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Jennifer Phillips, PhD

  • Jennifer M Phillips

Especialidades médicas y/o especialidades quirúrgicas

Psychology

Trabajo y educación

Primeros años de residencia

University of Texas Southwestern Medical Center, Dallas, TX, 06/30/1999

Subespecialidad

Arizona State University, Tempe, AR, 06/30/2001

Stanford University School of Medicine Registrar, Palo Alto, CA, 06/30/2002

Servicios

Autismo

Experiencia

Autism

Todo Publicaciones

A Pivotal Response Treatment Package for Children With Autism Spectrum Disorder: An RCT. Pediatrics Gengoux, G. W., Abrams, D. A., Schuck, R., Millan, M. E., Libove, R., Ardel, C. M., Phillips, J. M., Fox, M., Frazier, T. W., Hardan, A. Y. 2019

Abstract

OBJECTIVES: Our aim was to conduct a randomized controlled trial to evaluate a pivotal response treatment package (PRT-P) consisting of parent training and clinician-delivered in-home intervention on the communication skills of children with autism spectrum disorder.METHODS: Forty-eight children with autism spectrum disorder and significant language delay between 2 and 5 years old were randomly assigned to PRT-P (n = 24) or the delayed treatment group (n = 24) for 24 weeks. The effect of treatment on child communication skills was assessed via behavioral coding of parent-child interactions, standardized parent-report measures, and blinded clinician ratings.RESULTS: Analysis of child utterances during the structured laboratory observation revealed that, compared with the delayed treatment group, children in PRT-P demonstrated greater improvement in frequency of functional utterances (F1,41 = 6.07; P = .026; d = 0.61). The majority of parents in the PRT-P group (91%) were able to implement pivotal response treatment (PRT) with fidelity within 24 weeks. Children receiving PRT-P also demonstrated greater improvement on the Brief Observation of Social Communication Change, on the Clinical Global Impressions Improvement subscale, and in number of words used on a parent-report questionnaire.CONCLUSIONS: This is the first 24-week randomized controlled trial in which community treatment is compared with the combination of parent training and clinician-delivered PRT. PRT-P was effective for improving child social communication skills and for teaching parents to implement PRT. Additional research will be needed to understand the optimal combination of treatment settings, intensity, and duration, and to identify child and parent characteristics associated with treatment response.

View details for DOI 10.1542/peds.2019-0178

View details for PubMedID 31387868

Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research Mariscal, M. G., Oztan, O., Rose, S. M., Libove, R. A., Jackson, L. P., Sumiyoshi, R. D., Trujillo, T. H., Carson, D. S., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2019

Abstract

Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N=34) and TD children (N=30) aged 6-12years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration*group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F1,50 =7.4987; P=0.0085). Specifically, blood OXT concentration was positively related to contagious yawning behavior in children with ASD, but not in TD children. This finding was not due to delayed perception of yawn stimuli and was observed whether attention paid to test stimuli and clinical symptom severity were included in the analysis or not. These findings suggest that only a biologically defined subset of children with ASD exhibits reduced empathy, as measured by the impaired contagious yawn response, and that prior conflicting reports of this behavioral phenomenon may be attributable, at least in part, to variable mean OXT concentrations across different ASD study cohorts. Autism Res 2019. 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism may contagiously yawn (i.e., yawn in response to another's yawn) less often than people without autism. We find that people with autism who have lower levels of blood oxytocin (OXT), a hormone involved in social behavior and empathy, show decreased contagious yawning, but those who have higher blood OXT levels do not differ in contagious yawning from controls. This suggests that decreased contagious yawning may only occur in a biologically defined subset of people with autism.

View details for DOI 10.1002/aur.2135

View details for PubMedID 31132232

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019; 11 (491)
Effect of Wearable Digital Intervention for Improving Socialization in Children With Autism Spectrum Disorder A Randomized Clinical Trial JAMA PEDIATRICS Voss, C., Schwartz, J., Daniels, J., Kline, A., Haber, N., Washington, P., Tariq, Q., Robinson, T. N., Desai, M., Phillips, J. M., Feinstein, C., Winograd, T., Wall, D. P. 2019; 173 (5): 44654
Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder AUTISM Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2019; 23 (3): 71325
A pilot investigation of neuroimaging predictors for the benefits from pivotal response treatment for children with autism JOURNAL OF PSYCHIATRIC RESEARCH Hegarty, J. P., Gengoux, G. W., Berquist, K. L., Milian, M., Tamura, S. M., Karve, S., Rosenthal, M. D., Phillips, J. M., Hardan, A. Y. 2019; 111: 14044
Effect of Wearable Digital Intervention for Improving Socialization in Children With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA pediatrics Voss, C., Schwartz, J., Daniels, J., Kline, A., Haber, N., Washington, P., Tariq, Q., Robinson, T. N., Desai, M., Phillips, J. M., Feinstein, C., Winograd, T., Wall, D. P. 2019

