Bio

Clinical Focus


  • Child and Adolescent Psychiatry
  • Psychiatry

Administrative Appointments


  • Acting Director, Division of Child and Adolescent Psychiatry (2013 - Present)
  • Medical Director, Outpatient Program, Division of Child and Adolescent Psychiatry (2011 - Present)
  • Director, Autism and Developmental Disabilities Clinic (2006 - Present)

Professional Education


  • Internship:St Elizabeth Hospital (1991) DC
  • Medical Education:St Joseph's University (1988) Lebanon
  • Board Certification: Child and Adolescent Psychiatry, American Board of Psychiatry and Neurology (1997)
  • Fellowship:University of Pittsburgh (1996) PA
  • Board Certification: Psychiatry, American Board of Psychiatry and Neurology (1995)
  • Residency:Strong Memorial Hospital (1993) NY

Research & Scholarship

Current Research and Scholarly Interests


The neurobiology of autism
Neuroimaging in individuals with autism
Psychopharmacological treatment of children and adults with autism and/or developmental disorders

Clinical Trials


  • Study of Pharmacokinetics, Safety, Efficacy, and Tolerability of Memantine in Children With Autism Not Recruiting

    The purpose of this study is to investigate the safety and efficacy of memantine extended release, as well as its extent of absorption in pediatric patients with autism.

    Stanford is currently not accepting patients for this trial. For more information, please contact Robin Libove, (650) 736 - 1235.

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  • An Evaluation of a Developmentally-Based Parent Training Program for Children With Autism Recruiting

    The purpose of this study is to assess the efficacy of a parent training program in the treatment of social and communication deficits in children with autism. Specifically, this study will evaluate a developmentally based parent delivered intervention in the community developed by Pacific Autism Center for Education (PACE).

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  • An Open-Label Study of N-Acetyl Cysteine in Children With Autism Not Recruiting

    The purpose of the study is to test the tolerability and efficacy of N-Acetyl Cysteine (NAC) in children with Autism.

    Stanford is currently not accepting patients for this trial. For more information, please contact Robin Libove, (650) 736 - 1235.

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  • Randomized Controlled Study of Donepezil in Fragile X Syndrome Not Recruiting

    Fragile X syndrome (FraX) is the most common known heritable cause of human intellectual disability. Though recent research has revealed much about the genetic and neurobiological bases of FraX, knowledge about specific and effective treatments for affected individuals is lacking. Based on information from both human and animal studies, one cause of intellectual disability in FraX may be related to deficits in a particular brain neurotransmitter system (the "cholinergic" system). Thus, the investigators propose to use a specific medication, donepezil, to augment cholinergic system in adolescents affected by FraX. If found to be effective, the knowledge generated by this research may also be relevant to other developmental disorders that share common disease pathways with FraX.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai K Manchanda, AB, 650-704-9763.

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  • Intranasal Oxytocin Treatment for Social Deficits in Children With Autism Recruiting

    Autism is a pervasive developmental disorder characterized by core deficits in social behavior and communication, and the presence of repetitive or stereotyped behaviors. It is one of three recognized disorders in the autism spectrum which affects an estimated 1 in 88 children in the United States. At present, pharmacotherapies target only associated features of autism, with no effective drug treatments for the social impairments. Several lines of evidence now suggest that the neuropeptide oxytocin (OT) may be an effective treatment for the core social deficits in autism. Here we will test the effects of twice daily intranasal OT (24 IU) over a 4-week period for enhancing social deficits in male and female children aged 6-12 years with autism. This research has high potential to lead to the development of more effective treatments and earlier interventions for children with autism.

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  • Pivotal Response Treatment for Individuals With Intellectual Disabilities Recruiting

    The investigators will assess the efficacy of Pivotal Response Treatment (PRT) in the treatment of communication deficits in children with intellectual disabilities. By collecting information about parent and child functioning before and after PRT, The investigators will be able to determine whether the intervention is effective in improving child communication and reducing parent stress.

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  • Pivotal Response Group Treatment for Parents of Young Children With Autism Not Recruiting

    This is a research study examining the effectiveness of pivotal response treatment group (PRTG) in targeting language skills in young children with autism. Research has demonstrated that behavioral interventions, such as Pivotal Response Training (PRT), lead to improvements in the core symptoms of autism. The purpose of this study is to further examine the effectiveness of teaching pivotal response treatment to parents of children with autism in a group format. To determine the effectiveness of pivotal response training group (PRTG) it will be compared to another parent education group by conducting a randomized controlled 12-week trial.

    Stanford is currently not accepting patients for this trial.

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  • The Role of Vasopressin in the Social Deficits of Autism Recruiting

    Researchers at the Stanford University School of Medicine are seeking participants for a study examining the effectiveness of vasopressin, a neuropeptide, in treating children with autism spectrum disorder. Difficulty with social interactions is characteristic of people with autism, who often have problems interpreting facial expressions or maintaining eye contact while talking with someone. There are currently no effective medicines available to treat social problems in individuals with autism. Neuropeptides, such as vasopressin and oxytocin, are molecules used by neurons in the brain to communicate with one another. Vasopressin is closely related to oxytocin, which is currently being tested as a treatment for autism, and has been shown to enhance social functioning in animals. Animal studies have shown that when the proper functioning of vasopressin is experimentally altered, animals develop a variety of social deficits, including impaired memory for peers and a reduced interest in social interaction. Researchers found that when vasopressin was administered to mice with a genetically induced form of autism, their social functioning improved. Vasopressin is already approved by the Food and Drug Administration for use in humans, and has proved to be a successful treatment for some common pediatric conditions, including bedwetting. Similar to oxytocin, it also has been shown to improve social cognition and memory in people who do not have autism. The researchers will test the effects of vasopressin on social impairments in 50 boys and girls with autism, ages 6 to 12 years old. The study will last four weeks for each participant. Participants will receive either vasopressin or a placebo nasal spray. At the end of this phase of the study, those who received the placebo will have the option of participating in a four-week trial during which they will be given vasopressin. Stanford is the only site for the study. Participants do not need to live locally but will need to come to the Stanford University Department of Psychiatry and Behavioral Sciences for study visits.

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  • A Study of RG7314 to Investigate Efficacy and Safety in Individuals With Autism Spectrum Disorders Recruiting

    This multi-center, randomized, double-blind, parallel group, placebo-controlled, proof of concept study will investigate the efficacy and safety of RG7314 in adult patients with autism spectrum disorders. In stage I of the study, patients will be randomized to receive daily oral doses of 1.5 mg RG7314or placebo for 12 weeks. After an independent safety review, the study may proceed to stage II. In stage II of the study, additional patients will be randomized to receive daily oral doses of 1.5mg, 4 mg of RG7314 or placebo for 12 weeks. After an interim efficacy and safety analysis, additional patients may be randomized to receive daily oral doses of 1.5 mg, 4 mg of RG7314 or placebo for 12 weeks. The anticipated time on study treatment is 12 weeks.

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  • A Study of Pregnenolone in the Treatment of Individuals With Autism Recruiting

    This study will assess the tolerability and effectiveness of pregnenolone in the treatment of behavioral deficits in adults with autism. Pregnenolone is a naturally occurring hormone found in the body which has been shown to help with the function of nerve cells. It is also shown to modulate the activity of certain brain receptors implicated in autism. We hope to examine the tolerability of pregnenolone in adults with autism.

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  • A Study of N-Acetyl Cysteine in Children With Autism Not Recruiting

    The purpose of the study is to test the tolerability and efficacy of N-Acetyl Cysteine (NAC) in children with Autism. NAC is a compound that increases the levels of Glutathione, the body's main antioxidant. Glutathione is a compound in the blood that is part of a natural defense system (the antioxidant system). Anti-oxidants protect the body from damage caused by internal toxins called "free radicals." It is possible that children with Autism tend to have lower levels of glutathione, an important compound in our bodies that helps combat the effects of toxic free radicals. We hope that by studying the antioxidant system in more detail, we will increase our understanding of the reasons why people develop Autism so that we can design better ways to treat individuals with this condition. This study is meant to test the safety tolerability of NAC and its effectiveness in the treatment of behavioral difficulties in children with autism. It will also examine the possible benefit of this agent in improving the core deficits in autism such as social deficits.

    Stanford is currently not accepting patients for this trial. For more information, please contact Robin Libove, (650) 736 - 1235.

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Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Behavioral and cognitive characteristics of females and males with autism in the simons simplex collection. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Georgiades, S., Bishop, S. L., Hardan, A. Y. 2014; 53 (3): 329-340 e3

    Abstract

    To examine differences in behavioral symptoms and cognitive functioning between males and females with autism spectrum disorder (ASD).We analyzed data from 2,418 probands with autism (304 females and 2,114 males) included in the Simons Simplex Collection. Sex differences were evaluated across measures of autism symptoms, cognitive and motor functioning, adaptive behavior, and associated behavior problems. Measurement bias was examined using latent variable models of symptoms. Unadjusted and propensity-adjusted analyses were computed to ensure that sex differences were not due to unbalanced sampling. Moderator and mediator analyses evaluated whether sex differences were modified by clinical characteristics or were driven by cognitive ability.Females with ASD had greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females. IQ reductions mediated greater social impairment and reduced adaptive behavior in females with ASD, but did not mediate reductions in restricted interests or increases in irritability.A specific female ASD phenotype is emerging that cannot be accounted for by differential symptom measurement. The present data suggest that the relatively low proportion of high-functioning females may reflect the effect of protective biological factors or may be due to under-identification. Additional carefully accrued samples are needed to confirm the present pattern and to evaluate whether observed sex ratios in high-functioning cases are reduced if female-specific indicators of restricted interests are included.

