenatal cocaine or tobacco exposure can differentially affect structural brain maturation during adolescence and underlie enhanced susceptibility to impulsivity. Additional studies with larger sample sizes are warranted.
PMCID: PMC4467165  PMID: 23400239
6.  Atypical Cry Acoustics in 6-Month-Old Infants at Risk for Autism Spectrum Disorder 
This study examined differences in acoustic characteristics of infant cries in a sample of babies at risk for autism and a low-risk comparison group. Cry samples derived from vocal recordings of 6-month-old infants at risk for autism spectrum disorder (ASD; n = 21) and low-risk infants (n = 18) were subjected to acoustic analyses using analysis software designed for this purpose. Cries were categorized as either pain-related or non-pain-related based on videotape coding. At-risk infants produced pain-related cries with higher and more variable fundamental frequency (F0) than low-risk infants. At-risk infants later classified with ASD at 36 months had among the highest F0 values for both types of cries and produced cries that were more poorly phonated than those of nonautistic infants, reflecting cries that were less likely to be produced in a voiced mode. These results provide preliminary evidence that disruptions in cry acoustics may be part of an atypical vocal signature of autism in early life.
PMCID: PMC3517274  PMID: 22890558
autism; infancy; cry; vocalizations; acoustic analysis
7.  The Rhode Island Consortium for Autism Research and Treatment (RI-CART): A New Statewide Autism Collaborative 
Autism is a neurodevelopmental disorder characterized by core deficits in social interaction, language and repetitive behaviors. The need for services is rising sharply as the number of children identified with autism increases. The Rhode Island Consortium for Autism Research and Treatment (RI-CART) was founded in 2009 with the goal of increasing communication among autism researchers throughout the state and improving treatment for children with autism. RI-CART members have several exciting projects in progress, with its larger aim being the creation of a statewide research registry. A statewide registry would benefit research in Rhode Island and allow for larger collaborations nationally.
PMCID: PMC4134665  PMID: 24791265
RI-CART; autism; autism spectrum disorder; registry; Rhode Island
8.  Prenatal Substance Exposure: Neurobiological Organization at One Month 
The Journal of pediatrics  2013;163(4):989-994.e1.
To examine the autonomic nervous system and neurobehavioral response to a sustained visual attention challenge among 1-month old infants with prenatal substance exposure.
Study design
We measured heart rate (HR), respiratory sinus arrhythmia (RSA), and neurobehavior during sustained visual orientation tasks included in the NICU Network Neurobehavioral Scale (NNNS) in 1,129, 1-month infants with prenatal substance exposure. Four groups were compared: infants with prenatal cocaine and opiate exposure, infants with cocaine exposure, infants with opiate exposure, and infants with exposure to other substances (i.e. alcohol, marijuana, and tobacco).
Infants with prenatal cocaine and opiate exposure had the highest HRs and lowest levels of RSA during a sustained visual attention procedure compared with the other three groups. Infants with prenatal cocaine and opiate exposure had poorer quality of movement and more hypertonicity during the NNNS exam compared with the other three exposure groups. Infants with prenatal cocaine and opiate exposure had more nonoptimal reflexes and stress/abstinence signs compared with infants with prenatal cocaine exposure only and infants with prenatal exposure to alcohol, tobacco, and marijuana.
Problems with arousal regulation were identified among infants with prenatal substance exposure. Autonomic dysregulation has been implicated as a mechanism by which these difficulties occur. Our results suggest that infants with both prenatal cocaine and opiate exposure have the greatest autonomic response to the challenge of a sustained visual attention task, which may place these infants at risk for developing problems associated with physiological and behavioral regulation, a necessary prerequisite for early learning.
PMCID: PMC3773295  PMID: 23743094
in utero drug exposure; physiology; neurobehavioral
9.  Bottom-Up Attention Orienting in Young Children with Autism 
We examined the impact of simultaneous bottom-up visual influences and meaningful social stimuli on attention orienting in young children with autism spectrum disorders (ASDs). Relative to typically-developing age and sex matched participants, children with ASDs were more influenced by bottom-up visual scene information regardless of whether social stimuli and bottom-up scene properties were congruent or competing. This initial reliance on bottom-up strategies correlated with severity of social impairment as well as receptive language impairments. These data provide support for the idea that there is enhanced reliance on bottom-up attention strategies in ASDs, and that this may have a negative impact on social and language development.