Abstract

Importance: Autism behavioral therapy is effective but expensive and difficult to access. While mobile technology-based therapy can alleviate wait-lists and scale for increasing demand, few clinical trials exist to support its use for autism spectrum disorder (ASD) care.Objective: To evaluate the efficacy of Superpower Glass, an artificial intelligence-driven wearable behavioral intervention for improving social outcomes of children with ASD.Design, Setting, and Participants: A randomized clinical trial in which participants received the Superpower Glass intervention plus standard of care applied behavioral analysis therapy and control participants received only applied behavioral analysis therapy. Assessments were completed at the Stanford University Medical School, and enrolled participants used the Superpower Glass intervention in their homes. Children aged 6 to 12 years with a formal ASD diagnosis who were currently receiving applied behavioral analysis therapy were included. Families were recruited between June 2016 and December 2017. The first participant was enrolled on November 1, 2016, and the last appointment was completed on April 11, 2018. Data analysis was conducted between April and October 2018.Interventions: The Superpower Glass intervention, deployed via Google Glass (worn by the child) and a smartphone app, promotes facial engagement and emotion recognition by detecting facial expressions and providing reinforcing social cues. Families were asked to conduct 20-minute sessions at home 4 times per week for 6 weeks.Main Outcomes and Measures: Four socialization measures were assessed using an intention-to-treat analysis with a Bonferroni test correction.Results: Overall, 71 children (63 boys [89%]; mean [SD] age, 8.38 [2.46] years) diagnosed with ASD were enrolled (40 [56.3%] were randomized to treatment, and 31 (43.7%) were randomized to control). Children receiving the intervention showed significant improvements on the Vineland Adaptive Behaviors Scale socialization subscale compared with treatment as usual controls (mean [SD] treatment impact, 4.58 [1.62]; P=.005). Positive mean treatment effects were also found for the other 3 primary measures but not to a significance threshold of P=.0125.Conclusions and Relevance: The observed 4.58-point average gain on the Vineland Adaptive Behaviors Scale socialization subscale is comparable with gains observed with standard of care therapy. To our knowledge, this is the first randomized clinical trial to demonstrate efficacy of a wearable digital intervention to improve social behavior of children with ASD. The intervention reinforces facial engagement and emotion recognition, suggesting either or both could be a mechanism of action driving the observed improvement. This study underscores the potential of digital home therapy to augment the standard of care.Trial Registration: ClinicalTrials.gov identifier: NCT03569176.

View details for PubMedID 30907929

Impaired voice processing in reward and salience circuits predicts social communication in children with autism ELIFE Abrams, D., Padmanabhan, A., Chen, T., Odriozola, P., Baker, A. E., Kochalka, J., Phillips, J. M., Menon, V. 2019; 8
Impaired voice processing in reward and salience circuits predicts social communication in children with autism. eLife Abrams, D. A., Padmanabhan, A., Chen, T., Odriozola, P., Baker, A. E., Kochalka, J., Phillips, J. M., Menon, V. 2019; 8

Abstract

Engaging with vocal sounds is critical for children's social-emotional learning, and children with autism spectrum disorder (ASD) often 'tune out' voices in their environment. Little is known regarding the neurobiological basis of voice processing and its link to social impairments in ASD. Here, we perform the first comprehensive brain network analysis of voice processing in children with ASD. We examined neural responses elicited by unfamiliar voices and mother's voice, a biologically salient voice for social learning, and identified a striking relationship between social communication abilities in children with ASD and activation in key structures of reward and salience processing regions. Functional connectivity between voice-selective and reward regions during voice processing predicted social communication in children with ASD and distinguished them from typically developing children. Results support the Social Motivation Theory of ASD by showing reward system deficits associated with the processing of a critical social stimulus, mother's voice, in children with ASD.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (see decision letter).

View details for PubMedID 30806350

A pilot investigation of neuroimaging predictors for the benefits from pivotal response treatment for children with autism. Journal of psychiatric research Hegarty, J. P., Gengoux, G. W., Berquist, K. L., Millan, M. E., Tamura, S. M., Karve, S., Rosenthal, M. D., Phillips, J. M., Hardan, A. Y. 2019; 111: 14044

Abstract

Children with autism spectrum disorder (ASD) frequently exhibit language delays and functional communication deficits. Pivotal response treatment (PRT) is an effective intervention for targeting these skills; however, similar to other behavioral interventions, response to PRT is variable across individuals. Thus, objective markers capable of predicting treatment response are critically-needed to identify which children are most likely to benefit from this intervention. In this pilot study, we investigated whether structural neuroimaging measures from language regions in the brain are associated with response to PRT. Children with ASD (n=18) who were receiving PRT to target their language deficits were assessed with MRI at baseline. T1-weighted images were segmented with FreeSurfer and morphometric measures of the primary language regions (inferior frontal (IFG) and superior temporal (STG) gyri) were evaluated. Children with ASD and language deficits did not exhibit the anticipated relationships between baseline structural measures of language regions and baseline language abilities, as assessed by the number of utterances displayed during a structured laboratory observation (SLO). Interestingly, the level of improvement on the SLO was correlated with baseline asymmetry of the IFG, and the size of the left STG at baseline was correlated with the level of improvement on standardized parental questionnaires. Although very preliminary, the observed associations between baseline structural properties of language regions and improvement in language abilities following PRT suggest that neuroimaging measures may be able to help identify which children are most likely to benefit from specific language treatments, which could help improve precision medicine for children with ASD.

View details for PubMedID 30771619

Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder. Molecular psychiatry Hegarty, J. P., Pegoraro, L. F., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

Abstract

Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n=164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.