    View details for DOI 10.1016/j.jaac.2013.12.004

    View details for PubMedID 24565360

  • A preliminary longitudinal volumetric MRI study of amygdala and hippocampal volumes in autism PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Frazier, T. W., Piacenza, L., Minshew, N. J., Keshavan, M. S., Reiss, A. L., Hardan, A. Y. 2014; 48: 124-128

    Abstract

    Previous studies suggest that amygdala volume, when compared with healthy controls, is increased in young children with autism, is unchanged in cohorts of older youth, and is smaller in adults. Hippocampal volume, however, does not appear to have age-related changes, and it is unclear whether individuals with autism have volumetric differences in this structure. The goal of this pilot investigation is to characterize the developmental trajectories of the amygdala and hippocampus in children with autism between the ages of 8 and 14years and to examine clinical correlates of volume change.Twenty-three children with autism and 23 controls between the ages of 8 and 12 underwent a magnetic resonance imaging procedure of the brain (T1-weighted) at two time points. Nine children with autism and 14 controls had good quality scans from both time points; however, all usable scans from all subjects (15 children with autism and 22 controls) were included in a mixed effect analysis. Regression models were used to estimate group differences in amygdala and hippocampal volumes. Changes in amygdala and hippocampal volumes (Time 2-Time 1) were correlated with clinical severity measures.Amygdala volume changes with time were similar between the two groups. Within the autism group, right amygdala volume change was correlated with the ability to establish appropriate eye contact. Right hippocampal volume was significantly increased in the autism group when compared with controls. Differences in right hippocampal volume change with time between the two groups approached significance.This study provides preliminary evidence of normalization of amygdala volumes in late childhood and adolescence. It also suggests that hippocampal volumetric differences may exist in autism in late childhood and adolescence.

    View details for DOI 10.1016/j.pnpbp.2013.09.010

    View details for Web of Science ID 000328074200018

    View details for PubMedID 24075822

  • A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism. Frontiers in genetics Carayol, J., Schellenberg, G. D., Dombroski, B., Amiet, C., Génin, B., Fontaine, K., Rousseau, F., Vazart, C., Cohen, D., Frazier, T. W., Hardan, A. Y., Dawson, G., Rio Frio, T. 2014; 5: 33

    Abstract

    Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score (GS) based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7 × 10(-7) in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.

    View details for DOI 10.3389/fgene.2014.00033

    View details for PubMedID 24600472

  • A Twin Study of Heritable and Shared Environmental Contributions to Autism. Journal of autism and developmental disorders Frazier, T. W., Thompson, L., Youngstrom, E. A., Law, P., Hardan, A. Y., Eng, C., Morris, N. 2014

    Abstract

    The present study examined genetic and shared environment contributions to quantitatively-measured autism symptoms and categorically-defined autism spectrum disorders (ASD). Participants included 568 twins from the Interactive Autism Network. Autism symptoms were obtained using the Social Communication Questionnaire and Social Responsiveness Scale. Categorically-defined ASD was based on clinical diagnoses. DeFries-Fulker and liability threshold models examined etiologic influences. Very high heritability was observed for extreme autism symptom levels ([Formula: see text]). Extreme levels of social and repetitive behavior symptoms were strongly influenced by common genetic factors. Heritability of categorically-defined ASD diagnosis was comparatively low (.21, 95 % CI 0.15-0.28). High heritability of extreme autism symptom levels confirms previous observations of strong genetic influences on autism. Future studies will require large, carefully ascertained family pedigrees and quantitative symptom measurements.

    View details for DOI 10.1007/s10803-014-2081-2

    View details for PubMedID 24604525

  • A two-year longitudinal pilot MRI study of the brainstem in autism. Behavioural brain research Jou, R. J., Frazier, T. W., Keshavan, M. S., Minshew, N. J., Hardan, A. Y. 2013; 251: 163-167

    Abstract

    Research has demonstrated the potential role of the brainstem in the pathobiology of autism. Previous studies have suggested reductions in brainstem volume and a relationship between this structure and sensory abnormalities. However, little is known regarding the developmental aspects of the brainstem across childhood and adolescence. The goal of this pilot study was to examine brainstem development via MRI volumetry using a longitudinal research design. Participants included 23 boys with autism and 23 matched controls (age range=8-17 years), all without intellectual disability. Participants underwent structural MRI scans once at baseline and again at two-year follow-up. Brainstem volumetric measurements were performed using the BRAINS2 software package. There were no significant group differences in age, gender, handedness, and total brain volume; however, full-scale IQ was higher in controls. Autism and control groups showed different patterns of growth in brainstem volume. While whole brainstem volume remained stable in controls over the two-year period, the autism group showed increases with age reaching volumes comparable to controls by age 15 years. This increase of whole brainstem volume was primarily driven by bilateral increases in gray matter volume. Findings from this preliminary study are suggestive of developmental brainstem abnormalities in autism primarily involving gray matter structures. These findings are consistent with autism being conceptualized as a neurodevelopmental disorder with alterations in brain-growth trajectories. More longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral data to confirm and elucidate the clinical significance of these atypical growth patterns.

    View details for DOI 10.1016/j.bbr.2013.04.021

    View details for PubMedID 23619132

  • Impact of Pivotal Response Training Group Therapy on Stress and Empowerment in Parents of Children With Autism JOURNAL OF POSITIVE BEHAVIOR INTERVENTIONS Minjarez, M. B., Mercier, E. M., Williams, S. E., Hardan, A. Y. 2013; 15 (2): 71-78
  • Parental Interest in a Genetic Risk Assessment Test for Autism Spectrum Disorders CLINICAL PEDIATRICS Narcisa, V., Discenza, M., Vaccari, E., Rosen-Sheidley, B., Hardan, A. Y., Couchon, E. 2013; 52 (2): 139-146

    Abstract

    To better understand parental opinions regarding the diagnostic process and use of genetic testing to assess risk for autism spectrum disorders (ASDs) in the younger siblings of affected children in the Unites States, we conducted a survey of parents who had at least one child with ASD. A total of 162 surveys were completed anonymously using an Internet-based survey tool. The mean reported time to ASD diagnosis and age at diagnosis were 35.2 months and 56.6 months, respectively. Seventy-two percent of parents felt there was a delay in diagnosis. Most parents indicated they would want to pursue genetic testing if a test were available that could identify risk in a younger sibling (80%). Earlier evaluation/intervention, closer monitoring, and lessened anxiety were reasons cited for testing. Our survey indicates most parents would pursue genetic risk assessment testing in children at high risk for ASD.

    View details for DOI 10.1177/0009922812466583

    View details for Web of Science ID 000314475300005

    View details for PubMedID 23193169

  • Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis Autism Frazier, T., Youngstrom, E., Embacher, R., Hardan, A., Constantino, J., Law, P., Findling, R., Eng, C. 2013
  • Priapism Associated with Risperidone in a 21-Year-Old Male with Autism. Journal of child and adolescent psychopharmacology Pradhan, T., Hardan, A. 2013

    View details for PubMedID 23738870

  • 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. 2013

    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

  • Underutilization of Genetics Services for Autism: The Importance of Parental Awareness and Provider Recommendation JOURNAL OF GENETIC COUNSELING Vande Wydeven, K., Kwan, A., Hardan, A. Y., Bernstein, J. A. 2012; 21 (6): 803-813

    Abstract

    Reasons for the underutilization of genetics services by families of children with autism spectrum disorders (ASD) are not well understood. We report the identification of factors associated with this underuse. Survey-based study of parents and/or guardians of children with ASD. One hundred fifty-five families completed the questionnaire. Thirty-one of 155 (20%) children had seen a genetics professional. Forty-nine of 154 (32%) children had undergone genetic testing. Parents whose child saw a genetics professional were more likely to 1) Have a primary provider refer for or suggest a genetics evaluation 2) Have asked for a referral, and/or 3) Know another person with a genetic cause of ASD. amilies of children with ASD who have not received genetics services are less aware of their availability and utility. They are also less likely to have their provider recommend a clinical genetics evaluation. Efforts should be taken to increase awareness of both health providers and parents regarding the usefulness of genetics services for ASD.

    View details for DOI 10.1007/s10897-012-9494-x

    View details for Web of Science ID 000311509200011

    View details for PubMedID 22415587

  • Clinical practice pathways for evaluation and medication choice for attention-deficit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics Mahajan, R., Bernal, M. P., Panzer, R., Whitaker, A., Roberts, W., Handen, B., Hardan, A., Anagnostou, E., Veenstra-VanderWeele, J. 2012; 130: S125-38

    Abstract

    Hyperactivity, impulsivity, and inattention (referred to as "ADHD [attention-deficit/hyperactivity disorder] symptoms") occur in 41% to 78% of children with autism spectrum disorders (ASDs). These symptoms often affect quality of life, interfering with learning or interventions that target primary ASD symptoms. This practice pathway describes the guidelines for evaluation and treatment of children and adolescents with ASD and comorbid ADHD symptoms.Current research in this area is limited, and, therefore, these recommendations are based on a systematic literature review and expert consensus in the Autism Speaks Autism Treatment Network Psychopharmacology Committee.The recommended practice pathway includes the Symptom Evaluation Pathway for systematic assessment of ADHD symptoms across settings; examination for comorbid sleep, medical, or psychiatric comorbidities that may contribute to symptoms; and evaluation of behavioral interventions that may ameliorate these symptoms. For children for whom medication is being considered to target the ADHD symptoms, the medication choice pathway provides guidance on the selection of the appropriate agent based on a review of available research, assessment of specific advantages and disadvantages of each agent, and dosing considerations.These recommendations provide a framework for primary care providers treating children who have ASD and ADHD symptoms. Our systematic review of the current evidence indicates the need for more randomized controlled trials of the medications for ADHD symptoms in ASD. There will also be a need for studies of the effectiveness of these practice pathways in the future.

    View details for DOI 10.1542/peds.2012-0900J

    View details for PubMedID 23118243

  • A Two-Year Longitudinal MRI Study of the Corpus Callosum in Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Frazier, T. W., Keshavan, M. S., Minshew, N. J., Hardan, A. Y. 2012; 42 (11): 2312-2322

    Abstract

    A growing body of literature has identified size reductions of the corpus callosum (CC) in autism. However, to our knowledge, no published studies have reported on the growth of CC volumes in youth with autism. Volumes of the total CC and its sub-divisions were obtained from 23 male children with autism and 23 age- and gender-matched controls at baseline and 2-year follow-up. Persistent reductions in total CC volume were observed in participants with autism relative to controls. Only the rostral body subdivision showed a normalization of size over time. Persistent reductions are consistent with the diagnostic stability and life-long impairment observed in many individuals with autism. Multi-modal imaging studies are needed to identify specific fiber tracks contributing to CC reductions.