PMCID: PMC4089391  PMID: 23996226
Bottom-up attention; Saliency; Visual attention; Autism; Eye tracking; Social attention
10.  Attention and word learning in autistic, language delayed and typically developing children 
Previous work has demonstrated that patterns of social attention hold predictive value for language development in typically developing infants. The goal of this research was to explore how patterns of attention in autistic, language delayed, and typically developing children relate to early word learning and language abilities. We tracked patterns of eye movements to faces and objects while children watched videos of a woman teaching them a series of new words. Subsequent test trials measured participants‘ recognition of these novel word-object pairings. Results indicated that greater attention to the speaker‘s mouth was related to higher scores on standardized measures of language development for autistic and typically developing children (but not for language delayed children). This effect was mediated by age for typically developing, but not autistic children. When effects of age were controlled for, attention to the mouth among language delayed participants was negatively correlated with standardized measures of language learning. Attention to the speaker‘s mouth and eyes while she was teaching the new words was also predictive of faster recognition of those words among autistic children. These results suggest that language delays among children with autism may be driven in part by aberrant social attention, and that the mechanisms underlying these delays may differ from those in language delayed participants without autism.
PMCID: PMC4033261  PMID: 24904503
autism spectrum disorders; eye tracking; word learning; attention to faces; language development
11.  Functional MRI and Response Inhibition in Children Exposed to Cocaine in utero 
Developmental Neuroscience  2009;31(1-2):159-166.
This study investigated the potential long-term effects of cocaine exposure on brain functioning using fMRI in school-aged children. The sample included 12 children with prenatal cocaine exposure and 12 non-exposed children (8–9 years old). Groups did not differ on IQ, socioeconomic status, or perinatal risk factors. A response inhibition task was administered during an fMRI scan using a 1.5-T MRI system. Task performance did not differentiate groups, but groups were differentiated by patterns of task-related brain activity. Cocaine-exposed children showed greater activation in the right inferior frontal cortex and caudate during response inhibition, whereas non-exposed children showed greater activations in temporal and occipital regions. These preliminary findings suggest that prenatal cocaine may affect the development of brain systems involved in the regulation of attention and response inhibition.
PMCID: PMC2951722  PMID: 19372696
Prenatal cocaine; Neuroimaging; Cognitive development; Inhibition
12.  Screening for Autism Spectrum Disorders in Extremely Preterm Infants 
Extremely preterm (EP) infants screen positive for Autism Spectrum Disorders (ASD) at high rates. However it is not clear whether this is due to high rates of ASD in EPs or to high rates of false positive screens for ASD in children with a high rate of underlying neurodevelopmental impairments. Combining a parent questionnaire designed to distinguish developmental delay from ASD with direct observation of infant behavior may more accurately screen for ASD in EPs.
To determine rates of positive screen for ASD at 18–22months(m) in EPs using three screens; to determine factors associated with a positive screen.
554 infants born <27 weeks were screened at 18–22m using the Pervasive Developmental Disorders Screening Test, 2nd edition, Stage 2 (PDDST-II) and the response to name and response to joint attention items from the Autism Diagnostic Observation Schedule. Infants with severe cerebral palsy, deafness and blindness were excluded. Associations between positive screen and neonatal/infant characteristics were determined.
113/554 (20 %) had ≥1 positive screen. 10% had a positive PDDST-II, 6% response to name, 9% response to joint attention; in only 1% were all 3 screens positive. Positive screen was associated with male gender, more hospital days, white race, lower maternal education, abnormal behavioral scores, and cognitive/language delay.
The use of three screens for ASD in EPs results in higher screen positive rates than use of one screen alone. Diagnostic confirmation is needed before true rates of ASD in EPs are known.
PMCID: PMC3434239  PMID: 22926660
Autism; Prematurity; Screening
13.  An Initial Investigation of Baseline Respiratory Sinus Arrhythmia as a Moderator of Treatment Outcome for Young Children Born Premature with Externalizing Behavior Problems 
Behavior therapy  2012;43(3):652-665.