View details for PubMedID 30659287

Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome PEDIATRIC NEUROLOGY Srivastava, S., Scherrer, B., Prohl, A. K., Filip-Dhima, R., Kapur, K., Kolevzon, A., Buxbaum, J. D., Berry-Kravis, E., Soorya, L., Thurm, A., Powell, C. M., Bernstein, J. A., Warfield, S. K., Sahin, M., Buxbaum, J., Kravis, E., Powell, C., Warfield, S., Dies, K., Siper, P., Hanson, E., Phillips, J. M., White, S. P., Dev Synaptopathies Consortium 2019; 90: 3743
A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Science translational medicine Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019

Abstract

The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial's primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F1,20 = 9.853; P = 0.0052; p2 = 33.0%; Cohen's d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

View details for PubMedID 31043522

Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder. Autism : the international journal of research and practice Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2018: 1362361318775538

Abstract

Developmental approaches to autism treatment aim to establish strong interpersonal relationships through joint play. These approaches have emerging empirical support; however, there is a need for further research documenting the procedures and demonstrating their effectiveness. This pilot study evaluated changes in parent behavior and child autism symptoms following a 12-week Developmental Reciprocity Treatment parent-training program. A total of 22 children with autism spectrum disorder between 2 and 6years (mean age=44.6months, standard deviation=12.7) and a primary caregiver participated in 12 weekly sessions of Developmental Reciprocity Treatment parent training, covering topics including introduction to developmental approaches, supporting attention and motivation, sensory regulation and sensory-social routines, imitation/building nonverbal communication, functional language development, and turn taking. Results indicated improvement in aspects of parent empowerment and social quality of life. Improvement in core autism symptoms was observed on the Social Responsiveness Scale total score (F(1,19): 5.550, p=0.029), MacArthur-Bates Communicative Development Inventories number of words produced out of 680 (F(1,18): 18.104, p=0.000), and two subscales of the Repetitive Behavior Scale, Revised (compulsive, p=0.046 and restricted, p=0.025). No differences in sensory sensitivity were observed on the Short Sensory Profile. Findings from this pilot study indicate that Developmental Reciprocity Treatment shows promise and suggest the need for future controlled trials of this developmentally based intervention.

View details for PubMedID 29775078

Plasma anandamide concentrations are lower in children with autism spectrum disorder MOLECULAR AUTISM Karhson, D. S., Krasinska, K. M., Dallaire, J., Libove, R. A., Phillips, J. M., Chien, A. S., Garner, J. P., Hardan, A. Y., Parker, K. J. 2018; 9: 18

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N=112).Anandamide concentrations significantly differentiated ASD cases (N=59) from controls (N=53), such that children with lower anandamide concentrations were more likely to have ASD (p=0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p=0.034).These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

View details for PubMedID 29564080

Feasibility Testing of a Wearable Behavioral Aid for Social Learning in Children with Autism APPLIED CLINICAL INFORMATICS Daniels, J., Haber, N., Voss, C., Schwartz, J., Tamura, S., Fazel, A., Kline, A., Washington, P., Phillips, J., Winograd, T., Feinstein, C., Wall, D. P. 2018; 9 (1): 12940

Abstract

Recent advances in computer vision and wearable technology have created an opportunity to introduce mobile therapy systems for autism spectrum disorders (ASD) that can respond to the increasing demand for therapeutic interventions; however, feasibility questions must be answered first.We studied the feasibility of a prototype therapeutic tool for children with ASD using Google Glass, examining whether children with ASD would wear such a device, if providing the emotion classification will improve emotion recognition, and how emotion recognition differs between ASD participants and neurotypical controls (NC).We ran a controlled laboratory experiment with 43 children: 23 with ASD and 20 NC. Children identified static facial images on a computer screen with one of 7 emotions in 3 successive batches: the first with no information about emotion provided to the child, the second with the correct classification from the Glass labeling the emotion, and the third again without emotion information. We then trained a logistic regression classifier on the emotion confusion matrices generated by the two information-free batches to predict ASD versus NC.All 43 children were comfortable wearing the Glass. ASD and NC participants who completed the computer task with Glass providing audible emotion labeling (n=33) showed increased accuracies in emotion labeling, and the logistic regression classifier achieved an accuracy of 72.7%. Further analysis suggests that the ability to recognize surprise, fear, and neutrality may distinguish ASD cases from NC.This feasibility study supports the utility of a wearable device for social affective learning in ASD children and demonstrates subtle differences in how ASD and NC children perform on an emotion recognition task.

View details for DOI 10.1055/s-0038-1626727

View details for Web of Science ID 000428690000006

View details for PubMedID 29466819

View details for PubMedCentralID PMC5821509

Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome. Pediatric neurology Srivastava, S., Scherrer, B., Prohl, A. K., Filip-Dhima, R., Kapur, K., Kolevzon, A., Buxbaum, J. D., Berry-Kravis, E., Soorya, L., Thurm, A., Powell, C. M., Bernstein, J. A., Warfield, S. K., Sahin, M. 2018

Abstract

Phelan-McDermid syndrome is caused by haploinsufficiency of SHANK3 on terminal chromosome 22. Knowledge about altered neuroanatomic circuitry in Phelan-McDermid syndrome comes from mouse models showing striatal hypertrophy in the basal ganglia, and from humans with evidence of cerebellar atrophy. To date, no studies have performed volumetric analysis on Phelan-McDermid syndrome patients.We performed volumetric analysis on baseline brain MRIs of Phelan-McDermid syndrome patients (ages three to 21 years) enrolled in a prospective natural history study (ClinicalTrials.gov NCT02461420). Using MRI segmentations carried out with PSTAPLE algorithm, we measured relative volumes (volume of the structure divided by the volume of the brain parenchyma) of basal ganglia and cerebellar structures. We compared these measurements to those of age- and sex-matched healthy controls part of another study. Among the patients, we performed linear regression of each relative volume using Repetitive Behavior Scale-Revised total score and Aberrant Behavior Checklist stereotypy score. Eleven patients with Phelan-McDermid syndrome (six females, five males) and 11 healthy controls were in this analysis.At time of MRI, the mean age of the patients and controls was 9.24 (5.29) years and 9.00 (4.49) years, respectively (P = 0.66). Compared to controls, patients had decreased caudate (P 0.013), putamen (P 0.026), and left pallidum (P=0.033) relative volumes. Relative volume of cerebellar vermal lobules I to V (beta coefficient = -17119, P=0.017) decreased with increasing Repetitive Behavior Scale-Revised total score.The volumes of the striatum and left pallidum are decreased in individuals with Phelan-McDermid syndrome. Cerebellar vermis volume may predict repetitive behavior severity in Phelan-McDermid syndrome. These findings warrant further investigation in larger samples.