    View details for DOI 10.1007/s10803-012-1478-z

    View details for Web of Science ID 000310088600004

    View details for PubMedID 22350341

  • A Retrospective Review of the Effectiveness of Aripiprazole in the Treatment of Sensory Abnormalities in Autism JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Fung, L. K., Chahal, L., Libove, R. A., Bivas, R., Hardan, A. Y. 2012; 22 (3): 245-248

    Abstract

    Although sensory deficits are frequently observed in autistic individuals, pharmacologic interventions targeting these abnormalities are lacking. The goal of this investigation was to assess the effectiveness of aripiprazole in targeting sensory deficits in children and adolescents with autism. Using an outpatient clinic registry for pervasive developmental disorder, 13 individuals who had received aripiprazole for treating disruptive behaviors and had completed behavioral rating scales (aberrant behavior checklist [ABC] and sensory profile questionnaire [SPQ]) were identified. Mean treatment duration was 24.4 weeks with a mean final aripiprazole dosage of 10.8 mg. Aripiprazole yielded improvements in the total ABC and in several items of the SPQ including registration, inattention/distractibility, auditory processing, and modulation of visual input affecting emotional responses and activity level, suggesting that aripiprazole might be beneficial in targeting sensory abnormalities in autism.

    View details for DOI 10.1089/cap.2010.0103

    View details for Web of Science ID 000305337300009

    View details for PubMedID 22537360

  • A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Fung, L. K., Libove, R. A., Obukhanych, T. V., Nair, S., Herzenberg, L. A., Frazier, T. W., Tirouvanziam, R. 2012; 71 (11): 956-961

    Abstract

    An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism.This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale.Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

    View details for DOI 10.1016/j.biopsych.2012.01.014

    View details for Web of Science ID 000303814800007

    View details for PubMedID 22342106

  • Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Tirouvanziam, R., Obukhanych, T. V., Laval, J., Aronov, P. A., Libove, R., Banerjee, A. G., Parker, K. J., O'Hara, R., Herzenberg, L. A., Herzenberg, L. A., Hardan, A. Y. 2012; 42 (5): 827-836

    Abstract

    The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.

    View details for DOI 10.1007/s10803-011-1314-x

    View details for Web of Science ID 000302771500017

    View details for PubMedID 21713591

  • Validation of Proposed DSM-5 Criteria for Autism Spectrum Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Youngstrom, E. A., Speer, L., Embacher, R., Law, P., Constantino, J., Findling, R. L., Hardan, A. Y., Eng, C. 2012; 51 (1): 28-40

    Abstract

    The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for autism spectrum disorder (ASD).We analyzed symptoms from 14,744 siblings (8,911 ASD and 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth 2 through 18 years of age were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and subdimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD.A hybrid model that included both a category (ASD versus non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and subsamples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (0.97 versus 0.86); however sensitivity was lower (0.81 versus 0.95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (0.93 versus 0.81), with minimal reduction in specificity (0.95 versus 0.97).Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I Field Trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources.

    View details for DOI 10.1016/j.jaac.2011.09.021

    View details for Web of Science ID 000298530300005

    View details for PubMedID 22176937

  • Advances in clinical neuroimaging: implications for autism spectrum disorders. Expert opinion on medical diagnostics Barnea-Goraly, N., Hardan, A. 2011; 5 (6): 475-482

    Abstract

    Introduction: Neuroimaging research has been labeled 'modern phrenology', suggesting that this line of research does not advance our knowledge of neuropsychiatric disorders beyond spatial localization of brain abnormalities. In this paper, we argue against this claim and discuss the application of neuroimaging techniques in neuropsychiatric disorders in general and in autism spectrum disorders (ASDs) in particular. Areas covered: Recent neuroimaging literature, and its role in increasing our understanding of the neurobiologic underpinnings of several disorders, is reviewed. Neuroimaging is discussed, with respect to the identification of at-risk individuals, prediction of treatment response and development of new treatment approaches. Furthermore, the authors discuss the clinical relevance of such methodologies in the context of autism. Specifically, the article shows how recent advances in the understanding of psychiatric and neurologic disorders, through the use of neuroimaging techniques, can be beneficially applied to the unique needs of ASD diagnosis and treatment. Expert opinion: This is an exciting time for neuroimaging research. Studies have already shown the potential of neuroimaging to better inform clinicians about disorders such as depression, anxiety and psychosis. The application of neuroimaging to ASD may provide new insight into the disorder and help deliver better care for affected individuals.

    View details for DOI 10.1517/17530059.2011.595785

    View details for PubMedID 23484746

  • Multivariate Searchlight Classification of Structural Magnetic Resonance Imaging in Children and Adolescents with Autism BIOLOGICAL PSYCHIATRY Uddin, L. Q., Menon, V., Young, C. B., Ryali, S., Chen, T., Khouzam, A., Minshew, N. J., Hardan, A. Y. 2011; 70 (9): 833-841

    Abstract

    Autism spectrum disorders (ASD) are neurodevelopmental disorders with a prevalence of nearly 1:100. Structural imaging studies point to disruptions in multiple brain areas, yet the precise neuroanatomical nature of these disruptions remains unclear. Characterization of brain structural differences in children with ASD is critical for development of biomarkers that may eventually be used to improve diagnosis and monitor response to treatment.We use voxel-based morphometry along with a novel multivariate pattern analysis approach and searchlight algorithm to classify structural magnetic resonance imaging data acquired from 24 children and adolescents with autism and 24 age-, gender-, and IQ-matched neurotypical participants.Despite modest voxel-based morphometry differences, multivariate pattern analysis revealed that the groups could be distinguished with accuracies of approximately 90% based on gray matter in the posterior cingulate cortex, medial prefrontal cortex, and bilateral medial temporal lobes-regions within the default mode network. Abnormalities in the posterior cingulate cortex were associated with impaired Autism Diagnostic Interview communication scores. Gray matter in additional prefrontal, lateral temporal, and subcortical structures also discriminated between groups with accuracies between 81% and 90%. White matter in the inferior fronto-occipital and superior longitudinal fasciculi, and the genu and splenium of the corpus callosum, achieved up to 85% classification accuracy.Multiple brain regions, including those belonging to the default mode network, exhibit aberrant structural organization in children with autism. Brain-based biomarkers derived from structural magnetic resonance imaging data may contribute to identification of the neuroanatomical basis of symptom heterogeneity and to the development of targeted early interventions.

    View details for DOI 10.1016/j.biopsych.2011.07.014

    View details for Web of Science ID 000296228000010

    View details for PubMedID 21890111

  • Safety and Efficacy of Donepezil in Children and Adolescents with Autism: Neuropsychological Measures JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Handen, B. L., Johnson, C. R., McAuliffe-Bellin, S., Murray, P. J., Hardan, A. Y. 2011; 21 (1): 43-50

    Abstract

    There has been recent interest in the use of cognitive enhancing drugs, such as cholinesterase inhibitors, as a possible treatment for executive functioning (EF) deficits in autism spectrum disorder (ASD). The goal of this study was to assess the tolerability, safety, and efficacy of donepezil on EF in a sample of children and adolescents with ASD.Thirty-four children and adolescents with ASD (age range 8-17 years; IQ >75) were enrolled in a 10-week, double-blind, placebo-controlled trial of donepezil (doses of 5 and 10?mg), followed by a 10-week open label trial for placebo nonresponders.The effect of donepezil treatment on EF was examined. Despite improvement on a number of EF measures, no statistically significant between-group differences were found (with gains observed for both the placebo and donepezil groups).The results suggest that short-term treatment with donepezil may have limited impact on cognitive functioning in ASD. Future controlled trials may need to consider a longer treatment period to detect significant gains on EF measures.

    View details for DOI 10.1089/cap.2010.0024

    View details for Web of Science ID 000287230000004

    View details for PubMedID 21309696

  • Reduced central white matter volume in autism: Implications for long-range connectivity PSYCHIATRY AND CLINICAL NEUROSCIENCES Jou, R. J., Mateljevic, N., Minshew, N. J., Keshavan, M. S., Hardan, A. Y. 2011; 65 (1): 98-101

    Abstract

    Cortical and central white matter (WM) volumes were measured to assess short- and long-range connectivity in autism, respectively. Subjects included 23 boys with autism and 23 matched controls, all without intellectual disability. Magnetic resonance imaging data obtained at 1.5 T were analyzed using BRAINS2 software (University of Iowa, Iowa City, IA, USA). Central WM volume was quantified by subtracting cortical from supratentorial WM volumes. Reduced central WM volume was observed in the autism group. IQ was higher in controls with no observed correlations between WM volumes and IQ. This preliminary evidence of reduced central WM volume in autism suggests abnormal long-range connectivity.

    View details for DOI 10.1111/j.1440-1819.2010.02164.x

    View details for Web of Science ID 000286620700014

    View details for PubMedID 21265943

  • Pivotal Response Group Treatment Program for Parents of Children with Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Minjarez, M. B., Williams, S. E., Mercier, E. M., Hardan, A. Y. 2011; 41 (1): 92-101

    Abstract

    The number of children diagnosed with autism spectrum disorders is increasing, necessitating the development of efficient treatment models. Research has demonstrated that parent-delivered behavioral interventions are a viable treatment model; however, little research has focused on teaching parents in groups. The aim of this study was to demonstrate that parents can learn Pivotal Response Training (PRT) in group therapy, resulting in correlated gains in children's language. Baseline and post-treatment data were obtained and examined for changes in (a) parent fidelity of PRT implementation, and (b) child functional verbal utterances. Significant differences were observed for both variables. These findings suggest that parents can learn PRT in a group format, resulting in correlated child language gains, thus future controlled studies are warranted.