The aim of the current study was to examine the moderating effect of baseline respiratory sinus arrhythmia (RSA) on Parent-Child Interaction Therapy (PCIT), a behavioral parent-training intervention, for young children born premature. In this pilot randomized controlled trial, 28 young children (mean age of 37.79 months), who were born < 37 weeks gestation and presented with elevated externalizing behavior problems, were randomly assigned to an immediate treatment or waitlist control group. RSA, which provides an approximate marker of individual differences in cardiac vagal tone, was measured during a baseline period. Past research has generally shown that higher levels of baseline RSA correlate with various positive psychological states (e.g., empathy, sustained attention), whereas lower levels of baseline RSA correlate with less optimal psychological states (e.g., higher externalizing behavior problems). Results indicated that baseline RSA significantly interacted with treatment condition in predicting changes in child disruptive behavior. Specifically, low levels of baseline RSA were associated with greater improvements in child disruptive behavior following PCIT. While acknowledging the caveats of measuring and interpreting RSA and the need to include a sympathetic-linked cardiac measure in future research, these findings provide preliminary evidence that children with lower capacity for emotion regulation receive even greater treatment gains. Future research should also examine the moderating effect of RSA in larger samples and explore the potential mediating role of RSA on behavioral parenting interventions.
PMCID: PMC3475510  PMID: 22697452
respiratory sinus arrhythmia; emotion regulation; prematurity; behavior problems; behavioral parent training
14.  Evidence-Based Intervention for Young Children Born Premature: Preliminary Evidence for Associated Changes in Physiological Regulation 
Infant behavior & development  2012;35(3):417-428.
The current study examined whether changes in maternal behaviors following an evidence-based treatment—Parent Child Interaction Therapy (PCIT)—was associated with improvements in cardiac vagal regulation in young children born premature. Participants included 28 young children (mean age = 37.79 months) that were born premature and presented with elevated externalizing behavior problems. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (withdrawal or suppression) to a clean-up task were derived pre and post-treatment. Results indicated that an increase in behaviors mothers are taught to use during treatment (i.e., do skills—praise, reflection, and behavioral descriptions) were associated with an improvement in children’s post-treatment RSA suppression levels. The current study illustrates the important role of caregiver behavior in promoting physiological regulation in children born premature.
PMCID: PMC3409342  PMID: 22721742
cardiac vagal regulation; RSA suppression; emotion regulation; prematurity; child; parent training
15.  Physiologic Arousal to Social Stress in Children with Autism Spectrum Disorders: A Pilot Study 
Little is known about arousal to socially stressful situations in children with Autism Spectrum Disorders. This preliminary study investigates physiologic arousal in children with high functioning autism (HFA, n=19) compared to a comparison group (n=11) before, during, and after the Trier Social Stress Test. The HFA group was more likely to have a decrease in salivary cortisol following the stressor, while the comparison group was more likely to have an increase (p=.02). However, there was no difference in electrodermal activity, a measure of sympathetic arousal, or vagal tone, a measure of parasympathetic activity, between groups. These findings implicate a differential neuroendocrine response to social stress in children with HFA despite similar sympathetic and parasympathetic responses during a stressor. Further studies are required to substantiate this finding.
PMCID: PMC3212393  PMID: 22081773
psychophysiology; Trier Social Stress Test; high functioning autism; stress
16.  The impact of prenatal exposure to cocaine and tobacco on diffusion tensor imaging and sensation seeking in adolescents 
The Journal of pediatrics  2011;159(5):771-775.
To study white matter integrity using diffusion tensor imaging (DTI) in adolescents with prenatal cocaine and/or tobacco exposure.
Study design
Subjects included 20 adolescents with prenatal cocaine exposure (15 with tobacco exposure) and 20 non-cocaine-exposed subjects (8 with tobacco exposure). DTI measures were assessed in 5 subregions of the corpus callosum. The Sensation Seeking Scale for Children was administered to evaluate behavioral inhibition.
No significant differences were found between cocaine-exposed and non-cocaine-exposed group in each subregion of the corpus callosum on measures of fractional anisotropy (FA) and mean diffusivity (MD), although the cocaine-exposed showed a trend (P = 0.06) toward higher FA in projections to the supplementary motor area (SMA) and premotor cortex (PMC) . Prenatal tobacco exposure was associated with decreased FA in SMA-PMC projections after adjustment for relevant covariates (P = 0.03). Decreased FA was related to more sensation seeking in the adolescents who were prenatally exposed to tobacco.
Prenatal tobacco exposure could affect white matter integrity which is related to sensation seeking in adolescents. Developmental neurotoxins might have differential influences on white matter maturation in adolescence.