View details for PubMedID 30396833

A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry Hegarty, J. P., Gu, M., Spielman, D. M., Cleveland, S. C., Hallmayer, J. F., Lazzeroni, L. C., Raman, M. M., Frazier, T. W., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2017

Abstract

Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with (1)H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

View details for PubMedID 28941767

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

Abstract

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

View details for DOI 10.1073/pnas.1705521114

View details for PubMedCentralID PMC5544319

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 811924

Abstract

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

View details for PubMedID 28696286

Biomarker discovery for disease status and symptom severity in children with autism. Psychoneuroendocrinology Oztan, O., Jackson, L. P., Libove, R. A., Sumiyoshi, R. D., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2017; 89: 3945

Abstract

Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.

View details for PubMedID 29309996

Intranasal Vasopressin Treatment Improves Social Abilities in Children With Autism Parker, K., Oztan, O., Libove, R., Sumiyoshi, R., Summers, J., Hinman, K., Fung, L., Motonaga, K., Carson, D., Phillips, J., Garner, J., Hardan, A. NATURE PUBLISHING GROUP. 2016: S341
White matter structure in the uncinate fasciculus: Implications for socio-affective deficits in Autism Spectrum Disorder. Psychiatry research Samson, A. C., Dougherty, R. F., Lee, I. A., Phillips, J. M., Gross, J. J., Hardan, A. Y. 2016; 255: 66-74

Abstract

Individuals with Autism Spectrum Disorder (ASD) have social and communication deficits and difficulties regulating emotions. The brain bases of these socio-affective deficits are not yet clear, but one candidate is structural connectivity in the left uncinate fasciculus, which connects limbic temporal and frontal areas thought to be involved in socio-affective processing. In this study, we assessed white matter structure in the left and right uncinate fasciculus in 18 high-functioning individuals with ASD and 18 group-matched typically developing (TD) controls using Diffusion Tensor Imaging. To test specificity of the associations, we also examined the association between both uncinate fasciculi and restricted and repetitive behaviors. Compared to TD individuals, individuals with ASD had significantly lower fractional anisotropy (FA) in the left and right uncinate. Group status significantly moderated the association between left uncinate and socio-affective deficits, indicating that within the ASD group, FA was associated with socio-affective deficits: Individuals with ASD with lower FA in the left uncinate had significantly more social and emotion regulation deficits. There was no association with restricted and repetitive behaviors. This study provides evidence that the left uncinate may play a critical role in socio-affective skills in individuals with ASD.

View details for DOI 10.1016/j.pscychresns.2016.08.004

View details for PubMedID 27552717

Brain State Differentiation and Behavioral Inflexibility in Autism. Cerebral cortex Uddin, L. Q., Supekar, K., Lynch, C. J., Cheng, K. M., Odriozola, P., Barth, M. E., Phillips, J., Feinstein, C., Abrams, D. A., Menon, V. 2015; 25 (12): 4740-4747

Abstract

Autism spectrum disorders (ASDs) are characterized by social impairments alongside cognitive and behavioral inflexibility. While social deficits in ASDs have extensively been characterized, the neurobiological basis of inflexibility and its relation to core clinical symptoms of the disorder are unknown. We acquired functional neuroimaging data from 2 cohorts, each consisting of 17 children with ASDs and 17 age- and IQ-matched typically developing (TD) children, during stimulus-evoked brain states involving performance of social attention and numerical problem solving tasks, as well as during intrinsic, resting brain states. Effective connectivity between key nodes of the salience network, default mode network, and central executive network was used to obtain indices of functional organization across evoked and intrinsic brain states. In both cohorts examined, a machine learning algorithm was able to discriminate intrinsic (resting) and evoked (task) functional brain network configurations more accurately in TD children than in children with ASD. Brain state discriminability was related to severity of restricted and repetitive behaviors, indicating that weak modulation of brain states may contribute to behavioral inflexibility in ASD. These findings provide novel evidence for a potential link between neurophysiological inflexibility and core symptoms of this complex neurodevelopmental disorder.

View details for DOI 10.1093/cercor/bhu161

View details for PubMedID 25073720

View details for PubMedCentralID PMC4635916

Maladaptive Behavior in Autism Spectrum Disorder: The Role of Emotion Experience and Emotion Regulation. Journal of autism and developmental disorders Samson, A. C., Hardan, A. Y., Lee, I. A., Phillips, J. M., Gross, J. J. 2015; 45 (11): 3424-3432

Abstract

Maladaptive behavior is common in Autism Spectrum Disorder (ASD). However, the factors that give rise to maladaptive behavior in this context are not well understood. The present study examined the role of emotion experience and emotion regulation in maladaptive behavior in individuals with ASD and typically developing (TD) participants. Thirty-one individuals with ASD and 28 TD participants and their parents completed questionnaires assessing emotion experience, regulation, and maladaptive behavior. Compared to TD participants, individuals with ASD used cognitive reappraisal less frequently, which was associated with increased negative emotion experience, which in turn was related to greater levels of maladaptive behavior. By decreasing negative emotions, treatments targeting adaptive emotion regulation may therefore reduce maladaptive behaviors in individuals with ASD.