    View details for DOI 10.1007/s10803-010-1027-6

    View details for Web of Science ID 000285928200010

    View details for PubMedID 20440638

  • Cortical Gyrification in Autistic and Asperger Disorders: A Preliminary Magnetic Resonance Imaging Study JOURNAL OF CHILD NEUROLOGY Jou, R. J., Minshew, N. J., Keshavan, M. S., Hardan, A. Y. 2010; 25 (12): 1462-1467

    Abstract

    The validity of Asperger disorder as a distinct syndrome from autism is unclear partly because of the paucity of differentiating neurobiological evidence. Frontal lobe cortical folding between these disorders was compared using the gyrification index. Twenty-three boys underwent structural magnetic resonance imaging: 6 with high-functioning autism, 9 with Asperger disorder, and 8 controls. Using the first coronal slice anterior to the corpus callosum, total and outer cortical contours were traced to calculate the gyrification index. This index was also calculated for superior and inferior regions to examine dorsolateral prefrontal and orbitofrontal cortices, respectively. Analysis of variance revealed differences in the left inferior gyrification index, which was higher in the autism group compared with Asperger and control groups. There were no differences in age, intelligence quotient, and brain volume. These preliminary findings suggest that cortical folding may be abnormally high in the frontal lobe in autism but not Asperger disorder, suggesting distinct frontal lobe neuropathology.

    View details for DOI 10.1177/0883073810368311

    View details for Web of Science ID 000285147100002

    View details for PubMedID 20413799

  • Enlarged right superior temporal gyrus in children and adolescents with autism BRAIN RESEARCH Jou, R. J., Minshew, N. J., Keshavan, M. S., Vitale, M. P., Hardan, A. Y. 2010; 1360: 205-212

    Abstract

    The superior temporal gyrus has been implicated in language processing and social perception. Therefore, anatomical abnormalities of this structure may underlie some of the deficits observed in autism, a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. In this study, volumes of the left and right superior temporal gyri were measured using magnetic resonance imaging obtained from 18 boys with high-functioning autism (mean age=13.5±3.4years; full-scale IQ=103.6±13.4) and 19 healthy controls (mean age=13.7±3.0years; full-scale IQ=103.9±10.5), group-matched on age, gender, and handedness. When compared to the control group, right superior temporal gyral volumes was significantly increased in the autism group after controlling for age and total brain volume. There was no significant difference in the volume of the left superior temporal gyrus. Post-hoc analysis revealed a significant increase of the right posterior superior temporal gyral volume in the autism group, before and after controlling for age and total brain volume. Examination of the symmetry index for the superior temporal gyral volumes did not yield statistically significant between-group differences. Findings from this preliminary investigation suggest the existence of volumetric alterations in the right superior temporal gyrus in children and adolescents with autism, providing support for a neuroanatomical basis of the social perceptual deficits characterizing this severe neurodevelopmental disorder.

    View details for DOI 10.1016/j.brainres.2010.09.005

    View details for Web of Science ID 000284252600020

    View details for PubMedID 20833154

  • Risperidone: Switching from Brand Name to Generic JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Fung, L. K., Amin, H. 2010; 20 (5): 457-458

    View details for DOI 10.1089/cap.2010.0013

    View details for Web of Science ID 000283436700013

    View details for PubMedID 20973719

  • Dorsolateral Prefrontal Cortex Magnetic Resonance Imaging Measurements and Cognitive Performance in Autism JOURNAL OF CHILD NEUROLOGY Griebling, J., Minshew, N. J., Bodner, K., Libove, R., Bansal, R., Konasale, P., Keshavan, M. S., Hardan, A. 2010; 25 (7): 856-863

    Abstract

    This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. Magnetic resonance imaging (MRI) scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the 2 groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction.

    View details for DOI 10.1177/0883073809351313

    View details for Web of Science ID 000279409100008

    View details for PubMedID 20097663

  • Evidence for Anatomical Alterations in the Corpus Callosum in Autism Spectrum Disorders European Psychiatric Review Frazier T, Barnea-Goraly N, Hardan A 2010; 3: 29-33
  • A Meta-Analysis of the Corpus Callosum in Autism BIOLOGICAL PSYCHIATRY Frazier, T. W., Hardan, A. Y. 2009; 66 (10): 935-941

    Abstract

    Previous magnetic resonance imaging (MRI) studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the magnitude and/or region contributing to CC reductions. The present study determined the significance and magnitude of reductions in CC total and regional area measures in autism.PubMed and PsycINFO databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (mean age = 14.58, SD = 6.00) and 250 healthy control subjects (mean age = 14.47, SD = 5.31). Of these 10 studies, 8 reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), and 6 reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify differences in total and region CC area measurements.Total CC area was reduced in autism and the magnitude of the reduction was medium (weighted mean d = .48, 95% confidence interval [CI] = .30-.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d = .49, mid/body d = .43, posterior d = .37). Witelson subdivision 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing premotor/supplementary motor neurons.Corpus callosum reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions.

    View details for DOI 10.1016/j.biopsych.2009.07.022

    View details for Web of Science ID 000271497400006

    View details for PubMedID 19748080

  • Corpus callosum volume in children with autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Pabalan, M., Gupta, N., Bansal, R., Melhem, N. M., Fedorov, S., Keshavan, M. S., Minshew, N. J. 2009; 174 (1): 57-61

    Abstract

    The corpus callosum (CC) is the main commissure connecting the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. However, most studies examined the mid-sagittal area and investigations applying novel methods are warranted. The goal of this investigation is to apply a volumetric method to examine the size of the CC in autism and to identify any association with clinical features. An MRI-based morphometric study of the total CC volume and its seven subdivisions was conducted and involved 22 children with autism (age range 8.1-12.7 years) and 23 healthy, age-matched controls. Reductions in the total volume of the CC and several of its subdivisions were found in the autism sample. Associations were observed between CC structures and clinical features including social deficits, repetitive behaviors, and sensory abnormalities. Volumetric alterations of the CC observed in this investigation are consistent with midsagittal area tracings of decreased CC size in autism. These findings support the aberrant connectivity hypothesis with possible decrease in interhemispheric communications.

    View details for DOI 10.1016/j.pscychresns.2009.03.005

    View details for Web of Science ID 000271686900008

    View details for PubMedID 19781917

  • A Preliminary Longitudinal Magnetic Resonance Imaging Study of Brain Volume and Cortical Thickness in Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Libove, R. A., Keshavan, M. S., Melhem, N. M., Minshew, N. J. 2009; 66 (4): 320-326

    Abstract

    Autism is a developmental neurobiologic disorder associated with structural and functional abnormalities in several brain regions including the cerebral cortex. This longitudinal study examined developmental changes in brain volume and cortical thickness (CT) using magnetic resonance imaging (MRI) in children with autism.MRI scans and behavioral measures were obtained at baseline and after a 30-month interval in a sample of male subjects with autism (n = 18) and healthy age-, and sex-matched control subjects (n = 16) between ages 8 and 12 years at baseline.No differences in brain volumes were observed between the autism and control subjects at baseline or follow-up. However, differences in total gray matter volumes were observed over time with significantly greater decreases in the autism group compared with control subjects. Differences in CT were observed over time with greater decreases in the autism group compared with control subjects in several brain regions including the frontal lobe. When accounting for multiple comparisons, differences between the two groups became nonsignificant except for changes in occipital CT. Furthermore, associations were observed between several clinical features and changes in CT with greater thinning of the cortex being correlated with more severe symptomatology.Findings from this study provide preliminary evidence for age-related changes in gray matter volume and CT in children with autism that are associated with symptoms severity. Future longitudinal studies of larger sample sizes are needed to evaluate developmental changes and examine the relationships between structural abnormalities and clinical expressions of the disorder.

    View details for DOI 10.1016/j.biopsych.2009.04.024

    View details for Web of Science ID 000268840200005

    View details for PubMedID 19520362

  • Brainstem volumetric alterations in children with autism PSYCHOLOGICAL MEDICINE Jou, R. J., Minshew, N. J., Melhem, N. M., Keshavan, M. S., Hardan, A. Y. 2009; 39 (8): 1347-1354

    Abstract

    Although several studies have examined brainstem volume in autism, results have been mixed and no investigation has specifically measured gray- and white-matter structures. The aim of this investigation was to assess gray- and white-matter volumes in children with autism.Subjects included 22 right-handed, non-mentally retarded boys with autism and 22 gender- and age-matched controls. Magnetic resonance imaging (MRI) scans were obtained using a 1.5-T scanner and volumetric measurements were performed using the BRAINS2 software package. Gray- and white-matter volumes were measured using a semi-automated segmentation process.There were no significant differences in age and total brain volume (TBV) between the two groups but full-scale IQ was higher in controls. A decrease in brainstem gray-matter volume was observed in the autism group before and after controlling for TBV. No significant differences were observed in white-matter volume. A significant relationship was observed between brainstem gray-matter volume and oral sensory sensitivity as measured by the Sensory Profile Questionnaire (SPQ).Findings from this study are suggestive of brainstem abnormalities in autism involving gray-matter structures with evidence supporting the existence of a relationship between these alterations and sensory deficits. These results are consistent with previous investigations and support the existence of disturbances in brainstem circuitry thought to be implicated in the sensory dysfunction observed in autism.

    View details for DOI 10.1017/S0033291708004376

    View details for Web of Science ID 000268165300013

    View details for PubMedID 18812009

  • Corpus Callosum Volume and Neurocognition in Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Keary, C. J., Minshew, N. J., Bansal, R., Goradia, D., Fedorov, S., Keshavan, M. S., Hardan, A. Y. 2009; 39 (6): 834-841

    Abstract

    The corpus callosum has recently been considered as an index of interhemispheric connectivity. This study applied a novel volumetric method to examine the size of the corpus callosum in 32 individuals with autism and 34 age-, gender- and IQ-matched controls and to investigate the relationship between this structure and cognitive measures linked to interhemispheric functioning. Participants with autism displayed reductions in total corpus callosum volume and in several of its subdivisions. Relationships were also observed between volumetric alterations and performance on several cognitive tests including the Tower of Hanoi test. These findings provide further evidence for anatomical alterations in the corpus callosum in autism, but warrant additional studies examining the relationship of this structure and specific measures of interhemispheric connectivity.

