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Translation of Science to Service: Jean A. Frazier, MD, University of Massachusetts

May 18th, 2010


Translation of Science to Service: Series on Pediatric Bipolar Disorder Scientific Evolution
Jean A. Frazier, M.D.
and David Kennedy, Ph.D.
Child and Adolescent NeuroDevelopment Initiative (CANDI)
Department of Psychiatry
UMASS Medical School

Our Approach

The Child and Adolescent Neurodevelopment Initiative is a research program at UMASS that is committed to rapidly advancing the understanding, diagnosis and treatment of individuals with neurodevelopmental disorders such as early onset bipolar disorder (BPD), schizophrenia and autism.  We study all three diagnostic groups since there is often overlap in the clinical symptoms, genetics, and the neuroimaging findings of these disorders and in the clinical interventions used to treat them. We feel that the research with each diagnostic group of children informs the work done with the other diagnostic groups.  For example, children with autism can have mood dysregulation when asked to shift activities and a significant subset can suffer from a comorbid bipolar disorder or depressive disorder.  Children with schizophrenia can also look like they have bipolar disorder with psychotic features and figuring out the diagnostic boundaries can be challenging.  By studying all three groups of children, we hope to find biomarkers that might be specific to each diagnosis. In addition, we hope to find biomarkers that may be less specific to diagnosis but more pertinent to disorders of neurodevelopment in general.  The overarching goal is for our research efforts to lead to improved care of children and families affected by these disorders.

Our team is involved in a variety of research pursuits including genetic studies, intervention studies and neuroimaging efforts. We collaborate with a number of investigators both locally and nationally in order to tackle difficult questions. Our neuroimaging studies use technologies such as magnetic resonance imaging (MRI) to investigate the development of brain structure and function. Using these techniques we hope to characterize normal development and advance the understanding of issues surrounding mental illness and atypical development and their interventions.

We feel that our research informs our clinical practice and makes us better providers and that our clinical practice informs the research that we do because our patients and their families ask the most pertinent questions.

Mission Statement: CANDI is committed to the development and effective deployment of health care solutions to the complex challenges presented by neurodevelopmental disorders such as autism, early onset bipolar disorder and schizophrenia and their associated disabilities.

Key Contributions from Our Research in the Area of Pediatric BPD:
Our research team was one of a handful of groups to first pursue neuroimaging work in children and adolescents with bipolar disorder.    We found that the frontal-limbic neurocircuitry is abnormal in youths with bipolar disorder (Frazier et al, 2005a; Frazier et al, 2005b).  In our work, the various brain regions that have been found to differ in youth with BPD from healthy controls include: total cerebral volume, gray matter volumes including hippocampal volume (in BPD girls only), nucleus accumbens, temporal lobe, parietal lobe, right middle frontal gyrus, parahippocampal gyri, and white matter volumes including middle and posterior regions of the corpus callosum (Frazier et al, 2005a; Frazier et al, 2005b, Ahn et al, 2007; Frazier et al, 2008; Lopez-Larson et al, submitted).

We also were the first investigative team to publish a diffusion tensor imaging (DT-MRI) study in children with BPD, compared with those who were at genetic risk for the disorder and compared to healthy controls. DT-MRI is an MRI sequence that allows for the study of axonal structure and white matter coherence by measuring diffusion of water across white matter fibers. We found that children at risk for BPD had white matter abnormalities in one track called the superior longitudinal fasciculus I that was also abnormal in youths with BPD, which might indicate that this abnormality is a trait related (or genetically based) brain finding of BPD.  The youths with BPD had some additional white matter abnormalities but the most significant difference from the children who were at genetic risk was found in one tract, the cingulate-paracingulate white matter. This finding may be a disease (state) related abnormality of early onset BPD (Frazier et al, 2007).

Our group recently reported that children with BPD and comorbid ADHD had brain findings similar to children with BPD without comorbid ADHD and dissimilar from findings in children with ADHD (Lopez-Larson et al, 2009), with limbic as opposed to basal ganglia abnormalities.  The limbic findings were more pronounced in the youths with BPD+ADHD, which may suggest that this subgroup is a more severe form of pediatric BPD.