View details for DOI 10.1007/s10803-015-2388-7

View details for PubMedID 25711546

Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Gengoux, G. W., Berquist, K. L., Salzman, E., Schapp, S., Phillips, J. M., Frazier, T. W., Minjarez, M. B., Hardan, A. Y. 2015; 45 (9): 2889-2898

Abstract

This study's objective was to assess maintenance of treatment effects 3months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N=23) were followed for an additional 12weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p=.009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p=.001] and the Mullen Scales of Early Learning Composite score [F(1, 20)=5.43, p=.03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12weeks post treatment.

View details for DOI 10.1007/s10803-015-2452-3

View details for Web of Science ID 000360545800018

Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation. Journal of autism and developmental disorders Gengoux, G. W., Berquist, K. L., Salzman, E., Schapp, S., Phillips, J. M., Frazier, T. W., Minjarez, M. B., Hardan, A. Y. 2015; 45 (9): 2889-2898

Abstract

This study's objective was to assess maintenance of treatment effects 3months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N=23) were followed for an additional 12weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p=.009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p=.001] and the Mullen Scales of Early Learning Composite score [F(1, 20)=5.43, p=.03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12weeks post treatment.

View details for DOI 10.1007/s10803-015-2452-3

View details for PubMedID 25911977

Emotion regulation in autism spectrum disorder: evidence from parent interviews and children's daily diaries. Journal of child psychology and psychiatry, and allied disciplines Samson, A. C., Wells, W. M., Phillips, J. M., Hardan, A. Y., Gross, J. J. 2015; 56 (8): 903-913

Abstract

Although emotion dysregulation is not a defining feature of Autism Spectrum Disorder (ASD), there is a growing consensus that emotional problems play a prominent role in this disorder.The present study examined a wide range of emotion regulation (ER) strategies in 32 individuals with ASD compared to 31 group-matched typically developing (TD) participants in three emotional domains (anger, anxiety, and amusement). Parents of individuals with ASD and TD individuals were interviewed about their child's emotional experience and the use and efficacy of 10 ER strategies. In addition, participants filled out daily diaries on experience and regulation in the same emotional domains.Compared to TD individuals, parents reported that individuals with ASD experienced more anger and anxiety and less amusement, made less frequent use of a variety of adaptive ER strategies (e.g. problem solving, cognitive reappraisal), and made more frequent use of maladaptive strategies (e.g. repetitive behavior). Moreover, individuals with ASD were less effective at utilizing adaptive ER strategies. Self-reports showed differences in experience of amusement and in ER strategies for anger and anxiety, but not in experience of anger and anxiety.This study provides evidence that individuals with ASD less frequently use adaptive - but more frequently use maladaptive - ER strategies. Implications for ASD treatments that focus on increasing the use of adaptive strategies are discussed.

View details for DOI 10.1111/jcpp.12370

View details for PubMedID 25442191

A randomized controlled trial of Pivotal Response Treatment Group for parents of children with autism. Journal of child psychology and psychiatry, and allied disciplines Hardan, A. Y., Gengoux, G. W., Berquist, K. L., Libove, R. A., Ardel, C. M., Phillips, J., Frazier, T. W., Minjarez, M. B. 2015; 56 (8): 884-892

Abstract

With rates of autism diagnosis continuing to rise, there is an urgent need for effective and efficient service delivery models. Pivotal Response Treatment (PRT) is considered an established treatment for autism spectrum disorder (ASD); however, there have been few well-controlled studies with adequate sample size. The aim of this study was to conduct a randomized controlled trial to evaluate PRT parent training group (PRTG) for targeting language deficits in young children with ASD.Fifty-three children with autism and significant language delay between 2 and 6years old were randomized to PRTG (N=27) or psychoeducation group (PEG; N=26) for 12weeks. The PRTG taught parents behavioral techniques to facilitate language development. The PEG taught general information about ASD (clinical trial NCT01881750; http://www.clinicaltrials.gov).Analysis of child utterances during the structured laboratory observation (primary outcome) indicated that, compared with children in the PEG, children in the PRTG demonstrated greater improvement in frequency of utterances (F(2, 43)=3.53, p=.038, d=0.42). Results indicated that parents were able to learn PRT in a group format, as the majority of parents in the PRTG (84%) met fidelity of implementation criteria after 12weeks. Children also demonstrated greater improvement in adaptive communication skills (Vineland-II) following PRTG and baseline Mullen visual reception scores predicted treatment response to PRTG.This is the first randomized controlled trial of group-delivered PRT and one of the largest experimental investigations of the PRT model to date. The findings suggest that specific instruction in PRT results in greater skill acquisition for both parents and children, especially in functional and adaptive communication skills. Further research in PRT is warranted to replicate the observed results and address other core ASD symptoms.