    View details for DOI 10.1007/s10803-009-0689-4

    View details for Web of Science ID 000266089900002

    View details for PubMedID 19165587

  • Guanfacine in children with autism and/or intellectual disabilities JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Handen, B. L., Sahl, R., Hardan, A. Y. 2008; 29 (4): 303-308

    Abstract

    Attention-deficit/hyperactivity disorder (ADHD) affects 3%-5% of typical school-age children. However, considerably higher rates of ADHD (15%-25%) are observed in children with intellectual disability and autism. Studies of psychostimulants in the latter two populations have found poorer response rates compared to typically developing children. In addition, evidence suggests that children with developmental disabilities experience higher rates of adverse events. Guanfacine, an alpha2-adrenergic receptor agonist, has shown some promise as an alternative to psychostimulants.The present study involved a double-blind, placebo-controlled, crossover trial of guanfacine in 11 children (ages 5-9 years) with developmental disabilities and symptoms of inattention/overactivity. The 6-week trial involved a maximum dose of 3 mg/day of guanfacine.Significant benefits were observed on the Hyperactivity subscale of the parent and teacher Aberrant Behavior Checklist (ABC) and Global Improvement Ratings. No gains were noted on other ABC subscales. Five of the 11 subjects (45%) were judged to be responders based on a 50% decrease in the ABC Hyperactivity subscale score between the placebo and guanfacine conditions. Several side effects were reported, including drowsiness and irritability.While guanfacine appears to be an alternative to psychostimulants among children with developmental disabilities, clinicians need to remain vigilant to the possibility of side effects.

    View details for Web of Science ID 000258411900012

    View details for PubMedID 18552703

  • An MRI and proton spectroscopy study of the thalamus in children with autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Minshew, N. J., Melhem, N. M., Srihari, S., Jo, B., Bansal, R., Keshavan, M. S., Stanley, J. A. 2008; 163 (2): 97-105

    Abstract

    Thalamic alterations have been reported in autism, but the relationships between these abnormalities and clinical symptoms, specifically sensory features, have not been elucidated. The goal of this investigation is to combine two neuroimaging methods to examine further the pathophysiology of thalamic anomalies in autism and to identify any association with sensory deficits. Structural MRI and multi-voxel, short echo-time proton magnetic resonance spectroscopy ((1)H MRS) measurements were collected from 18 male children with autism and 16 healthy children. Anatomical measurements of thalamic nuclei and absolute concentration levels of key (1)H MRS metabolites were obtained. Sensory abnormalities were assessed using a sensory profile questionnaire. Lower levels of N-acetylaspartate (NAA), phosphocreatine and creatine, and choline-containing metabolites were observed on the left side in the autism group compared with controls. No differences in thalamic volumes were observed between the two groups. Relationships, although limited, were observed between measures of sensory abnormalities and (1)H MRS metabolites. Findings from this study support the role of the thalamus in the pathophysiology of autism and more specifically in the sensory abnormalities observed in this disorder. Further investigations of this structure are warranted, since it plays an important role in information processing as part of the cortico-thalamo-cortical pathways.

    View details for DOI 10.1016/j.pscychresns.2007.12.002

    View details for Web of Science ID 000257581200001

    View details for PubMedID 18508243

  • Brief report: Abnormal association between the thalamus and brain size in Asperger's disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., GirgiS, R. R., Adams, J., Gilbert, A. R., Melhem, N. M., Keshavan, M. S., Minshew, N. J. 2008; 38 (2): 390-394

    Abstract

    The objective of this study was to examine the relationship between thalamic volume and brain size in individuals with Asperger's disorder (ASP). Volumetric measurements of the thalamus were performed on MRI scans obtained from 12 individuals with ASP (age range: 10-35 years) and 12 healthy controls (age range: 9-33 years). A positive correlation was found between total brain volume and thalamic size in controls, but not in ASP subjects. This occurred in the absence of differences in mean thalamic volumes between the study groups. Findings from this investigation point to an abnormal relationship between the thalamus and its projection areas in ASP and are consistent with similar studies in autism, supporting that these disorders are qualitatively similar and possibly quantitatively different.

    View details for DOI 10.1007/s10803-007-0385-1

    View details for Web of Science ID 000252673600017

    View details for PubMedID 17641963

  • Morphology of the orbitofrontal cortex in first-episode schizophrenia: Relationship with negative symptomatology PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Lacerda, A. L., Hardan, A. Y., Yorbik, O., Vemulapalli, M., Prasad, K. M., Keshavan, M. S. 2007; 31 (2): 510-516

    Abstract

    Different studies have documented OFC abnormalities in schizophrenia, but it is unclear if they are present at disease onset or are a consequence of disease process and/or drug exposure. The evaluation of first-episode, drug-naïve subjects allows us to clarify this issue. Magnetic resonance imaging was performed on 43 first-episode, antipsychotic-naïve schizophrenia patients and 53 healthy comparison subjects matched for age, gender, race, and handedness. Gray matter OFC volumes were measured blind to the diagnoses. As compared to controls, patients had greater volumes in left total OFC (p=0.048) and left lateral OFC (p=0.037). Severity of negative symptoms (anhedonia, flattened affect, and alogia) positively correlated with both the left lateral (Spearman's, rho=0.37, p=0.019; rho=0.317, p=0.041; r=0.307, p=0.048, respectively) and the left total OFC (Spearman's, rho=0.384, p=0.014; rho=0.349, p=0.023; rho=0.309, p=0.047, respectively). The present results suggest that first-episode, antipsychotic-naïve schizophrenia subjects exhibit increased OFC volumes that correlate with negative symptoms severity. The OFC, through extensive and complex interconnections with several brain structures with putative role in pathophysiology of schizophrenia including amygdala, hippocampus, thalamus, DLPFC, and superior temporal lobe, may mediate schizophrenia symptoms such as blunting of emotional affect and impaired social functioning. Although the specific neuropathological mechanisms underlying structural abnormalities of the OFC remain unclear, increased OFC volumes might be related to deviations in neuronal migration and/or pruning. Future follow-up studies examining high-risk individuals who subsequently develop schizophrenia at different stages of disease could be especially instructive.

    View details for DOI 10.1016/j.pnpbp.2006.11.022

    View details for Web of Science ID 000244808800031

    View details for PubMedID 17239513

  • Volumetric alterations of the orbitofrontal cortex in autism PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY GirgiS, R. R., Minshew, N. J., Melhern, N. M., Nutche, J. J., Keshavan, M. S., Hardan, A. Y. 2007; 31 (1): 41-45

    Abstract

    Recent evidence has implicated the orbitofrontal cortex (OFC) in the pathophysiology of social deficits in autism. An MRI-based morphometric study of the OFC was conducted involving 11 children with autism (age range 8.1-12.7 years) and 18 healthy, age-matched controls (age range 8.9-12.8 years). Decreased grey matter volume in the right lateral OFC in the patient group was found, and correlations were observed between social deficits and white, but not grey, matter structures of the OFC. These findings support the role of OFC in autism and warrant further investigations of this structure using structural and functional methodologies.

    View details for DOI 10.1016/j.pnpbp.2006.06.007

    View details for Web of Science ID 000243738000005

    View details for PubMedID 16863674

  • Abnormal brain size effect on the thalamus in autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., GirgiS, R. R., Adams, J., Gilbert, A. R., Keshavan, M. S., Minshew, N. J. 2006; 147 (2-3): 145-151

    Abstract

    This study was conducted to examine the volume of the thalamus in autism and to investigate the effect of brain size on this structure in an attempt to replicate, in a larger sample, findings from a previous study reporting the existence of a relationship between brain volume and thalamus in healthy controls but not in individuals with autism. Additionally, the relationships between thalamic volumes and clinical features were examined. Volumetric measurements of the right and left thalamic nuclei were performed on MRI scans obtained from 40 high-functioning individuals with autism (age range: 8-45 years) and 41 healthy controls (age range: 9-43 years). No differences were observed between the two groups for unadjusted thalamic volumes. However, the expected linear relationship between TBV and thalamic volume was not observed in individuals with autism. Furthermore, no correlations were observed between thalamic volumes and clinical features. Findings from this larger study are consistent with the previous report of an abnormal brain size effect on the thalamus in autism and support the possibility of abnormal connections between cortical and subcortical structures in this disorder.

    View details for DOI 10.1016/j.pscychresns.2005.12.009

    View details for Web of Science ID 000241326800006

    View details for PubMedID 16945509

  • Magnetic resonance imaging study of the orbitofrontal cortex in autism JOURNAL OF CHILD NEUROLOGY Hardan, A. Y., GirgiS, R. R., Lacerda, A. L., Yorbik, O., Kilpatiick, M., Keshavan, M. S., Minshew, N. J. 2006; 21 (10): 866-871

    Abstract

    The orbitofrontal cortex is involved in multiple psychologic functions, such as emotional and cognitive processing, learning, and social behavior. These functions are variably impaired in individuals with autism. The present study examined the size of the orbitofrontal cortex, and its medial and lateral subdivisions, using magnetic resonance imaging (MRI) scans obtained from 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any of the orbitofrontal cortex measurements. However, when compared with controls, a smaller right lateral orbitofrontal cortex was observed in children and adolescents with autism, whereas a larger right lateral orbitofrontal cortex was found in adult patients. Interestingly, a positive relationship was found in the patient group between circumscribed interests and all orbitofrontal cortex structures. The present study suggests the absence of global volumetric abnormalities in the orbitofrontal cortex in autism and indicates that the functional disturbances in this structure might not be related to anatomic alterations.

    View details for DOI 10.2310/7010.2006.00199

    View details for Web of Science ID 000243206700007

    View details for PubMedID 17005103

  • Open-label, prospective trial of olanzapine in adolescents with subaverage intelligence and disruptive behavior disorders JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Handen, B. L., Hardan, A. Y. 2006; 45 (8): 928-935

    Abstract

    Olanzapine, an atypical antipsychotic, has been shown to be efficacious for treatment of psychotic and mood disorders in adults. This prospective, open-label study was conducted to examine the safety and usefulness of olanzapine in treating disruptive behavior disorders in adolescents with subaverage intelligence.Sixteen adolescents (ages 13-17 years) with borderline to moderate mental retardation and disruptive behavior were enrolled in an 8-week olanzapine trial (5-20 mg/day). Dependent measures included the Aberrant Behavior Checklist, Conners Parent Rating Scale, Clinical Global Impressions, and two side effects scales.Statistically significant improvement (p <.002) was found on the Irritability and Hyperactivity subscales of the Aberrant Behavior Checklist and the Conners Parent Rating Scale Hyperactivity Index. No subjects developed extrapyramidal side effects. However, four were terminated prematurely from the trial because of either worsening of symptoms (requiring psychiatric inpatient hospitalization in two subjects) or side effects. The most common side effect for the sample was weight gain (averaging 12.7 lb), with 67% of subjects gaining > or =10 lb. Although there was also a statistically significant increase in prolactin levels, no subjects reported prolactin-related side effects (e.g., gynecomastia, galactorhea, amenorrhea).Olanzapine may be useful in treating disruptive behavior in adolescents with subaverage intelligence. However, side effects, especially weight gain, are a significant issue. Future double-blind, placebo-controlled studies need to confirm these findings and assess long-term safety and outcome of olanzapine treatment.