Since our lab focuses on three diagnostic groups of children, we have the capacity to determine what brain regions/neurocircuits might be specifically abnormal in one diagnostic group versus another, which is important given some of the clinical symptom overlap and the overlap in terms of biomarkers. Our group recently compared youth with BPD (those with psychosis and those without) to youth with schizophrenia and to healthy controls (Frazier et al, 2008). We found that there were brain volumetric abnormalities that were specific to BPD and others that were unique to schizophrenia when we compared the two groups to each other and to a healthy comparison group. For example, we found that while the nucleus accumbens (a brain structure that plays a role in reward and motivation) was larger in youth with bipolar disorder, the thalamus (the part of the brain that helps individuals to appropriately process sensory information and integrate activity among forebrain regions) was smaller in youth with schizophrenia.
The neuroimaging efforts of our lab have also found that not only are various brain regions affected in those with the diagnosis of bipolar disorder but that boys and girls with bipolar disorder have different brain findings and clinical features.  For example, the smaller hippocampal volume that was reported in our earlier work was found only in girls with BPD and not in boys (Frazier et al, 2008). Our work highlights the importance of gender differences in disease expression, which may have implications for treatment. The differences seen between little girls and boys with the disorder are driven predominantly by the pubertal girls with BPD which highlights the fact that understanding what happens peripubertally to brain structure and function and clinical presentation would be essential to more fully inform the field about these gender differences (Frazier et al, in preparation).

Current Ongoing Efforts and Future Directions:
Over the next 5-10 years, we will continue our multifaceted approach to understanding the complexities of these disorders by integrating longitudinal neuroimaging, genetics, epigenetics and clinical intervention studies.  We are especially interested in understanding the associations between pubertal development, brain function and clinical expression of disease.

Questions Being Asked

Overall our group is most interested in what is happening in brain function and connection in children with BPD. We are investigating what happens in the neurocircuitry over time as pubertal status progresses and the disease itself progresses.  We hope to find significant associations between brain anatomy, function and neurocircuitry, clinical phenotype and the hormones of puberty that will more fully inform the field about biomarkers and will aide in the development of more effective treatment interventions. 

To this end, our lab is currently or soon to be involved in the following funded research projects in early onset BPD (to view our studies involving youth with autism, early onset psychosis, and healthy controls, please click on our website http://labs.umassmed.edu/candi/).

Studies

Early Onset Bipolar Disorder Studies:
Clinical Trials

Lithium Study: A NIH/NICHD-funded multicenter study, led by Robert Findling at Case Western Reserve University Hospital, Dr. Frazier leads the UMASS effort.            

Best Pharmaceuticals for Children Act Pediatric Off-Patent Drug Study (PODS): Lithium for the Treatment of Pediatric Mania
This is a multiphase, multicenter contract that will comprehensively examine lithium for the treatment of pediatric bipolar disorder.

Lamictal: Dr. Frazier leads the UMASS effort on this Glaxo Smith Kline supported study for The Evaluation of Lamictal as an Add-on Treatment for Bipolar I in Children and Adolescents, age 10-17 years. The overall objective of the study is to evaluate the efficacy, safety, and tolerability of Lamictal compared to placebo, when added to conventional mono- or dual-therapy (mood stabilizer and/or antipsychotic) in children and adolescents with bipolar I disorder.

Neuroimaging

Lithium Magnetic Resonance Spectroscopy of Children and Adolescents with Bipolar Disorder is a collaborative project between Dr. Constance Moore at McLean Hospital/Harvard University and Dr. Frazier, funded by the NIMH. This study uses magnetic resonance imaging to measure lithium levels in the brain and correlates them with serum values as well as with clinical and behavioral variables.

CANDIShare represents a comprehensive neuroinformatics effort to promote data sharing in the area of child psychiatry research and is funded by the NIMH. Over the past decade, Dr. Frazier, in conjunction with Dr. David Kennedy, has been involved in a substantial number of neuroimaging studies. While each study produces a wealth of clinical and imaging data, most of this information remains an untapped resource due to ineffective use of the principles of data sharing and integration. This effort will develop a set of cohesive neuroinformatics resources to foster integrated research efforts in the study of children with mental illness. This effort is designed to capitalize on the extensive database of over 250 high-resolution volumetric MRI data and associated analyses that has been generated by the CANDI investigators, and the integrated web resources of the Internet Brain Segmentation Repository (IBSR) and the Internet Brain Volume Database (IBVD). As such, this will constitute the first known ‘Knowledge Environment’ for the integrated understanding of the quantitative neuroanatomy in this population of children with psychiatric disorders, which includes a significant subset with BPD.