View details for DOI 10.1111/jcpp.12354

View details for PubMedID 25346345

Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism PLOS ONE Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

Abstract

Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

View details for DOI 10.1371/journal.pone.0132224

View details for Web of Science ID 000358597100030

View details for PubMedCentralID PMC4511760

Emotion regulation in children and adolescents with autism spectrum disorder. Autism research Samson, A. C., Hardan, A. Y., Podell, R. W., Phillips, J. M., Gross, J. J. 2015; 8 (1): 9-18

Abstract

Emotion dysregulation is not a formal criterion for the diagnosis of autism spectrum disorder (ASD). However, parents and clinicians have long noted the importance of emotional problems in individuals with ASD (e.g. tantrums and "meltdowns"). In this study, 21 high-functioning children and adolescents with ASD and 22 age and gender group-matched typically developing (TD) controls completed a Reactivity and Regulation Situation Task. This task assesses emotional reactivity and spontaneous use of emotion regulation strategies (problem solving, cognitive reappraisal, avoidance, distraction, venting, suppression, and relaxation) in the context of age-appropriate ambiguous and potentially threatening negative scenarios. After the concept of cognitive reappraisal was explained, the scenarios were presented again to participants, and they were prompted to use this strategy. Results indicated that individuals with ASD exhibited the same level of reactivity to negative stimuli as TD participants. Furthermore, youth with ASD had a different emotion regulation profile than TD individuals, characterized by a less frequent use of cognitive reappraisal and more frequent use of suppression. When prompted to use cognitive reappraisal, participants with ASD were less able to implement reappraisal, but benefitted from this strategy when they were able to generate a reappraisal. Findings from this study suggest that cognitive reappraisal strategies may be useful to children and adolescents with ASD. Therefore, the development of treatment programs that focus on enhancing the use of adaptive forms of emotion regulation might decrease emotional problems and optimize long-term outcomes in youth with ASD. Autism Res 2014, : -. 2014 International Society for Autism Research, Wiley Periodicals, Inc.

View details for DOI 10.1002/aur.1387

View details for PubMedID 24863869

Emotion Regulation in Children and Adolescents With Autism Spectrum Disorder AUTISM RESEARCH Samson, A. C., Hardan, A. Y., Podell, R. W., Phillips, J. M., Gross, J. J. 2015; 8 (1): 9-18

Abstract

Emotion dysregulation is not a formal criterion for the diagnosis of autism spectrum disorder (ASD). However, parents and clinicians have long noted the importance of emotional problems in individuals with ASD (e.g. tantrums and "meltdowns"). In this study, 21 high-functioning children and adolescents with ASD and 22 age and gender group-matched typically developing (TD) controls completed a Reactivity and Regulation Situation Task. This task assesses emotional reactivity and spontaneous use of emotion regulation strategies (problem solving, cognitive reappraisal, avoidance, distraction, venting, suppression, and relaxation) in the context of age-appropriate ambiguous and potentially threatening negative scenarios. After the concept of cognitive reappraisal was explained, the scenarios were presented again to participants, and they were prompted to use this strategy. Results indicated that individuals with ASD exhibited the same level of reactivity to negative stimuli as TD participants. Furthermore, youth with ASD had a different emotion regulation profile than TD individuals, characterized by a less frequent use of cognitive reappraisal and more frequent use of suppression. When prompted to use cognitive reappraisal, participants with ASD were less able to implement reappraisal, but benefitted from this strategy when they were able to generate a reappraisal. Findings from this study suggest that cognitive reappraisal strategies may be useful to children and adolescents with ASD. Therefore, the development of treatment programs that focus on enhancing the use of adaptive forms of emotion regulation might decrease emotional problems and optimize long-term outcomes in youth with ASD. Autism Res 2014, : -. 2014 International Society for Autism Research, Wiley Periodicals, Inc.

View details for DOI 10.1002/aur.1387

View details for Web of Science ID 000350458000002

View details for PubMedID 24863869

Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism. PloS one Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

Abstract

Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

View details for DOI 10.1371/journal.pone.0132224

View details for PubMedID 26200852

Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

Abstract

The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.55.8years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.47.4 at baseline to 11.27.0 at 12weeks (p=0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p=0.046) and total Short Sensory Profile score (p=0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

View details for DOI 10.1007/s10803-014-2144-4

View details for Web of Science ID 000343724000027

Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Journal of autism and developmental disorders Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

Abstract

The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.55.8years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.47.4 at baseline to 11.27.0 at 12weeks (p=0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p=0.046) and total Short Sensory Profile score (p=0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

View details for DOI 10.1007/s10803-014-2144-4

View details for PubMedID 24849255

Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., Liao, C., Phillips, J. M., Hallmayer, J. F., Hardan, A. Y. 2014; 111 (33): 12258-12263

Abstract

The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

View details for DOI 10.1073/pnas.1402236111

View details for Web of Science ID 000340438800080

View details for PubMedID 25092315

Prenatal and perinatal risk factors in a twin study of autism spectrum disorders. Journal of psychiatric research Froehlich-Santino, W., Londono Tobon, A., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., Miller, J., Fedele, A., Collins, J., Smith, K., Lotspeich, L., Croen, L. A., Ozonoff, S., LaJonchere, C., Grether, J. K., O'Hara, R., Hallmayer, J. 2014; 54: 100-108

Abstract

Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently.Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed.Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95%CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95%CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95%CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95%CI 1.28-6.74).Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.

View details for DOI 10.1016/j.jpsychires.2014.03.019

View details for PubMedID 24726638

Emotion dysregulation and the core features of autism spectrum disorder. Journal of autism and developmental disorders Samson, A. C., Phillips, J. M., Parker, K. J., Shah, S., Gross, J. J., Hardan, A. Y. 2014; 44 (7): 1766-1772

Abstract

The aim of this study was to examine the relationship between emotion dysregulation and the core features of Autism Spectrum Disorder (ASD), which include social/communication deficits, restricted/repetitive behaviors, and sensory abnormalities. An 18-item Emotion Dysregulation Index was developed on the basis of expert ratings of the Child Behavior Checklist. Compared to typically developing controls, children and adolescents with ASD showed more emotion dysregulation and had significantly greater symptom severity on all scales. Within ASD participants, emotion dysregulation was related to all core features of the disorder, but the strongest association was with repetitive behaviors. These findings may facilitate the development of more effective therapeutic strategies targeting emotion dysregulation in order to optimize long-term outcomes for individuals with ASD.