    View details for DOI 10.1097/01.chi.0000223312.48406.6e

    View details for Web of Science ID 000239290500006

    View details for PubMedID 16865035

  • An MRI study of increased cortical thickness in autism AMERICAN JOURNAL OF PSYCHIATRY Hardan, A. Y., Muddasani, S., Vemulapalli, M., Keshavan, M. S., Minshew, N. J. 2006; 163 (7): 1290-1292

    Abstract

    The purpose of this study was to examine cortical thickness in autism in light of the postmortem evidence of cortical abnormalities of the disorder.Magnetic resonance imaging (MRI) scans were acquired from 17 children with autism and 14 healthy comparison subjects, and sulcal and gyral thickness were measured for the total brain and for all lobes.Increases in total cerebral sulcal and gyral thickness were observed in children with autism relative to comparison subjects. Similar findings were noted in the temporal and parietal lobes but not in the frontal and occipital lobes.These preliminary findings indicate that increased cortical thickness may contribute to the increased gray matter volume and total brain size that have been observed in autism and may also be related to anomalies in cortical connectivity.

    View details for Web of Science ID 000238712000032

    View details for PubMedID 16816240

  • An MRI study of minor physical anomalies in autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., Keshavan, M. S., Sreedhar, S., Vemulapalli, M., Minshew, N. J. 2006; 36 (5): 607-611

    Abstract

    The objective of this investigation was to examine the existence of minor physical anomalies (MPA) in autism. The interorbital and interlens distances were measured on MRI scans obtained from a sample of 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any measurements. However, when the analysis was conducted using a split median procedure, individuals with autism and either low FSIQ, PIQ, or VIQ had shorter interorbital distances when compared to controls. Hypotelorism is a MPA that may be present in a subgroup of individuals with autism. Additional research is warranted using large sample sizes with a wide range of intellectual functioning.

    View details for DOI 10.1007/s10803-006-0103-4

    View details for Web of Science ID 000239927900004

    View details for PubMedID 16609827

  • Risperidone in first-episode psychosis: A longitudinal, exploratory voxel-based morphometric study SCHIZOPHRENIA RESEARCH Girgis, R. R., Diwadkar, V. A., Nutche, J. J., Sweeney, J. A., Keshavan, M. S., Hardan, A. Y. 2006; 82 (1): 89-94

    Abstract

    Previous studies have provided evidence supporting a neuroplastic effect of atypical antipsychotics. The present investigation explores the short-term effects of risperidone on brain parenchyma by performing voxel-based morphometry on baseline and 6-week follow-up MRI scans obtained from 15 neuroleptic-naïve individuals with first-episode psychosis treated with risperidone and 15 healthy controls. The risperidone-treated subjects demonstrated changes in grey matter and white matter in several brain regions, including superior temporal gyrus. No areas of change were found in controls. The results of this exploratory investigation support the possibility that risperidone has short-term effects on brain parenchyma in individuals with first-episode psychosis.

    View details for DOI 10.1016/j.schres.2005.10.019

    View details for Web of Science ID 000235664100009

    View details for PubMedID 16413757

  • Reduced cortical folding in individuals at high risk for schizophrenia: a pilot study SCHIZOPHRENIA RESEARCH Jou, R. J., Hardan, A. Y., Keshavan, M. S. 2005; 75 (2-3): 309-313

    Abstract

    While cortical gyrification anomalies have been reported in schizophrenia, it is unknown if individuals at high risk for schizophrenia (HR) might also exhibit abnormal cortical folding. Using MRI scans, the gyrification index (GI) was calculated for 9 adolescent HR males and 12 healthy male controls. Using the first coronal slice anterior to the corpus callosum, cortical contours were manually traced to calculate the GI. The left GI was lower in HR when compared to controls, but no difference in the right GI was observed. These results are consistent with studies of affected individuals, supporting genetic and neurodevelopmental models of schizophrenia.

    View details for DOI 10.1016/j.schres.2004.11.008

    View details for Web of Science ID 000229665100017

    View details for PubMedID 15885522

  • Retrospective study of quetiapine in children and adolescents with pervasive developmental disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., Jou, R. J., Handen, B. L. 2005; 35 (3): 387-391

    Abstract

    A retrospective study was conducted in a clinic specialized in treating individuals with developmental disabilities to examine the effectiveness and tolerability of quetiapine in children and adolescents with pervasive developmental disorders. Ten consecutive outpatients (age = 12.0 +/- 5.1 years) treated with quetiapine (dose = 477 +/- 212 mg, duration = 22.0 +/- 10.1 weeks) were identified and six were judged to be responders based on impressions from chart review and Conners Parent Scale (CPS). Improvements were observed in the conduct, inattention, and hyperactivity subscales of the CPS. Adverse events were mild with sedation being the most common, and no patient required treatment termination. Quetiapine may be beneficial in children and adolescents with pervasive developmental disorders, however open-label and double-blind, placebo-controlled studies are warranted.

    View details for DOI 10.1007/s10803-005-3306-1

    View details for Web of Science ID 000230559200013

    View details for PubMedID 16119479

  • Retrospective assessment of atomoxetine in children and adolescents with pervasive developmental disorders JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Jou, R. J., Handen, B. L., Hardan, A. Y. 2005; 15 (2): 325-330

    Abstract

    A retrospective study was conducted to assess the effectiveness and tolerability of atomoxetine in children and adolescents with pervasive developmental disorders (PDD). An outpatient clinic registry of individuals with PDD was used to identify all children and adolescents who received atomoxetine over a period of 12 months. Patients were included if concomitant medications remained unchanged. Treatment response was assessed using the Global Improvement item of the Clinical Global Impressions scale (CGI-GI) based on the Conners Parent Rating Scale (CPRS) routinely completed by primary caretakers and other clinical information available in the registry. Twenty patients were identified, including 16 males and 4 females (age, 11.5 years; standard deviation, 3.5). Most patients (80%) were taking at least 1 concomitant medication. Treatment dose was 43.3 mg (standard deviation, 18.1) and duration was 19.5 weeks (standard deviation, 10.5). Twelve patients were judged to be responders, as defined by a score of 1 or 2 on the CGI-GI. Differences between baseline and the end of the trial period were observed in the following CPRS subscales: Conduct, hyperactivity, inattention, and learning. No differences were noted in the anxiety and psychosomatic subscales. One patient discontinued atomoxetine because of severe mood swings. Atomoxetine may be beneficial for treating secondary symptoms of PDD, and prospective open-label or double-blind, placebo-controlled studies are needed to assess its efficacy and safety.

    View details for Web of Science ID 000229787000021

    View details for PubMedID 15910217

  • Quetiapine in children and adolescents with subaverage IQ Journal of Pediatric Neurology Jou R, Handen BL, Hardan AY 2005; 3: 35-39
  • Psychostimulant treatment of adults with mental retardation and attention-deficit hyperactivity disorder. Australasian psychiatry Jou, R., Handen, B., Hardan, A. 2004; 12 (4): 376-379

    Abstract

    To examine the potential effectiveness and tolerability of psychostimulants in adults with mental retardation (MR) and attention-deficit hyperactivity disorder (ADHD).A retrospective chart review was conducted in a clinic specialized in treating individuals with developmental disabilities. Improvement was assessed using the Aberrant Behaviour Checklist-Community Version (ABC-C) and the global improvement item of the Clinical Global Impression scale.Ten consecutive adult outpatients were identified. Five were judged to be responders, based on impressions from chart review and the ABC-C. Significant improvements were observed in the hyperactivity and irritability subscales of the ABC-C. Adverse events were minimal and no patients required treatment termination.Psychostimulants might be effective and well-tolerated in the treatment of ADHD in adults with MR. However, larger prospective open-label studies, and, eventually, double-blind placebo-controlled studies are needed to confirm these findings.

    View details for PubMedID 15715811

  • A retrospective assessment of topiramate in children and adolescents with pervasive developmental disorders JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Jou, R. J., Handen, B. L. 2004; 14 (3): 426-432

    Abstract

    An open-label retrospective study was conducted to assess the effectiveness and tolerability of topiramate in children and adolescents with pervasive developmental disorders (PDD). Topiramate is a novel antiepileptic drug approved as an adjunctive treatment for seizure disorders. A retrospective chart review was conducted in an outpatient clinic specialized in treating individuals with developmental disabilities, to identify all children and adolescents with PDD who received topiramate. Patients were included if concomitant medications remained unchanged. Treatment response was assessed using the Global Improvement item of the Clinical Global Impressions scale (CGI-GI), based on a review of medical records and the Conners Parent Scale (CPS), as completed by parents. Fifteen patients were identified (12 male, 3 female; age = 14.7 +/- 3.3 years), including 11 patients with autistic disorder, 2 patients with Asperger's disorder, and 2 patients with PDD not otherwise specified (PDD, NOS). Eight patients (4 patients with autistic disorder, 2 patients with Asperger's disorder, and 2 patients with PDD, NOS) were judged to be responders, as defined by a score of 1 or 2 on the CGI-GI. Treatment duration was 25 +/- 16 weeks, and the mean dose was 235 +/- 88 mg. Differences between baseline and the end-of-trial period were observed in the following CPS subscales: conduct, hyperactivity, and inattention. No differences were noted in the psychosomatic, learning, and anxiety subscales. Three patients discontinued topiramate because of side effects, with 2 patients experiencing cognitive difficulties and 1 patient a skin rash. Topiramate may be beneficial for treating secondary symptoms of PDD, and prospective openlabel studies and double-blind, placebo-controlled studies to assess its efficacy and safety are needed.