PMCID: PMC3420810  PMID: 21723565
neuroimaging; impulsivity; prenatal drug exposure; response inhibition
17.  A Preliminary Study of Cortisol Reactivity and Behavior Problems in Young Children Born Premature 
Developmental psychobiology  2010;52(6):574-582.
The purpose of the present study was to examine the relation between cortisol reactivity and comorbid internalizing and externalizing behavior problems among children born premature. Children between the ages of 18 and 60 months who were born < 37 weeks gestation and presented with clinically significant externalizing behavior problems were included. Children were categorized based on those who mounted a cortisol response to a stressor and those who did not mount a cortisol response. Children demonstrating the cortisol response were reported to have more problems with attention, emotional reactivity, anxiety, and depression based on maternal report and displayed higher rates of negative verbalizations during a mother-child interaction than children without a cortisol response. These results extend the findings of the relation between cortisol reactivity and comorbid internalizing and externalizing behavior problems to a sample of children born premature.
PMCID: PMC2933079  PMID: 20806330
cortisol; prematurity; behavior problems; stress; assessment
18.  Parenting Intervention for Externalizing Behavior Problems in Children Born Premature: An Initial Examination 
To examine the initial efficacy of parent-child interaction therapy (PCIT) for treating behavior problems in young children who were born premature.
In this randomized, controlled trial, 28 children between the ages of 18 and 60 months, who were born <37 weeks gestation and presented with clinically significant externalizing behavior problems, were randomly assigned to an immediate treatment (IT) or waitlist (WL) control group.
After 4 months, children who received PCIT were reported by their mother to have less attention problems, aggressive behaviors, and externalizing and internalizing behavior problems, and they were observed to be more compliant to maternal commands than children in the WL group. In addition, mothers in the IT group interacted more positively with their child, reported lower parenting stress related to difficult child behavior and demonstrated improved parenting practices compared with WL mothers. Behavior change maintained for 80% of the IT children 4 months after treatment completion.
This study demonstrates preliminary efficacy of PCIT for the treatment of behavior problems in young children who were born premature.
PMCID: PMC2866142  PMID: 20375736
parent-child interaction therapy; behavior problems; prematurity
19.  The Effect of Parenting Stress on Child Behavior Problems in High-Risk Children with Prenatal Drug Exposure 
To examine the relationship between early parenting stress and later child behavior in a high risk sample and measure the effect of drug exposure on the relationship between parenting stress and child behavior.
A subset of child-caregiver dyads (n = 607) were selected from the Maternal Lifestyle Study, which is a large sample of children (n = 1388) with prenatal cocaine exposure and a comparison sample unexposed to cocaine. Of the 607 dyads, 221 were prenatally exposed to cocaine and 386 were unexposed to cocaine. Selection was based on the presence of a stable caregiver at 4 and 36 months with no evidence of change in caregiver between those time points.
Parenting stress at 4 months significantly predicted child externalizing behavior at 36 months. These relations were unaffected by cocaine exposure suggesting the relationship between parenting stress and behavioral outcome exists for high-risk children regardless of drug exposure history.
These results extend the findings of the relationship between parenting stress and child behavior to a sample of high-risk children with prenatal drug exposure. Implications for outcome and treatment are discussed.
PMCID: PMC2861499  PMID: 18626768
disruptive behavior; parenting stress; high-risk children; prenatal drug exposure; cocaine
20.  Parent-Child Interaction Therapy for Children Born Premature: A Case Study and Illustration of Vagal Tone as a Physiological Measure of Treatment Outcome 
Cognitive and behavioral practice  2009;16(4):468-477.
Evidence-based psychosocial interventions for externalizing behavior problems in children born premature have not been reported in the literature. This single-case study describes Parent-Child Interaction Therapy (PCIT) with a 23-month-old child born at 29 weeks gestation weighing 1,020 grams, who presented with significant externalizing behavior problems. Treatment outcome was assessed using standard measures of maternal and child functioning and observational measures of the parent-child interaction, as well as a physiological measure of heart rate variability (i.e., vagal tone) used to assess parasympathetic control in the child. Maternal reports of child behavior problems and their own stress and depressive symptoms decreased after treatment. Behavioral observations demonstrated improved parenting practices and child compliance, and vagal tone showed comparable increases as well. Results suggest that PCIT is a promising psychosocial intervention for children born premature with externalizing behavior problems, and that vagal tone may be a useful measure of treatment outcome.
PMCID: PMC2860291  PMID: 20428470

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