View details for DOI 10.1007/s10803-013-2022-5

View details for PubMedID 24362795

Brain Organization Underlying Superior Mathematical Abilities in Children with Autism BIOLOGICAL PSYCHIATRY Iuculano, T., Rosenberg-Lee, M., Supekar, K., Lynch, C. J., Khouzam, A., Phillips, J., Uddin, L. Q., Menon, V. 2014; 75 (3): 223-230

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits. While such deficits have been the focus of most research, recent evidence suggests that individuals with ASD may exhibit cognitive strengths in domains such as mathematics.Cognitive assessments and functional brain imaging were used to investigate mathematical abilities in 18 children with ASD and 18 age-, gender-, and IQ-matched typically developing (TD) children. Multivariate classification and regression analyses were used to investigate whether brain activity patterns during numerical problem solving were significantly different between the groups and predictive of individual mathematical abilities.Children with ASD showed better numerical problem solving abilities and relied on sophisticated decomposition strategies for single-digit addition problems more frequently than TD peers. Although children with ASD engaged similar brain areas as TD children, they showed different multivariate activation patterns related to arithmetic problem complexity in ventral temporal-occipital cortex, posterior parietal cortex, and medial temporal lobe. Furthermore, multivariate activation patterns in ventral temporal-occipital cortical areas typically associated with face processing predicted individual numerical problem solving abilities in children with ASD but not in TD children.Our study suggests that superior mathematical information processing in children with ASD is characterized by a unique pattern of brain organization and that cortical regions typically involved in perceptual expertise may be utilized in novel ways in ASD. Our findings of enhanced cognitive and neural resources for mathematics have critical implications for educational, professional, and social outcomes for individuals with this lifelong disorder.

View details for DOI 10.1016/j.biopsych.2013.06.018

View details for Web of Science ID 000329130500011

View details for PubMedID 23954299

View details for PubMedCentralID PMC3897253

Brain hyperconnectivity in children with autism and its links to social deficits. Cell reports Supekar, K., Uddin, L. Q., Khouzam, A., Phillips, J., Gaillard, W. D., Kenworthy, L. E., Yerys, B. E., Vaidya, C. J., Menon, V. 2013; 5 (3): 738-747

Abstract

Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show that there are more instances of greater functional connectivity in the brains of children with ASD in comparison to those of typically developing children. Hyperconnectivity in ASD was observed at the whole-brain and subsystems levels, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyperconnectivity predicted symptom severity in ASD, such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain of children with ASD is largely functionally hyperconnected in ways that contribute to social dysfunction. Our findings provide unique insights into brain mechanisms underlying childhood autism.

View details for DOI 10.1016/j.celrep.2013.10.001

View details for PubMedID 24210821

Head circumferences in twins with and without autism spectrum disorders. Journal of autism and developmental disorders Froehlich, W., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., Miller, J., Fedele, A., Collins, J., Smith, K., Lotspeich, L., Croen, L. A., Ozonoff, S., LaJonchere, C., Grether, J. K., Hallmayer, J. 2013; 43 (9): 2026-2037

Abstract

To determine the genetic relationship between head circumference (HC) and Autism Spectrum Disorders (ASDs). Twin pairs with at least one twin with an ASD were assessed. HCs in affected and unaffected individuals were compared, as were HC correlations in monozygotic and dizygotic pairs. 404 subjects, ages 4-18, were included. 20% of males and 27% of females with an ASD had macrocephaly. Unaffected co-twins showed similar rates (16% of males and 22% of females). Statistical analysis revealed no significant difference in HCs between affected and unaffected twins. Twins with ASDs and unaffected co-twins have similar HCs and increased rates of macrocephaly. Correlations demonstrated partial inheritance of HCs. Thus, macrocephaly may represent an endophenotype in ASDs.

View details for DOI 10.1007/s10803-012-1751-1

View details for PubMedID 23321801

Default Mode Network in Childhood Autism: Posteromedial Cortex Heterogeneity and Relationship with Social Deficits BIOLOGICAL PSYCHIATRY Lynch, C. J., Uddin, L. Q., Supekar, K., Khouzam, A., Phillips, J., Menon, V. 2013; 74 (3): 212-219

Abstract

BACKGROUND: The default mode network (DMN), a brain system anchored in the posteromedial cortex, has been identified as underconnected in adults with autism spectrum disorder (ASD). However, to date there have been no attempts to characterize this network and its involvement in mediating social deficits in children with ASD. Furthermore, the functionally heterogeneous profile of the posteromedial cortex raises questions regarding how altered connectivity manifests in specific functional modules within this brain region in children with ASD. METHODS: Resting-state functional magnetic resonance imaging and an anatomically informed approach were used to investigate the functional connectivity of the DMN in 20 children with ASD and 19 age-, gender-, and IQ-matched typically developing (TD) children. Multivariate regression analyses were used to test whether altered patterns of connectivity are predictive of social impairment severity. RESULTS: Compared with TD children, children with ASD demonstrated hyperconnectivity of the posterior cingulate and retrosplenial cortices with predominately medial and anterolateral temporal cortex. In contrast, the precuneus in ASD children demonstrated hypoconnectivity with visual cortex, basal ganglia, and locally within the posteromedial cortex. Aberrant posterior cingulate cortex hyperconnectivity was linked with severity of social impairments in ASD, whereas precuneus hypoconnectivity was unrelated to social deficits. Consistent with previous work in healthy adults, a functionally heterogeneous profile of connectivity within the posteromedial cortex in both TD and ASD children was observed. CONCLUSIONS: This work links hyperconnectivity of DMN-related circuits to the core social deficits in young children with ASD and highlights fundamental aspects of posteromedial cortex heterogeneity.