    View details for Web of Science ID 000224838500017

    View details for PubMedID 15650499

  • Increased frontal cortical folding in autism: a preliminary MRI study PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Jou, R. J., Keshavan, M. S., Varma, R., Minshew, N. J. 2004; 131 (3): 263-268

    Abstract

    The gyrification index (GI), the ratio of total to outer cortical contour, was applied to measure the cerebral folding patterns in autism. GI was examined on a frontal coronal slice obtained from MRI scans of 30 nonmentally retarded individuals with autism and 32 matched healthy controls. In the autistic group, left frontal GI was higher in children and adolescents but not in adults. Cortical folding was decreased bilaterally with age in the total autistic sample but not in controls. These preliminary findings suggest that the gyrification patterns in autism may be abnormal, which could be related to the various cortical anomalies observed in this disorder.

    View details for DOI 10.1016/j.pscychresns.2004.06.001

    View details for Web of Science ID 000224608800008

    View details for PubMedID 15465295

  • Neuropsychiatric problems in tuberous sclerosis complex JOURNAL OF CHILD NEUROLOGY Asato, M. R., Hardan, A. Y. 2004; 19 (4): 241-249

    Abstract

    Tuberous sclerosis complex is an autosomal dominant disorder characterized by abnormal cellular differentiation and proliferation, as well as abnormal neuronal migration. It is a disease affecting multiple organ systems and typically has brain involvement, causing severe disabilities. This article reviews the literature of the commonly associated neuropsychiatric complications, including mental retardation, autism-like features, and other behavior problems, which are discussed in the context of the neuropathology and epilepsy observed in tuberous sclerosis complex. The potential pathogenesis of neuropsychiatric problems is explored, including links to the genetics, neuropathology, neurotrophins, and epilepsy factors associated with tuberous sclerosis complex. Treatment of neuropsychiatric symptoms, including autism-like features, attention deficits, and sleep disorders, is also discussed.

    View details for Web of Science ID 000221419000001

    View details for PubMedID 15163088

  • Anatomic evaluation of the orbitofrontal cortex in major depressive disorder BIOLOGICAL PSYCHIATRY Lacerda, A. L., Keshavan, M. S., Hardan, A. Y., Yorbik, O., Brambilla, P., Sassi, R. B., NICOLETTI, M., Mallinger, A. G., Frank, E., Kupfer, D. J., Soares, J. C. 2004; 55 (4): 353-358

    Abstract

    The orbitofrontal cortex (OFC) plays a major role in neuropsychologic functioning including exteroceptive and interoceptive information coding, reward-guided behavior, impulse control, and mood regulation. This study examined the OFC and its subdivisions in patients with MDD and matched healthy control subjects.Magnetic resonance imaging (MRI) was performed on 31 unmedicated MDD and 34 control subjects matched for age, gender, and race. Gray matter volumes of the OFC and its lateral and medial subdivisions were measured blindly.The MDD patients had smaller gray matter volumes in right medial [two-way analysis of covariance F(1,60) = 4.285; p =.043] and left lateral OFC [F(1,60) = 4.252; p =.044]. Left lateral OFC volume correlated negatively with age in patients but not in control subjects. Male, but not female patients exhibited smaller left and right medial OFC volumes compared with healthy control subjects of the same gender.These findings suggest that patients with MDD have reduced OFC gray matter volumes. Although this reduction might be important in understanding the pathophysiology of MDD, its functional and psychopathologic consequences are as yet unclear. Future studies examining the relationship between specific symptomatic dimensions of MDD and OFC volumes could be especially informative.

    View details for DOI 10.1016/j.biopsych.2003.08.021

    View details for Web of Science ID 000188964700004

    View details for PubMedID 14960287

  • The functional neuroanatomy of autism FUNCTIONAL NEUROLOGY Brambilla, P., Hardan, A. Y., di Nemi, S. U., Caverzasi, E., Soares, J. C., Perez, J., Barale, F. 2004; 19 (1): 9-17

    Abstract

    Autism is a neurodevelopmental syndrome characterized by impaired social and executive functions. Functional magnetic resonance imaging (fMRI) is a non-invasive technique that allows investigation of the neural networks underlying cognitive impairments in autism. In this article, brain imaging studies investigating the functional brain anatomy of autism are reviewed. Face recognition, theory of mind and executive functions have all been explored in functional neuroimaging studies involving autistic patients. The available literature suggests an involvement of abnormal functional mechanisms in face recognition, mentalization and executive functions in adults with high-functioning autism or Asperger's syndrome, possibly due to brain maturation abnormalities, and resulting in dysfunctional reciprocal cortico-subcortical connections. Future functional neuroimaging research should investigate subgroups of autistic children and adolescents longitudinally and attempt to integrate genetic, cognitive and empirical approaches. Such studies will be instrumental in furthering understanding of the pathophysiology of autism and in exploring the importance of dimensional measures of the broader phenotype currently defined as autism.

    View details for Web of Science ID 000222004200002

    View details for PubMedID 15212111

  • Brain anatomy and development in autism: review of structural MRI studies BRAIN RESEARCH BULLETIN Brambilla, P., Hardan, A., di Nemi, S. U., Perez, J., Soares, J. C., Barale, F. 2003; 61 (6): 557-569

    Abstract

    Autism is a neurodevelopmental disorder that severely disrupts social and cognitive functions. MRI is the method of choice for in vivo and non-invasively investigating human brain morphology in children and adolescents. The authors reviewed structural MRI studies that investigated structural brain anatomy and development in autistic patients. All original MRI research papers involving autistic patients, published from 1966 to May 2003, were reviewed in order to elucidate brain anatomy and development of autism and rated for completeness using a 12-item check-list. Increased total brain, parieto-temporal lobe, and cerebellar hemisphere volumes were the most replicated abnormalities in autism. Interestingly, recent findings suggested that the size of amygdala, hippocampus, and corpus callosum may also be abnormal. It is conceivable that abnormalities in neural network involving fronto-temporo-parietal cortex, limbic system, and cerebellum may underlie the pathophysiology of autism, and that such changes could result from abnormal brain development during early life. Nonetheless, available MRI studies were often conflicting and could have been limited by methodological issues. Future MRI investigations should include well-characterized groups of autistic and matched healthy individuals, while taking into consideration confounding factors such as IQ, and socioeconomic status.

    View details for DOI 10.1016/j.brainresbull.2003.06.001

    View details for Web of Science ID 000189133800001

    View details for PubMedID 14519452

  • Measurement of the orbitofrontal cortex: a validation study of a new method NEUROIMAGE Lacerda, A. L., Hardan, A. Y., Yorbik, O., Keshavan, M. S. 2003; 19 (3): 665-673

    Abstract

    The orbital frontal cortex (OFC) plays a critical role in the pathophysiology of several neuropsychiatric disorders. Few morphometric neuroimaging studies have examined the OFC using different methodologies and have reported discrepant values. Substantial variability in gyri and sulci across individuals as well as unclear landmarks underline the difficulties in obtaining accurate and reliable measurements. We propose a new geometrical method for measuring the OFC taking into account individual brain variability. The OFC was defined by using the intercommissural line and the inferior edge of the frontal lobe as the main landmarks. The medial and lateral subdivisions of OFC were also separately measured using the olfactory sulcus as the boundary to distinguish between them. After resampling and refitting, 10 scans were independently traced by two trained researchers using BRAINS software. Talairach coordinates were identified on each scan from the OFC and surrounding adjacent brain regions to assess the validity of this method. Brain regions were assigned using Talairach Daemon system. OFC volumes were comparable with those previously reported. Sensitivity and specificity for OFC gray matter were 87.6 and 84.8%, respectively. Intraclass coefficients (ICCs) for gray, white, and total OFC were 0.995, 0.994, and 0.997, respectively. ICCs for OFC medial and lateral subdivisions ranged between 0.996 and 0.998. This method appears to be a valid method for measuring the OFC with excellent reliability. This uncomplicated approach is easy to apply and has the potential to be a valuable alternative to the previously published methods.

    View details for DOI 10.1016/S1053(03)00137-X

    View details for Web of Science ID 000184485400017

    View details for PubMedID 12880797

  • Motor performance and anatomic magnetic resonance imaging (MRI) of the basal ganglia in autism JOURNAL OF CHILD NEUROLOGY Hardan, A. Y., Kilpatrick, M., Keshavan, M. S., Minshew, N. J. 2003; 18 (5): 317-324

    Abstract

    This study was conducted to examine the volume of the basal ganglia in individuals with autism and to evaluate whether performance on specific motor tasks correlated with the volume of these structures. Volumetric measurements of the caudate nucleus and putamen were obtained from magnetic resonance images (MRI) of 40 non-mentally retarded individuals with autism and 41 healthy controls. Motor performance was assessed in these subjects by using the Finger Tapping Test, the Grooved Pegboard Test, and the measurement of Grip Strength. No volumetric differences of the basal ganglia were found between the two groups after adjusting for brain volume. The autistic subjects' performance was slower on the Grooved Pegboard Test and weaker on Grip Strength. Our findings suggest that the motor deficits observed in autism may not be related to structural abnormalities of the basal ganglia, and other brain regions, such as the cerebellum and the frontal lobe, may be involved in the pathophysiology of motor disturbances in autism.

    View details for Web of Science ID 000183405600002

    View details for PubMedID 12822815

  • A retrospective open trial of adjunctive donepezil in children and adolescents with autistic disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Handen, B. L. 2002; 12 (3): 237-241

    Abstract

    In light of the recently reported neuropathologic and neurochemical abnormalities of the cholinergic pathways in autism, donepezil, a cholinesterase inhibitor, is a potentially useful agent in the treatment of cognitive and behavioral symptoms observed in this disorder. A retrospective pilot study was conducted to determine whether donepezil is effective in the treatment of children and adolescents with autism. Eight patients (mean age = 11.0 +/- 4.1 years; range 7-19 years) who met Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria for autistic disorder were openly treated with donepezil. All patients were on concomitant psychoactive medications. Four of these patients (50%) demonstrated significant improvement as assessed by the Aberrant Behavior Checklist and the Clinical Global Impression Scale. Decreases in the Irritability and Hyperactivity subscales were observed, but no changes in the Inappropriate Speech, Lethargy, and Stereotypies subscales were noted. Limited and transient side effects were reported, with one patient experiencing gastrointestinal disturbances and another reporting mild irritability. Double-blind, placebo-controlled investigations are needed to provide further evidence of the potential benefits of donepezil to patients with autistic disorder.