Developmental Trajectory
Brain-Behavior-Hormone Project, funded by an individual anonymous donor, will contribute to our knowledge regarding the neurodevelopmental model of BPD; the study will assess the interaction between brain-body and disease, by measuring gonadal and adrenal hormone concentrations in prepubertal and pubertal girls with unmodified BPD (DSM-IV-TR), depressed or mixed, and age-and pubertal matched healthy comparison girls, between the ages of 6 and 14 years. Associations between hormone concentrations, clinical presentation and neuroimaging findings will be assessed. The data generated from this study holds the promise of laying the foundation for innovative adjunctive therapeutic interventions that are known to have thymoleptic properties and to be neuroprotective.

Connection to where there is Action:

1. Research Contact: 
Email:  ChildResearch@umassmed.edu. 
Phone 508-856-5896; FAX 508-856-8211

        Mailing Address:
        Child and Adolescent NeuroDevelopment Initiative
        Department of Psychiatry
        University of Massachusetts Medical School
        Suite 100, Biotech One, 365 Plantation Street
        Worcester, MA 01605

2. Clinical Contact:

a. Community Health Link - Youth and Family Services
275 Belmont Street
Worcester, MA 01605
508-791-3261

Community Healthlink, Inc.’s Youth & Family services (affiliated with UMASS) offers counseling for youngsters and parents, as well as family therapy.  Previously known as the Worcester Youth Guidance Center it was established in 1920 and is one of the longest-running services of its kind in the nation. More than 3000 youngsters and teens receive services annually through programs available in Worcester, Clinton, Leominster, Fitchburg and Gardner.

b. Massachusetts Child Psychiatry Access Project?
University of Massachusetts Medical Center
55 Lake Avenue North, Worcester, MA  01655
508-334-3240

The Massachusetts Child Psychiatry Access Project (MCPAP) assists pediatricians to meet the mental health needs of their patients and families. MCPAP offers pediatricians direct real time consultation, training, information, and referral services, as well as access to child evaluation and brief treatment. Pediatricians who have agreed to continue to support the child's mental health needs on an ongoing basis are the sole referrers to this program.

3. Community Support in the Local Region:
Parent’s Advocacy League of Central, MA
Parent/Professional Advocacy League (PAL) is an organization that promotes a strong voice for families of children and adolescents with mental health needs. PAL advocates for supports, treatment and policies that enable families to live in their communities in an environment of stability and respect.
Meri Viano, Program Manager
508-767-9725 
Maviano@aol.com

Mary Lambert, Family Support Specialist
508-767-9725
marylambert@charter.net

References:
 Frazier JA, Chiu S, Breeze JL, Makris N, Lange N, Kennedy DK, Herbert MK, Bent EK, Koneru VK, Dieterich ME, Hodge SM, Rauch SL, Grant PE, Cohen BM, Seidman LJ, Caviness VS, Biederman J. Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. American Journal of Psychiatry 2005; 162:1256-65.
Frazier JA, Breeze JL, Makris N, Giuliano AS, Herbert MR, Seidman L, Biederman J, Hodge SM, Dieterich ME, Gerstein E, Kennedy DN, Rauch SL, Cohen B, Caviness VS. Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric bipolar disorder. Bipolar Disorders 2005; 7:555-69
Ahn M, Breeze JL, Makris N, Kennedy DN, Herbert MR, Hodge SM, Seidman LJ, Biederman J, Caviness VS, Frazier JA. Anatomic brain magnetic resonance imaging (MRI) study of basal ganglia in pediatric bipolar disorder. Journal of Affective Disorders, 2007; 104:  147-154.
Frazier JA, Breeze JL, Papadimitriou G, Kennedy DN, Hodge SM, Moore CM, Howard JD, Rohan MP, Caviness V, Makris N. White matter abnormalities in children with and at risk for bipolar disorder. Bipolar Disorders, 2007; 9: 799-809.
Frazier JA, Hodge S, Breeze J, Giuliano A, Terry J, Kennedy D, Lopez-Larson M, Caviness V, Seidman L, Zablotsky B, Makris N.  Diagnostic and Sex Effects on Limbic Volumes in Early-Onset Bipolar Disorder and Schizophrenia.  Schizophrenia Bulletin, 2008; 34: 37-46.
Lopez-Larson M, Michaels E, Moore C, Terry J, Breeze JL, Kennedy DN, Makris N, Hodge SM, Caviness VS, Frazier JA.  Subcortical volumes: Differences between youths with bipolar disorder and comorbid attention-deficit/hyperactivity disorder compared to youths with attention-deficit/hyperactivity disorder.  Journal of Child and Adolescent Psychopharmacology, 2009; 19:31-9

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