View details for DOI 10.1016/j.biopsych.2012.12.013

View details for Web of Science ID 000321443100012

View details for PubMedID 23375976

Salience Network-Based Classification and Prediction of Symptom Severity in Children With Autism JAMA PSYCHIATRY Uddin, L. Q., Supekar, K., Lynch, C. J., Khouzam, A., Phillips, J., Feinstein, C., Ryali, S., Menon, V. 2013; 70 (8): 869-879

Abstract

IMPORTANCE Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. OBJECTIVES To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. DESIGN, SETTING, AND PARTICIPANTS Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. MAIN OUTCOMES AND MEASURES Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. RESULTS We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual's salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen-level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. CONCLUSIONS AND RELEVANCE Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD.

View details for DOI 10.1001/jamapsychiatry.2013.104

View details for Web of Science ID 000322833600013

View details for PubMedID 23803651

Underconnectivity between voice-selective cortex and reward circuitry in children with autism PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Abrams, D. A., Lynch, C. J., Cheng, K. M., Phillips, J., Supekar, K., Ryali, S., Uddin, L. Q., Menon, V. 2013; 110 (29): 12060-12065

Abstract

Individuals with autism spectrum disorders (ASDs) often show insensitivity to the human voice, a deficit that is thought to play a key role in communication deficits in this population. The social motivation theory of ASD predicts that impaired function of reward and emotional systems impedes children with ASD from actively engaging with speech. Here we explore this theory by investigating distributed brain systems underlying human voice perception in children with ASD. Using resting-state functional MRI data acquired from 20 children with ASD and 19 age- and intelligence quotient-matched typically developing children, we examined intrinsic functional connectivity of voice-selective bilateral posterior superior temporal sulcus (pSTS). Children with ASD showed a striking pattern of underconnectivity between left-hemisphere pSTS and distributed nodes of the dopaminergic reward pathway, including bilateral ventral tegmental areas and nucleus accumbens, left-hemisphere insula, orbitofrontal cortex, and ventromedial prefrontal cortex. Children with ASD also showed underconnectivity between right-hemisphere pSTS, a region known for processing speech prosody, and the orbitofrontal cortex and amygdala, brain regions critical for emotion-related associative learning. The degree of underconnectivity between voice-selective cortex and reward pathways predicted symptom severity for communication deficits in children with ASD. Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.

View details for DOI 10.1073/pnas.1302982110

View details for Web of Science ID 000322086100085

View details for PubMedID 23776244

Socio-emotional processing and functioning of youth at high risk for bipolar disorder. Journal of affective disorders Whitney, J., Howe, M., Shoemaker, V., Li, S., Marie Sanders, E., Dijamco, C., Acquaye, T., Phillips, J., Singh, M., Chang, K. 2013; 148 (1): 112-117

Abstract

The goal of this study was to investigate differences in socio-emotional processing and functioning in children and adolescents at high risk for bipolar disorder (BD) and healthy control participants.Children and adolescents with a parent with bipolar disorder, who had mood dysregulation but not fully syndromal BD (high risk, HR, n=24), were compared to participants with no personal or family history of psychopathology (healthy control, HC, n=27) across several neuropsychological domains. Social reciprocity was measured by the Social Responsiveness Scale, theory of mind was measured by use of the NEPSY, and affect recognition was measured by the NEPSY and the Diagnostic Test of Nonverbal Accuracy 2 (DANVA).The HR group demonstrated significant impairment in social reciprocity, including impairments in social awareness, social cognition, social communication, social motivation, and autistic mannerisms. There were no significant group differences in performance on theory of mind or affect recognition tasks.Lack of impairment in tasks associated with theory of mind or affect recognition indicate that social functioning difficulties are not likely due to impairments in these areas, or that the measures employed were not sufficiently sensitive to detect group differences.Youth at high risk for BD demonstrated impairments in numerous social domains, which may be due to innate differences in brain development governing socio-emotional functioning or may be due to disruptions in normal development caused by mood regulation difficulties.

View details for DOI 10.1016/j.jad.2012.08.016

View details for PubMedID 23123133

Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism ARCHIVES OF GENERAL PSYCHIATRY Hallmayer, J., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., Miller, J., Fedele, A., Collins, J., Smith, K., Lotspeich, L., Croen, L. A., Ozonoff, S., LaJonchere, C., Grether, J. K., Risch, N. 2011; 68 (11): 1095-1102

Abstract

Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins.To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment. Design, Setting, andTwin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services.Structured diagnostic assessments (Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD).For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD).Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

View details for DOI 10.1001/archgenpsychiatry.2011.76

View details for Web of Science ID 000296649800004

View details for PubMedID 21727249

Twins with KBG Syndrome and Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hah, M., Lotspeich, L. J., Phillips, J. M., Torres, A. D., Cleveland, S. C., Hallmayer, J. F. 2009; 39 (12): 1744-1746

View details for DOI 10.1007/s10803-009-0811-7

View details for Web of Science ID 000271767400013

View details for PubMedID 19597979

View details for PubMedCentralID PMC3413776