    View details for Web of Science ID 000178736200007

    View details for PubMedID 12427297

  • Posterior fossa magnetic resonance imaging in autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hardan, A. Y., Minshew, N. J., Harenski, K., Keshavan, M. S. 2001; 40 (6): 666-672

    Abstract

    To determine whether the sizes and volumes of the posterior fossa structures are abnormal in non-mentally retarded autistic adolescents and adults.Volume measurements of the cerebellum, vermis, and brainstem were obtained from coronal magnetic resonance imaging scans in 16 autistic subjects and 19 group-matched healthy controls. For the purpose of comparison with previous studies, area measurements of the midbrain, pons, medulla, total cerebellar vermis, and its three subregions were also obtained from a larger sample of 22 autistic males (mean age: 22.4 years; range: 12.2-51.8 years) and 22 individually matched controls (mean age 22.4 years; range: 12.9-52.2 years).The total volume of the cerebellum and the cerebellar hemispheres were significantly larger in the autistic subjects with and without correcting for total brain volume. Volumes of the vermis and the brainstem and all area measurements did not differ significantly between groups.There is an increase in the volume of the cerebellum in people with autism consistent with the increase in regional and total brain size reported in this developmental disorder. This finding is also concordant with evidence of cerebellar abnormalities from neuropathological and neuropsychological studies that point to the role of this structure, as part of a complex neural system, in the pathophysiology of autism.

    View details for Web of Science ID 000168786400011

    View details for PubMedID 11392344

  • Brain volume in autism JOURNAL OF CHILD NEUROLOGY Hardan, A. Y., Minshew, N. J., Mallikarjuhn, M., Keshavan, M. S. 2001; 16 (6): 421-424

    Abstract

    Increased brain size has been observed in individuals with autism with a wide range of cognitive functioning. The purpose of this investigation was to obtain measurements of the brain volume in a sample of nonmentally retarded autistic individuals. Magnetic resonance imaging scans from 16 nonmentally retarded individuals with autism and 19 male volunteer comparison subjects were obtained and the following structures were measured: third, fourth, and lateral ventricles and intracranial and cerebral volumes. Mean cerebral and third ventricle volumes in the autistic subjects were significantly greater than in the controls when adjusted for intracranial volume. No other significant results were found. Our finding of increased brain volume in autism is consistent with previous reports in the literature. Additional longitudinal neuroimaging and, more importantly, neuropathologic studies are warranted to provide a better understanding of the complexities underlying increased brain size in autism.

    View details for Web of Science ID 000171025800007

    View details for PubMedID 11417608

  • Corpus callosum size in autism NEUROLOGY Hardan, A. Y., Minshew, N. J., Keshavan, M. S. 2000; 55 (7): 1033-1036

    Abstract

    The size of the seven subregions of the corpus callosum was measured on MRI scans from 22 non-mentally retarded autistic subjects and 22 individually matched controls. Areas of the anterior subregions were smaller in the autistic group. In a subsample, measurements were adjusted for intracranial, total brain, and white matter volumes and the differences between groups remained significant. No differences were found in the other subregions. This observation is consistent with the frontal lobe dysfunction reported in autism.

    View details for Web of Science ID 000089696500025

    View details for PubMedID 11061265

  • Inositol as an add-on treatment for bipolar depression BIPOLAR DISORDERS Chengappa, K. N., Levine, J., Gershon, S., Mallinger, A. G., Hardan, A., Vagnucci, A., Pollock, B., Luther, J., Buttenfield, J., Verfaille, S., Kupfer, D. J. 2000; 2 (1): 47-55

    Abstract

    Inositol is a constituent of the intracellular phosphatidyl inositol (PI) second messenger system, which is linked to various neurotransmitter receptors. Inositol crosses the blood-brain barrier in pharmacological doses, and has shown efficacy in a small double-blind study of unipolar depression. This pilot study evaluated its potential efficacy and safety in bipolar depression.Twenty-four consenting adult men and women with DSM-IV bipolar depression (bipolar I = 21; bipolar II = 3) were randomly assigned to receive either 12 g of inositol or D-glucose as placebo for 6 weeks. Efficacy and safety ratings were done weekly. Thymoleptic medications (lithium, valproate, carbamazepine) in stable doses and at therapeutic levels at study entry were continued unchanged.Two subjects receiving placebo dropped out early due to worsening or non-adherence to the protocol. Among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects responded with a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of 'much' or 'very much' improved, as compared to three (30%) subjects assigned to placebo, a statistically nonsignificant difference. On the Montgomery-Asberg Depression Rating Scale (MADRS), eight (67%) of twelve inositol-treated subjects had a 50% or greater decrease in the baseline MADRS scores compared to four (33%) of twelve subjects assigned to placebo (p = 0.10). Inositol was well tolerated with minimal side effects, and thymoleptic blood levels were unaltered.These pilot data suggest a controlled study with an adequate sample size, and the appropriate rating scale may demonstrate efficacy for inositol in bipolar depression. The tolerability and the 'natural substance' aspect of inositol may be particularly appealing to subjects with bipolar depression.

    View details for Web of Science ID 000089479600007

    View details for PubMedID 11254020

  • Prolactin secretion in depressed children BIOLOGICAL PSYCHIATRY Hardan, A., Birmaher, B., Williamson, D. E., Dahl, R. E., Ambrosini, P., Rabinovich, H., Ryan, N. D. 1999; 46 (4): 506-511

    Abstract

    Few studies have examined the involvement of the central dopaminergic system in the pathophysiology of mood disorders. The study of prolactin (PRL) secretion may be an informative indirect method for the assessment of the dopaminergic system in children with major depressive disorder (MDD).Plasma PRL concentrations were measured at 20-min intervals over a 24-hr period in 40 pre-pubertal children with MDD, 18 with non-affective psychiatric disorders (PC), and 6 normal controls (NC). A subgroup of depressed children (n = 21) was restudied after recovery.There was no significant differences in either the amount or the pattern of PRL secretion between the MDD, PC, and NC groups. Children who recovered from their depression secreted less PRL during sleep and more while awake compared to when they were acutely depressed.Overall, there were no differences in baseline PRL secretion between children with MDD, NC and psychiatric control. These results suggest that the dopaminergic system as measured by baseline PRL blood levels is not compromised in children with MDD.

    View details for Web of Science ID 000082036700008

    View details for PubMedID 10459400

  • Suicidal behavior in children and adolescents with developmental disorders RESEARCH IN DEVELOPMENTAL DISABILITIES Hardan, A., SAHL, R. 1999; 20 (4): 287-296

    Abstract

    Children and adolescents with developmental disorders exhibit a wide range of self-destructive behaviors. Interestingly, suicidal ideation and gestures have been underreported in this population. This study was designed to examine suicidality in a clinically referred sample. The medical records of all individuals assessed in a specialized program during a 1-year period were reviewed looking at the incidence, the type and the clinical characteristics of any suicidal behavior. Forty-seven patients (20%) experienced either suicidal ideation, threats, or attempts with hanging being the most frequent method considered. Suicidality was more often encountered in individuals diagnosed with oppositional defiant disorder, depressive disorders, and post traumatic stress disorder, and less often in the autistic and the severely/profoundly mentally retarded groups. Suicidal behaviors were frequently encountered in children and adolescents with developmental disabilities. Prospective studies should be conducted to examine rigorously the variables associated with suicidality in this population.

    View details for Web of Science ID 000081321200004

    View details for PubMedID 10425656

  • Psychopathology in children and adolescents with developmental disorders RESEARCH IN DEVELOPMENTAL DISABILITIES Hardan, A., SAHL, R. 1997; 18 (5): 369-382

    Abstract

    Children and adolescents with developmental disorders suffer from a wide range of psychopathology. However, there are no published studies examining this subject exclusively in this population using recent diagnostic criteria. The primary purpose of this paper is to report on the diagnosis encountered in a clinical setting using DSM-III-R. The medical records of all individuals assessed in a specialized program during a 1-year period were reviewed looking at their demographic features, diagnoses, and target behaviors. Our sample consisted of 233 subjects and contained significantly more boys than girls. The most common psychiatric diagnoses were oppositional defiant disorder and attention deficit hyperactivity disorder. Pica, organic mental disorder NOS, and Autistic Disorder were more often encountered in individuals with low intellectual functioning. Depressive disorders, posttraumatic stress disorder, and developmental speech/language disorders were diagnosed more in high functioning subjects. The most common symptom was impulsivity. This retrospective study highlights the need for more rigorous examination of current diagnostic concepts and criteria in children and adolescents with developmental disorders. Prospective studies should be conducted with standardized instruments in clinics and community samples to provide more information on psychiatric disorders in this population.

    View details for Web of Science ID A1997XV51300005

    View details for PubMedID 9292930

  • Risperidone treatment of children and adolescents with developmental disorders JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hardan, A., Johnson, K., Johnson, C., HRECZNYJ, B. 1996; 35 (11): 1551-1556

    Abstract

    In a clinical trial, 20 children and adolescents with developmental disorders (age range 8 through 17 years) refractory to previous psychotropic treatments were administered the atypical neuroleptic risperidone (dose range 1.5 to 10 mg/day). In a follow-up period ranging from 8 to 15 months, risperidone demonstrated clinical efficacy in 13 children. Twelve patients were free of side effects and two had minor ones. Three patients had marked weight increase, and galactorrhea developed in two adolescent girls. In this open study, risperidone was associated with clinical improvement. However, controlled studies are needed to determine its relative efficacy and safety in this special population.

    View details for Web of Science ID A1996VN95400025

    View details for PubMedID 8936923

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